Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:4]2[CH:3]=1.[N:16]1([C:20]([C:22]2[CH:23]=[N:24][N:25]([CH3:30])[C:26]=2[C:27](O)=[O:28])=[O:21])[CH2:19][CH2:18][CH2:17]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:14]([O:13][C:11]([C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([NH:1][C:27]([C:26]3[N:25]([CH3:30])[N:24]=[CH:23][C:22]=3[C:20]([N:16]3[CH2:19][CH2:18][CH2:17]3)=[O:21])=[O:28])[CH:7]=[CH:6][N:5]2[N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1nc2cc(N)ccn2n1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 63.9 %

Procedure:
A mixture of ethyl 7-amino-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (540 mg, 2.62 mmol), 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (548 mg, 2.62 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.86 ml, 6.55 mmol) and diisopropylethylamine (1.37 ml, 7.86 mmol) in tetrahydrofurane (10 ml) is refluxed for 18 hours. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed several times with water and dried affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (665 mg, 63.9%) as a light brown solid. mp.: 252-5° C. MS: m/z=398.2 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([O:17][CH2:18][CH:19]1[O:23][N:22]=[C:21]([C:24](O)=[O:25])[CH2:20]1)[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.ClCCl.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:24]([C:21]1[CH2:20][CH:19]([CH2:18][O:17][CH2:15][CH3:16])[O:23][N:22]=1)=[O:25]
Reactant: CCOCC1CC(C(=O)O)=NO1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOCC1CC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)=NO1
Yield: 64.3 %

Procedure:
This compound was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.073 g; 0.311 mmol), 5-(ethoxymethyl)-4,5-dihydroisoxazole-3-carboxylic acid (0.054 g; 0.311 mmol), HATU (0.130 g; 0.343 mmol) and N,N-diisopropylethylamine (1.36 mL; 0.779 mmol) in DMF (3 mL). Flash chromatography on silica gel eluting with 1 to 10% of ethyl acetate in dichloromethane gave 0.070 g (64%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(ethoxymethyl)-4,5-dihydroisoxazole-3-carboxamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:25]=[CH:24][CH:23]=[CH:22][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:9](=[O:10])[C:8]2[CH:22]=[CH:23][CH:24]=[N:25][C:7]=2[O:6][C:5]2[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)c1cccnc1Oc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1

Procedure:
To a degassed solution of 2-(4-Fluoro-phenoxy)-N-(4-nitro-benzyl)-nicotinamide (0.800 g 2.17 mmole) in ethyl acetate was added 10% palladium on carbon (0.160 g). This was shaken under 40 psi hydrogen for 30 minutes. The catalyst was removed by filtration, and the solution was concentrated to give an oil that was purified by chromatography on silica gel eluting with 4% methanol/methylene chloride. Recrystalization from ethyl acetate/hexane gave a solid. (0.562 g). 1H NMR (400 mhz, CDCl3) d 3.64 (s, 2H), 4.58 (d, J=5.60 Hz, 2H), 6.64 (d, J=8.30 Hz, 2H), 7.05 (m, 7H), 8.02 (s, broad , 1H), 8.20 (m, 1H), 8.62 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:5]([CH3:7])([CH3:6])[C:4](=[O:8])[C:3]([CH3:10])([CH3:9])[CH2:2][OH:1]
Reactant: BrBr
Reactant: CC(C)C(=O)C(C)(C)CO
Solvent: ClC(Cl)Cl
Product: CC(C)(Br)C(=O)C(C)(C)CO
Reaction time: 8 h

