Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:26])[C:13](=[O:25])[N:14]([C:15]4[C:16]([CH3:24])=[N:17][N:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][O:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:26])[C:13](=[O:25])[N:14]([C:15]5[C:16]([CH3:24])=[N:17][N:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][CH:34]=1
Reactant: Cc1nn(CC(=O)O)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC(=O)O)nc2C)c(=O)n4C)cn1
Temperature: 105 °C
Reaction time: 1.25 h

Procedure:
A mixture of [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid (Stage 101.1.1b, 161 mg, 0.387 mmol), 2-methoxypyridine-5-boronic acid (Aldrich, Buchs, Switzerland, 77 mg, 0.503 mmol), and PdCl2(PPh3)2 (17 mg, 0.024 mmol) in DMF (4.0 ml) and 1 M aqueous K2CO3 (1.16 ml) was stirred under argon at 105° C. for 1.25 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing products were collected together concentrated, before being lyophilized to give the title compound as a TFA-salt and white powder. (HPLC: tR 2.38 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.22 (s, 1H), 8.46 (s, 1H), 8.23-8.14 (m, 3H), 7.87-7.79 (m, 1H), 7.74-7.68 (m, 1H), 6.94-6.88 (m, 1H), 5.15-4.98 (m, 2H), 3.89 (s, 3H), 3.60 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH2:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([CH2:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(CC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.50 g) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.050 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.45 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {1-benzyl-3-[(3-ethyl-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazol-4-yl}methanol as colorless crystals (0.35 g, yield 78%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 116-117° C.
Reaction SMILES: C[Mg]Cl.[C:4]1(=[O:14])[C:8]2(CCCC[CH2:9]2)[CH2:7]CC1.C1(=O)CCCC1.[Cl-].[NH4+].[CH3:23][C:24]1([OH:34])[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1.O1CCCC1>[C:4]([O:34][C:24]1([CH3:23])[C:28]2([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:27][CH2:26][CH2:25]1)(=[O:14])[C:8]([CH3:9])=[CH2:7]
Reactant: CC1(O)CCCC12CCCCC2
Reactant: O=C1CCCC12CCCCC2
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O=C1CCCC1
Product: C=C(C)C(=O)OC1(C)CCCC12CCCCC2
Temperature: 40 °C
Yield: 63 %

Procedure:
With stirring under nitrogen atmosphere at 40° C., 500 ml of toluene was added dropwise to a tetrahydrofuran solution of 0.95 mol methylmagnesium chloride (which had been prepared from 23 g of metallic magnesium, 500 ml of tetrahydrofuran and chloromethane), and then a mixture of 73 g of spiro[4.5]decan-1-one (which had been synthesized from cyclopentanone by a method as described in A. P. Krapcho, Synthesis, 1974, p 383 and references cited therein) and 1300 ml of toluene added. The reaction mixture was stirred overnight at 70° C. and returned to room temperature, after which a saturated ammonium chloride aqueous solution was added to stop the reaction. Through ordinary work-up of extraction, washing and drying, and subsequent vacuum distillation, there was obtained 50.2 g (yield 63%) of the target compound, 1-methylspiro[4.5]decan-1-ol.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:7])[CH2:4][CH2:5][OH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C(C)=CC=CC=1C>[Cl:1][CH2:2][C@H:3]([OH:7])[CH2:4][CH2:5][O:6][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC[C@@H](O)CCl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(S(=O)(=O)OCC[C@@H](O)CCl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.9 %

