Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[O-]CC.[Na+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=Cc1ccccc1
Reactant: COc1cc(CC#N)ccc1F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(C#N)=Cc2ccccc2)ccc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 4-fluoro-3-methoxyphenylacetonitrile (10.8 g, 65.4 mmol) in 200 ml EtOH was added a sodium ethoxide 21% solution in EtOH (26.9 ml, 71.9 mmol). Benzaldehyde was added (6.64 ml, 65.4 mmol) and stirred at room temperature over night. The white precipitate was filtered and washed with diethylether and dried to obtain 14.23 g of pale yellow crystals (86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])(C)(C)C.C(C1C=CC(S([N:41]=[N+:42]=[N-:43])(=O)=O)=CC=1)CCCCCCCCCCC.[NH4+].[Cl-]>O1CCCC1>[N:41]([C:4]1[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[N+:42]=[N-:43]
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cn1
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(F)cc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a −78° C. solution of N-(5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (1.34 g, 6.83 mmol) in tetrahydrofuran (25 mL) was added tert-butyllithium (1.31 mL of a 1.7 M solution, 20.5 mmol) drop wise. After 3 h at −78° C., 4-dodecylbenzenesulfonyl azide (3.60 g, 10.2 mmol) was added at the reaction was allowed to warm to room temperature. After 1 h, saturated aqueous NH4Cl was added, and the tetrahydrofuran was removed via rotary evaporator. Dichloromethane was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by two successive silica gel chromatographies (10%→80% EtOAc/hexanes, then 5%→42% EtOAc/hexanes) to give the title compound (0.275 g). MS 234.0 (M+1).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6]C)=[O:5].[CH3:8][O:9][CH:10]([CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:11]([O:13]C)=[O:12]>FC(F)(F)C(O)=O>[CH3:8][O:9][CH:10]([CH:15]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)CCS
Reactant: COC(=O)C(OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(C(=O)O)C(SCCC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 0.17 h

Procedure:
To trifluoroacetic acid (100 ml) under argon and cooled to 0° C., was added methyl 3-mercaptopropanoate (0.5 ml, 4.5 mmoles). The mixture was stirred for 10 minutes, after which the ice bath was removed. Methyl 2-methoxy-3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propanoate (1.5 g, 4 mmoles) was added and the mixture stirred for 18 hours. The reaction mixture was evaporated and diluted in methylene chloride. The organic layer was washed with 10% sodium hydroxide (ice cold) followed by ice water. The organic layer was dried over magnesium sulfate, filtered and evaporated. Flash chromatography on silica gel provided the desired product.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]([N:9]2[CH:13]=[C:12]([C:14]([Cl:19])=[O:16])[CH:11]=[N:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](c1ccccc1)n1cc(C(=O)O)cn1
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)n1cc(C(=O)Cl)cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Intermediate (6g), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid (0.5 g, 2.31 mmol) was stirred in toluene (20 mL) at RT and thionyl chloride (0.34 mL, 4.62 mmol) was added. The reaction mixture was slowly heated to 90° C. and heating continued for 3 hrs. After cooling the reaction was concentrated in vacuo. Toluene was added to the residue and concentrated in vacuo. This was repeated a further three times and the title compound, intermediate (6h), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride, was isolated as an oil, 0.544 g, quantitative.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14]Br)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(O)cc2)CC1
Yield: 52.4 %

Procedure:
A mixture of 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 10.0 g of hydroquinone, 10.0 g of anhydrous potassium carbonate and 250 ml of absolute butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) gave 2.9 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenol; m.p. 100°-101° C.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH:3]=1.[BH4-].[Na+].Cl>CO>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[CH:3]=1
Reactant: CC(=O)CCc1cc(O)n2nccc2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CCc1cc(O)n2nccc2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
The compound obtained in step (2) (5.7 g) was dissolved in 120 ml of methanol. Sodium borohydride (0.53 g) was added thereto while being ice-cooled. The mixture was stirred at 0° C. for 2 hours. After completion of the reaction, the reaction mixture was acidified by adding diluted hydrochloric acid dropwise and then extracted with chloroform. The organic layer was collected, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol-n-hexane to provide 4.16 g of 7-hydroxy-5-(3-hydroxybutyl)pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:45])([F:44])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31](B4OC(C)(C)C(C)(C)O4)=[CH:30][N:29]=[C:28]([S:41][CH3:42])[N:27]=3)[C@H:20]2[CH3:43])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Br[C:47]1[C:48]([O:54][CH3:55])=[N:49][CH:50]=[C:51]([Cl:53])[CH:52]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:47]4[C:48]([O:54][CH3:55])=[N:49][CH:50]=[C:51]([Cl:53])[CH:52]=4)=[CH:30][N:29]=[C:28]([S:41][CH3:42])[N:27]=3)[C@H:20]2[CH3:43])[CH:10]=[C:9]([C:8]([F:7])([F:44])[F:45])[CH:14]=1
Reactant: COc1ncc(Cl)cc1Br
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1ncc(Cl)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 170 °C
Reaction time: 0.17 h