Procedure:
To a stirred, refluxing solution of 69 g. (0.48 mole) of 1-hydroxy-2,2,4-trimethylpentan-3-one in 500 ml. of chloroform was added dropwise a solution of 77 g. (0.48 mole) bromine in 100 ml. of chloroform. When the addition was completed the mixture was stirred at reflux for one hour, allowed to cool and stand overnight at room temperature. Evaporation of solvent at reduced pressure afforded 127 g. of product which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=3)(=[O:27])=[O:26])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(-c3ccc(C#N)n3C)cc2)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using 4-isopropyl-benzenesulfonyl chloride (120 mg, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]4-isopropylbenzenesulfonamide (0.049 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:35]=[CH:34][C:22]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([O:31]CC)=[O:30])[N:28]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:35]=[CH:34][C:22]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([OH:31])=[O:30])[N:28]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(Cc2ccc(NC(=O)/C=C/c3cnn(C)c3-c3ccc(F)cc3)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(Cc3nc(C(=O)O)cs3)cc2)c1-c1ccc(F)cc1
Yield: 83.6 %

Procedure:
A mixture of ethyl 2-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxylate (0.52 g), a 1N aqueous sodium hydroxide solution (2 mL), tetrahydrofuran (2 mL) and ethanol (2 mL) was stirred at 50° C. for 30 min. 1N Hydrochloric acid (2 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration to give 2-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl }amino)benzyl]-1,3-thiazole-4-carboxylic acid as colorless crystals (0.41 g, yield 80%). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 226-227° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@H:36]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[F:59])=[CH:48][CH:47]=1)[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([F:59])=[C:52]([C:49]2[CH:48]=[CH:47][C:46]([CH2:45][C@@H:36]([NH:35][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=3)=[O:10])[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40])=[CH:51][CH:50]=2)[CH:57]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: CCc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.4 %

Procedure:
3-Ethylisoxazole-5-carboxylic acid (8 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (3.6 mg). MS m/z [M+H]+ calc'd for C25H26ClFN2O5, 489.15. found 490.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[CH2:17]([CH:19]([NH2:22])[CH2:20][CH3:21])[CH3:18]>C1(C)C=CC=CC=1>[CH2:17]([CH:19]([NH:22][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: COCc1c(C#N)c(Cl)nc(C)c1[N+](=O)[O-]
Reactant: CCC(N)CC
Solvent: Cc1ccccc1
Product: CCC(CC)Nc1nc(C)c([N+](=O)[O-])c(COC)c1C#N
Temperature: 50 °C