Procedure:
Thus obtained (R)-4-chloro-1,3-butanediol (35.8 g, 0.287 mol) was dissolved in 2,6-lutidine (180 mL). After adding p-toluenesulfonyl chloride (54.8 g, 287 mol) under ice cooling, temperature of the mixture was raised to room temperature and the mixture was stirred for 15 hours. After the reaction, 2,6-lutidine was removed in vacuo. To the residue were added ethyl acetate (150 mL) and water (75 mL) and the mixture was separated by a separating funnel. The organic layer was washed with 2N hydrochloric acid (100 mL) and saturated brine (70 mL), and the solvent was removed in vacuo to give (R)-4-chloro-3-hydroxy-1-p-toluenesulfonyloxybutane (56.7 g, yield: 70.8%).
Reaction SMILES: CC1C=CC(C(O[C@@H](C(O)=O)[C@@H](OC(=O)C2C=CC(C)=CC=2)C(O)=O)=O)=CC=1.[C:29]1([C@H:35]2[C@@H:40]([NH2:41])[CH2:39][CH2:38][CH2:37][NH:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[CH:48][C:45]=1[CH:46]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[ClH:78]>C(Cl)Cl.C(OCC)(=O)C>[ClH:78].[ClH:78].[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[CH:48][C:45]=1[CH2:46][NH:41][C@H:40]1[CH2:39][CH2:38][CH2:37][NH:36][C@H:35]1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1ccc(-c2ccc(F)cc2)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(C(=O)O[C@@H](C(=O)O)[C@@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(F)cc2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 25 ml of methylene chloride were suspended 281 mg of (2S,3S)-2-phenylpiperidin-3-ylamine (2R,3R)-bis(4-methylbenzoyloxy)succinate, 115 mg of 2-methoxy-5-(4-fluorophenyl)benzaldehyde and 212 mg of sodium triacetoxyborohydride. This reaction mixture was stirred at room temperature under nitrogen atmosphere for 16 hours, and then, a saturated aqueous sodium hydrogen carbonate solution was added and the resulting mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give a colorless oily product. This product was dissolved in ethyl acetate, and treated with an ethyl acetate solution containing 4N hydrochloric acid. Precipitated white crystal was collected by filtration, washed with ether and dried under reduced pressure to give 116 mg of [2-methoxy-5-(4-fluorophenyl)benzyl][(2S,3S)-2-phenylpiperidin-3-yl]amine dihydrochloride.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[NH:7][C@H:6]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)=O.[BH4-].[Li+].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1>[F:18][C:13]1[CH:12]=[C:11]([C@H:6]2[C@H:5]([CH2:3][OH:2])[O:9][C:8](=[O:10])[NH:7]2)[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: COC(=O)[C@@H]1OC(=O)N[C@H]1c1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](CO)O1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (200 mg, 0.8 mmol) in tetrahydrofuran (10 mL) at 0° C. was added a 2 M solution of lithium borohydride in tetrahydrofuran (0.4 mL, 0.8 mmol). After stirring for 20 min at 0° C., saturated sodium bicarbonate (20 mL) was added and the mixture stirred at ambient temperature for 20 min. Ethyl acetate (50 mL) was added and the layers separated. The organic layer was washed with brine (1×10 mL), dried with magnesium sulfate, filtered and concentrated in vacuo to provide (4S,5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][C:21]=1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)ccc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of N-(2-amino-phenyl)-4-chlorobenzenesulfonamide (1.0 mmol, prepared as in Example 11) in DCM (2 mL) and pyridine (2 mL), 2-chloro-5-(trifluoromethyl)benzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 419 mg of 2-chloro-N-[2-(4-chloro-benzenesulfonylamino)phenyl]-5-trifluoromethylbenzenesulfonamide. LC: Tr 1.25 min; MS: 525.9 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]=[C:9]([C:15](O)=[O:16])[C:8]2=[O:18])(=[O:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]=[C:9]([C:15]([Cl:21])=[O:16])[C:8]2=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2occ(C(=O)O)c(=O)c2c1
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1ccc2occ(C(=O)Cl)c(=O)c2c1