Procedure:
A dioxane (17.3 mL) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 2.0 g, 3.46 mmol), 3-bromo-5-chloro-2-methoxypyridine (0.925 g, 4.16 mmol) and 2M potassium phosphate tribasic (3.5 mL, 7.00 mmol) in a microwave vial was evacuated and charged three times with nitrogen. Then Pd(Ph3P)4 (0.400 g, 0.346 mmol) was added and the reaction vial was capped. The reaction was stirred for 10 minutes at 170° C. in a microwave reactor. LCMS showed complete conversion to the product. The reaction was diluted with acetonitrile (5 mL) and filtered through a 2 g plug of RP C18 silica, rinsing with 10 mL acetonitrile. The filtrate was concentrated and the crude was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate/hexanes to give the title compound as a pale yellow foam. LCMS (M+H)+: 593.3
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)=[O:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:29]=[CH:28][S:27][C:7]=12.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][C:9]([C:18]([N:20]2[CH2:21][CH2:22][C:23](=[O:26])[CH2:24][CH2:25]2)=[O:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:29]=[CH:28][S:27][C:7]=12
Reactant: O=C(c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2)N1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2sccc2CC3)CC1

Procedure:
A solution of 100 mg of 1-[(4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)carbonyl]-4-piperidinol in 5 ml of methylene chloride was treated with 51 mg of pyridinium chlorochromate. After the reaction was completed, the solvent was evaporated in vacuo and the residue was chromatographed over silica gel. The product was recrystallized from diethyl ether and there was obtained 1-[(4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)carbonyl]-4-piperidinone of m.p. 218°-220°.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:12])[CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([NH2:12])[CH:3]=1
Reactant: Cc1cc(N)c(C(=O)O)cc1C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)c1cc(C)c(C)cc1N

Procedure:
0.41 g Sodium nitrite in water is added to 1 g 4,5-dimethyl-2-nitroaniline in 3 mL conc. HCl and stirred for 1 hour at +4° C. This solution is added to a mixture of 0.67 g copper (I) cyanide, 0.98 g sodium cyanide, 0.32 g sodium carbonate, 25 mL of water and 3 mL toluene. The mixture is stirred for 12 hours at room temperature and worked up to give 0.45 g 4,5-dimethyl-2-nitrobenzonitrile. 4,5-Dimethyl-2-nitrobenzonitrile is reduced with iron powder in acetic acid to yield 4,5-dimethyl-2-aminobenzonitrile. 4,5-Dimethyl-2-aminobenzonitrile is heated at reflux for 12 hours in conc. HCl to give 4,5-dimethyl-2-aminobenzoic acid. 4,5-Dimethyl-2-aminobenzoic acid is reacted with trimethylsilyl-diazomethane to yield methyl 4,5-dimethyl-2-aminobenzoate (Chem. Pharm. Bull. Vol. 29, 1475 (1981)).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:20])([CH:17]([CH3:19])[CH3:18])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C1(C)C=CC=CC=1>[CH3:20][C:3]([NH:2][C:28](=[O:31])[CH2:29][CH3:30])([CH:17]([CH3:18])[CH3:19])[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5]
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
2-Amino-2,3-dimethyl-N-(p-tolylsulfonyl)-butyramide hydrochloride (1.2 g, 5.3 mol) is dissolved in 25 mL of toluene under N2. Then triethylamine (1.9 mL, 2.5 equivalents) is added, followed by immediate addition of propionyl chloride (0.55 mL, 6.36 mol). The reaction mixture is heated for one hour, and then solvents are removed under reduced pressure. The yellowish residue is recrystallized from EtOH/water, to yield the title product as a white solid having mp 166°-168° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:35][C:36]1[CH:37]=[C:38](O)[CH:39]=[CH:40][CH:41]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:35][C:36]1[CH:41]=[C:40]([CH:39]=[CH:38][CH:37]=1)[O:1][CH2:2][C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1CO
Reactant: Oc1cccc(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1COc1cccc(Cl)c1
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of (±)-(4R*,5R*)-5-(hydroxymethyl)-1-methyl-4-phenylpyrrolidin-2-one (Intermediate T prepared by Method 2, 220 mg, 1.1 mmol), PPh3 (422 mg, 1.6 mmol) and 3-chlorophenol (0.13 mL, 1.6 mmol) in THF (10 mL) was added DIAD (0.31 mL, 1.6 mmol). The reaction mixture was stirred overnight, then concentrated under reduced pressure and purified by flash chromatography (30% EtOAc/CH2Cl2) to afford (±)-(4R*,5R*)-5-[(3-chlorophenoxy)methyl]-1-methyl-4-phenylpyrrolidin-2-one (80 mg, 23%) as a colorless oil. TLC (75% EtoAc/25% hexanes) Rf 0.29, CI m/z (rel abundance) 316 ([MH]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5](NC1C=CC=C(C2CCN(CCNC)CC2)C=1)=[O:6].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH:36]=2)=[CH:31][C:30]=1[N+:48]([O-:50])=[O:49]>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH:36]=2)=[CH:31][C:30]=1[N+:48]([O-:50])=[O:49])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c([N+](=O)[O-])c2)CC1
Reactant: CNCCN1CCC(c2cccc(NC(=O)c3ccccc3OC)c2)CC1
Product: COc1ccccc1C(=O)Nc1ccc(C2=CCNCC2)cc1[N+](=O)[O-]
Yield: 71 %