Procedure:
2-Chloro-3-cyano-4-methoxymethyl-5-nitro-6-methylpyridine (4.8 grams, 0.02 mole), 1-ethylpropylamine (3.6 grams, 0.04 mole) and 100 ml of toluene were charged into a glass reaction vessel fitted with a stirrer, thermometer and condenser. The reaction mixture was stirred and heated to 50° C. for 34 hours. It was then filtered and the solvent stripped off under reduced pressure to yield the desired product 2-(1-ethylpropylamino)-3-cyano-4-methoxymethyl-5-nitro-6-methylpyridine as a brown solid having a melting point of 74°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:22])([CH3:21])[C:18](O)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:22])([CH3:21])[C:18]([Cl:29])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C(=O)O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C(=O)Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoic acid in DCM (8 mL) was added oxalyl chloride (208 μL, 2.34 mmol) followed by 3 drops of DMF. After 30 minutes, additional oxalyl chloride (2 mL, 22.5 mmol) was added. After 30 minutes stifling at ambient temperature the reaction was concentrated under reduced pressure and dried under high vacuum to afford the title compound as an oil. The crude product was used without further purification in the next step.
Reaction SMILES: [C:1]([N:5]1[C@H:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C@H:8]2[O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].C([Mg]Cl)(C)(C)C.C(O[C@H:28]1[NH:31][C:30](=[O:32])[C@@H:29]1[C@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH3:34])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[Si:36]([O:35][C@@H:33]([C@@H:29]1[C@@H:28]([C@@H:2]([CH3:3])[C:1]([N:5]2[C@H:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:8]3[O:7][C:6]2=[O:17])=[O:4])[NH:31][C:30]1=[O:32])[CH3:34])([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:37])[CH3:38]
Reactant: CCC(=O)N1C(=O)O[C@@H]2Cc3ccccc3[C@@H]21
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)O[C@@H]2Cc3ccccc3[C@@H]21
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, 231 mg (1.0 mmol) of 3-propionyl-(3aS-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one was charged in a 30-ml three-necked flask to dissolve it in 2 ml of tetrahydrofuran. To the resulting solution, 2.75 ml (2.2 mmol) of a tetrahydrofuran solution (0.8M) of t-butylmagnesium chloride was slowly added dropwise at room temperature. After the resulting mixture was allowed to react for 20 minutes under the same conditions, the reaction mixture was cooled to 5° C. and added with 2 ml of a tetrahydrofuran solution of 287 mg (1.0 mmol) of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one at the same temperature. After stirring for 10 minutes, 10 ml of ethyl acetate was added to the reaction mixture, followed by the dropwise addition of 2 ml of a 10% aqueous solution of citric acid. After separation, the organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium cloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by column chromatography, whereby 308 mg (0.67 mmol) of a condensation product was obtained (yield: 67%, β:α=95:5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[Si](C(C)C)(C(C)C)C(C)C)[CH:8]=[C:7]([C:30]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:38])[NH:4][C:5]1[CH:6]=[C:7]([C:30]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:8]=[C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:10]=1
Reactant: COC(=O)Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 0.160 g (0.31 mmol) of [3-(pyridine-3-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid methyl ester in 5 mL of THF was added 0.310 mL of 1M tetra-n-butylammonium fluoride in THF. The reaction was stirred 10 min, poured into water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate and brine and dried over sodium sulfate, and the volatiles were removed under reduced pressure. The crude product was chromatographed using 1-5% methanol/chloroform to give [3-(1H-indol-4-yl)-5-(pyridine-3-carbonyl)-phenyl]-carbamic acid methyl ester. 1H NMR (400 MHz, methanol-d4): δ 9.08 (s, 1H), 8.79 (d, J=3.9 Hz, 1H), 8.43 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.38-7.46 (m, 2H), 7.22-7.27 (m, 2H), 7.19 (d, J=7.0 Hz, 1H), 7.01 (s, 1H), 6.72 (s, 1H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][CH2:25][CH:26]=[O:27])[CH:12]=2)=[CH:7][CH:6]=1>CCOCC>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][CH2:25][CH:26]([OH:27])[CH3:1])[CH:12]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-n2nc(CCC=O)cc2-c2ccc(Cl)cc2)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: COc1ccc(-n2nc(CCC(C)O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of methyl magnesium bromide (MeMgBr) (2.20 ml, 7.04 mM) in Et2O (15 ml) at 0° C. was added a solution of the aldehyde 11 (1.60 g, 4.69 mM)in Et2O (70 ml) dropwise over a 30 minute period. After stirring for 1 hour the reaction was quenched with a saturated, aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and H2O. The EtOAc solution was dried (MgSO4), filtered, and concentrated in vacuo. Chromatography (65 g, Baker 40 gm silica gel) of the residue with Et2O as eluent afforded 20 (1.33 g, 79%) as a clear light yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[NH:25][CH:24]=[C:23]2[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=12)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25](OC)=[O:26])[C@@H:22]([NH:29][C:30](=[O:52])[C@H:31]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[NH:32][C:33]([O:35]CC2C=CC=CC=2)=O)[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.[CH2:53]([NH2:57])[CH2:54][CH2:55][CH3:56]>CO>[CH2:53]([NH:57][C:25](=[O:26])[C@H:23]1[O:24][C@@H:19]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][CH:17]=[N:18][C:10]=3[NH2:9])[C@H:20]([OH:21])[C@@H:22]1[NH:29][C:30](=[O:52])[C@H:31]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)[NH:32][C:33](=[O:35])[NH:14][CH2:19][CH2:20][CH2:22][CH3:23])[CH2:54][CH2:55][CH3:56]
Reactant: CCCCN
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1NC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Solvent: CO
Product: CCCCNC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1C(=O)NCCCC