Procedure:
In accordance with the procedure described in Example 5-a), 6-acetoxychromone-3-carboxylic acid (77 mg, 0.314 ml) was treated with thionyl chloride (0.1 ml, 1.4 mmol) to obtain 6-acetoxychromone-3-carbonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[O:6][C:7]1[CH:31]=[CH:30][C:10]([CH2:11][O:12][C:13]2[CH:14]=[C:15]3[N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][N:16]3[C:17](=[O:19])[N:18]=2)=[CH:9][C:8]=1[C:32]([F:35])([F:34])[F:33])#[N:2]>CN(C=O)C.CCOC(C)=O.O>[O:19]=[C:17]1[N:16]2[CH2:20][CH2:21][NH:22][C:15]2=[CH:14][C:13]([O:12][CH2:11][C:10]2[CH:30]=[CH:31][C:7]([O:6][C:5]3[CH:4]=[C:3]([CH:38]=[CH:37][CH:36]=3)[C:1]#[N:2])=[C:8]([C:32]([F:34])([F:35])[F:33])[CH:9]=2)=[N:18]1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cccc(C#N)c3)c(C(F)(F)F)c1)nc2=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ccc(COc3cc4n(c(=O)n3)CCN4)cc2C(F)(F)F)c1
Yield: 13.7 %

Procedure:
To a solution of tert-butyl 7-((4-(3-cyanophenoxy)-3-(trifluoromethyl)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (27 mg, 0.051 mmol) in DMF (2 mL) was added silica gel. The reaction mixture was sealed in a microwave vial and irradiated with a microwave at 120° C. for 4 h, and then diluted with EtOAc and water. Separated organic portions were dried over anhydrous Na2SO4, filtered and concentrated. Purification via MDAP afforded the title product (3 mg).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]3[N:10]2[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=3)=[CH:5][CH:4]=1.[OH-].[Na+:22]>C(O)C>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]3[N:10]2[CH:13]=[C:14]([C:16]([O-:18])=[O:17])[N:15]=3)=[CH:5][CH:4]=1.[Na+:22]
Reactant: CCOC(=O)c1cn2c(ccc3ccc(Cl)cc32)n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1cn2c(ccc3ccc(Cl)cc32)n1

Procedure:
1.37 g of ethyl 8-chloroimidazo-[1,2-a]-quinoline-2-carboxylate hydrobromide were suspended in 50 ml of ethanol and 7.7 ml of 1 N sodium hydroxide were added thereto. The mixture obtained was heated on a steam bath for 30 minutes and sodium 8-chloroimidazo-[1,2-a]-quinoline-2-carboxylate precipitated as a white solid melting at >300° C.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]([O:24]CC)=[O:23])[CH:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]([OH:24])=[O:23])[CH:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1cc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)cn1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1cc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)cn1

Procedure:
The title compound was prepared in a similar manner as described in Example 7 (step 5) from ethyl (4-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)acetate and aqueous NaOH.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[CH3:10][N:11]([CH3:16])[C:12](=[O:15])[CH:13]=[CH2:14].CC(O)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:14][CH2:13][C:12]([N:11]([CH3:16])[CH3:10])=[O:15]
Reactant: Nc1cc(Cl)ccc1S
Reactant: C=CC(=O)N(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)C(=O)CCSc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
A mixture of 2-amino-4-chlorobenzenethiol (327 mg, 2.05 mmol), N,N-dimethylacrylamide (203 mg, 2.05 mmol) and HOAc (0.5 ml) in CH2Cl2 (5 ml) was stirred at room temperature for 3 days. The reaction was quenched with NaHCO3 (aq.) and then extracted with CH2Cl2 (2×10 ml). The organic layer was washed with water and brine and concentrated in vacuo. The crude product was purified by chromatography on silica gel (50% ethyl acetate in hexane) to yield the title compound (284 mg, 54%).
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C1C=CC=CC=1>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:2][C:3]([CH2:5][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:4]
Reactant: Oc1ccccn1
Reactant: O=C(CBr)CBr
Solvent: c1ccccc1
Product: O=C(COc1ccccn1)COc1ccccn1
Yield: 14 %