Procedure:
A mixture of methyl 1-(6-benzoylamino-9H-purin -9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronate prepared in Example 56 (355 mg), n-butylamine (5 ml) and methanol (5 ml) was refluxed for 9 hours. The mixture was evaporated to dryness and the residue was triturated in diethyl ether to give N-n-butyl-1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(N-n-butylcarbamoyl-O-methyl-L-tyrosylamino)-β-D-ribofuranuronamide (208 mg), mp. 111°-115° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][N:22]=[CH:21][C:20]=1[F:26]>C(O)C>[F:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Fc1cncc(F)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2c(F)cncc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (227 mg, 1.6 mmol) was dissolved in absolute ethanol (20 mL), then triethylamine (335 μL, 2.4 mmol) and 4-(bromomethyl)-3,5-difluoropyridine (350 mg, 1.7 mmol) were added. The mixture was stirred overnight at room temperature. The solvent was removed by evaporation. The residue was triturated in methanol, filtered, washed with water plus diethyl ether, and then dried in vacuo to afford to 2-{[(3,5-difluoropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (179 mg, 42% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 4.45 (s, 2H), 6.01 (bs, 1H), 8.49 (s, 2H); LRMS (ES+) m/z 270 (100%, M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N+:28]([O-])=[CH:27][C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1.O.[Cl-].[NH4+]>C1COCC1.CS(C)=O.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[N:28]=[CH:27][C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: COC(=O)Cc1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)[n+]([O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)nc1
Reaction time: 8 h

Procedure:
Methyl (6-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]piperidin-1-yl}-1-oxidopyridin-3-yl)acetate (40 mg, 0.09 mmol) was stirred in THF (1.3 mL) at room temperature and water (1.3 mL) was added. Ammonium chloride (334 mg, 6.24 mmol) was added to the mixture followed by Zn dust (26 mg, 0.38 mmol). The reaction mixture was stirred overnight before diluting with 2 mL DMSO and filtering. The filtrate was purified by preparative HPLC to yield the title compound (Intermediate 102) as a gum; MS m/e MH+ 455.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8](O)=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].CS([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=O)=O.O>CN(C=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: CS(=O)(=O)CCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1CCc1ccccn1
Temperature: 75 °C

Procedure:
Vanillin (2.5 mmol) is added to mixture of K2CO3 (12.5 mmol) and 2-(2-Methanesulfonyl-ethyl)-pyridine (1) (2.5 mmol) in DMF (0.2 M), and the resulting reaction mixture is heated to 75° C. for 16 h. After cooling to approximately room temperature, water is added and the aqueous mixture is extracted 5 times with methylene chloride. The methylene chloride layers are combined and concentrated to afford a residue, which is recrystallized in diethyl ether.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[O:17]=[C:18]1[CH:27]([NH:28][C:29](=[O:31])[CH3:30])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1.C(OC(C)C)(C)C>C(O)(=O)C>[N+:1]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[NH:19][C:18](=[O:17])[CH:27]([NH:28][C:29](=[O:31])[CH3:30])[CH2:26]2)([O-:4])=[O:2]
Reactant: CC(=O)NC1Cc2ccccc2NC1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC1Cc2cccc([N+](=O)[O-])c2NC1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Fuming nitric acid (2 mL) was added dropwise to acetic anhydride (81 mL) at an internal temperature of 8° C. or lower, and sulfuric acid (81 μL) and a solution of N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (8.1 g) in acetic acid (81 mL) were sequentially added thereto, followed by stirring at room temperature for 3.5 hours. Diisopropyl ether (162 mL) was added to the mixture, and stirring was performed under cooling on ice for 30 minutes. The formed precipitates were recovered through filtration, washed with diisopropyl ether, and dried under reduced pressure, whereby a mixture of the title compound (A) and N-(8-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (B) (A:B=1:1) (7.15 g) was yielded.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=3)=[O:22])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1
Reactant: COc1cc(CN)on1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: Cl
Product: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)nn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-methoxy-5-isoxazole-methanamine hydrochloride as starting materials, 443.1 (M+H)+.