Procedure:
The bromomethyl ketone derivative X (3.2 g, 7.93 mmol), an intermediate in Preparation 5, was dissolved in benzene (30 ml), Ag2CO3 (2.62 g, 1.2 Eq) and 2-hydroxypyridine (0.93 g, 1.2 Eq) were added, and the mixture was stirred under reflux at 80□ for 3 days. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by column chromatography to give 2-pyridinyloxymethyl ketone derivative (XIf) (466 mg, Yield 14%).
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:15][CH2:16][C@@H:17]([N:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C@H:38]3[CH2:43][CH2:42][O:41][CH2:40][C@H:39]3[F:44])[N:32]=2)=[CH:27][C:26]1=[O:45])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)(C(C)(C)C)(C)C>CO>[Cl:24][C:20]1[CH:19]=[C:18]([C@H:17]([N:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C@H:38]4[CH2:43][CH2:42][O:41][CH2:40][C@H:39]4[F:44])[N:32]=3)=[CH:27][C:26]2=[O:45])[CH2:16][OH:15])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1cccc(Cl)c1)n1ccc(-c2ccnc(N[C@H]3CCOC[C@H]3F)n2)cc1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1cc(-c2ccnc(N[C@H]3CCOC[C@H]3F)n2)ccn1[C@H](CO)c1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
4M HCl in dioxane (0.939 mL, 3.76 mmol) was added to 1-((S)-2-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)ethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.105 g, 0.188 mmol) in MeOH (5 mL). After 30 minutes, the reaction mixture was evaporated, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield a crude product (0.08 g) as a film. This was chromatographed on a 10 g Biotage SNAP column with 10:1 EtOAc/1-PrOH. Fractions 9-16 contained 1-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-4-(2-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one as a solid foam. 1H NMR (400 MHz, CD3OD) δ 8.38 (d, 1H), 7.80 (d, 1H), 7.41-7.39 (m, 1H), 7.38-7.28 (m, 2H), 7.22 (d, 1H), 7.09 (d, 1H), 7.00-6.97 (m, 1H), 6.15-6.11 (m, 1H), 4.83-4.70 (m, 1H), 4.34-4.25 (m, 2H), 4.20-4.15 (m, 1H), 4.01-3.98 (m, 1H), 3.94-3.88 (m, 1H), 3.70-3.54 (m, 2H), 2.08-1.95 (m, 1H), 1.83-1.77 (m, 1H) 1.13 (d, 1H); m/z (APCI-pos) M+1=445.1; 97.5% e.e. by chiral HPLC (Chiral Tech, column OD-H, 4.6 mm×250 mm, 5 u, 20% ethanol/80% hexanes, 1 mL/minute).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(O)(=O)C>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)=[O:23]
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=C(CCl)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
Using the method of Example 10, 5-amino-2-nitro-3-phenylbenzofuran is reacted with α-chloroacetyl chloride in acetic acid to provide 5-(α-chloroacetamido)-2-nitro-3-phenylbenzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][Mg]Br.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([Cl:14])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)cc1Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1Cl

Procedure:
To a stirring solution of 4-bromo-2-chloro-N-methoxy-N-methylbenzamide (890 mg, 3195 μmol) in THF (10 mL) at −5° C. under nitrogen was slowly added methylmagnesium bromide 3.0 m in diethyl ether (1278 μl, 3834 μmol). After 30 min another 1.3 mL (3.8 mmol; 1.2 eq) of MeMgBr added at 23° C. After an additional hour, LCMS suggests 95% conversion. Reaction quenched with sat NH4Cl (10 mL) and resulting white cake washed repeatedly with diethyl ether. Combined organics washed with water and sat NaCl then pushed through a plug of silica (10 g). 1-(4-bromo-2-chlorophenyl)ethanone isolated as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH:10]=NO)=[CH:4][CH:3]=1.[OH:14]S(O)(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:9](=[O:13])[C:10]2=[O:14]
Reactant: O=C(C=NO)Nc1ccc(F)cc1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2ccc(F)cc2C1=O
Temperature: 80 °C

Procedure:
To a hot solution of conc. H2SO4 (20 mL) at 60° C., (N-(4-Fluoro-phenyl)-2-hydroxyimino-acetamide (5 g, 27.0 mmol) was added portion wise. After completion of the addition, the temperature was increased to 80° C. and maintained for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried to obtain the title compound as brick red solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C@@:13]1([O:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:26]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:25]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:24][C@H:14]1OC(=O)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:14]3[O:24][C@H:25]([CH2:36][O:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:26]([O:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@@:13]3([CH3:12])[O:46][C:47](=[O:54])[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Temperature: 70 °C
Reaction time: 22.5 h
Yield: 48.1 %

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 8 (903 mg, 3.23 mmol), 2-C-methyl-1,2,3,5-tetra-O-benzoyl-β-D-ribofuranose 9 (1.7 g, 2.93 mmol) and DBU (1.3 ml, 8.69 mmol) in MeCN (20 ml) was dropwise added TMSOTf (2.1 ml, 11.62 mmol) at 0° C. and the mixture was then stirred at 70° C. for 22.5 h. After cooling, the mixture was diluted with AcOEt (100 ml), washed with aq NaHCO3 (sat., 25 ml), water (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica (hexanes/toluene, 1:1; then hexanes/toluene/MeCN, 49:49:2→3:3:4) affording title compound 10 as a white foam (1.04 g, 48%). Compound was recrystallized from EtOH. Mp 95° C. [α]20D −69.3 (c 0.280, CHCl3). 1H NMR (500 MHz, CDCl3): 1.59 (s, 3H, CH3); 4.72 (td, 1H, J4′,3′=J4′,5′b=5.8, J4′,5′a=3.4, H-4′); 4.85 (dd, 1H, Jgem=12.2, J5′b,4′=5.8, H-5′b); 4.95 (dd, 1H, Jgem=12.2, J5′a,4′=3.4, H-5′a); 6.03 (d, 1H, J3′,4′=5.8, H-3′); 6.95 (s, 1H, H-1′); 7.34, 7.46 and 7.47 (3×m, 3×2H, H-m-Bz); 7.54, 7.59 and 7.61 (3×m, 3×1H, H-p-Bz); 7.69 (s, 1H, H-6); 7.96, 8.10 and 8.11 (3×m, 3×2H, H-o-Bz); 8.75 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 17.92 (CH3); 52.68 (C-5); 63.33 (CH2-5′); 75.55 (CH-3′); 80.04 (CH-4′); 84.93 (C-2′); 88.95 (CH-1′); 117.71 (C-4a); 128.49, 128.54 and 128.63 (CH-m-Bz); 128.65, 129.50 and 129.61 (C-i-Bz); 129.78, 129.83 and 129.92 (CH-o-Bz); 132.66 (CH-6); 133.38, 133.66, 133.72 (CH-p-Bz); 150.68 (C-7a); 151.17 (CH-2); 153.15 (C-4); 165.09, 165.33 and 166.32 (CO). IR (CHCl3): 3092, 3066, 3034, 1727, 1602, 1587, 1577, 1538, 1504, 1493, 1451, 1444, 1339, 1316, 1269, 1248, 1178, 1162, 1141, 1116, 1070, 1027, 1002, 952, 943, 843, 822, 725, 712, 686, 617, 600. MS (FAB): m/z 738 (M+H). HRMS (FAB) for C33H26ClIN3O7 [M+H] calcd: 738.0504. found: 738.0491. Anal. Calcd for C33H25ClIN3O7: C, 53.71; H, 3.41; N, 5.69. Found: C, 53.91; H, 3.29; N, 5.38.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[Cl:16][C:17]([Cl:21])([Cl:20])[CH2:18]O.C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:18][C:17]([Cl:21])([Cl:20])[Cl:16])=[O:14]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCCCCCCCCO)OCC(Cl)(Cl)Cl
Yield: 113.5 %

Procedure:
This compound was prepared from 12-hydroxydodecanoic acid (2.0 g; 9.2 mmol), 2,2,2-trichloroethanol (6.0 g; 40 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 4.1 g; 20 mmol), and pyridine (5.0 mL) in dry dichloromethane (50 mL) using the procedure of Example 12a. 3.63 g (66%) product was obtained (colorless oil).