Procedure:
The title compound 202 (1.04 g, 2.22 mmol, 71%) was prepared following the procedures described for the synthesis of 192 (scheme 33, Example 36, steps 5 and 6) using 201 (1.00 g, 3.13 mmol) in place of 190. LRMS (ESI): calc. 353.1, found 411.3 (MH)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[S:16](Cl)(=[O:18])=[O:17]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[S:16](=[O:17])(=[O:18])[N:2]([CH3:3])[CH3:1]
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CNC
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 10 ml of 40% dimethyl amine solution and 60 ml of methanol, there were added, portionswise, 5.1 g of 4'-chloro-3'-chlorosulfonylacetophenone, so that the reaction temperature did not exceed 30° C. The reaction mixture was stirred for 3 hours at room temperature and 15 minutes at 60° C. After cooling, the reaction mixture was poured into 200 ml of water and the crystals were filtered off. Melting point: 108° C.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)=O.C[O-].[Na+]>C(#N)C>[I:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2([CH3:11])[CH2:10][O:9]2)=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: CC1(c2ccc(I)cc2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 30 g of dimethyl sulfide in 30 ml of acetonitrile was added dropwise over a period of 30 minutes 30 g of dimethyl sulfate, while maintaining the temperature at 40° to 50° C., and the mixture was stirred for one hour at the same temperature. The reaction mixture was cooled to 25° C. and mixed with 30 g of 4-iodoacetophenone and 90 ml of acetonitrile. While stirring, 13.2 g of sodium methoxide was added to the mixture and stirring was continued for a further 30 minutes at room temperature to complete the reaction. Thereafter, the dimethyl sulfide and acetonitrile were removed by distillation, and to the residue were added 120 ml of cyclohexane and 120 ml of water, after which the mixture was thoroughly shaken. The organic layer was separated, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure to obtain 31.5 g (99% yield) of oily 2-(4-iodophenyl)-2-methyloxirane having a melting point of 44°-45° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([OH:13])[C:11]([C:14]([F:17])([F:16])[F:15])=[N:10][C:7]2=[N:8][CH:9]=1)([O-])=O.C(O)C.Cl.[H][H]>[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]([OH:13])[C:11]([C:14]([F:15])([F:17])[F:16])=[N:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2nc(C(F)(F)F)n(O)c2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cnc2nc(C(F)(F)F)n(O)c2c1

Procedure:
6-Nitro-1-hydroxy-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (4.9 grams) was mixed with 100 milliliters of ethanol and 3 milliliters of concentrated hydrochloric acid, and 1 gram of 5 percent palladium on carbon was added to the mixture. The mixture was hydrogenated to a 3 mole-equivalent uptake of hydrogen. The reaction mixture was then filtered and evaporated, yielding a gummy solid residue which was taken up in 150 milliliters of water and used directly in the reaction reported in the following example.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si](CC)(CC)CC)[CH2:16]I)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][NH2:31])=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of N-[2-benzyloxy-5-(2-iodo-(1R)-1-[(triethylsilyl)oxy]-ethyl)-phenyl}-methanesulfonamide (EP 0 659 737) (4.48 g, 8 mmol) and sodium azide (0.65 g, 10 mmol) in 100 mL of hexamethylphosphoramide was stirred at 60° C. overnight. After cooling to room temperature the mixture was diluted with diethyl ether, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in 200 mL of THF/H2O (10:1) and triphenylphosphine (2.62 g, 10 mmol) was added. After overnight stirring at room temperature, the solvents were removed and the residue was partitioned between ethyl acetate and water. The organic layers were combined and dried over MgSO4 and concentrated. The residue was redissolved in 100 mL of THF and tetrabutylammonium fluoride (10 mL, 1 M solution in THF) was added. The reaction was stirred for 2 hours then the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using triethylamine-methanol-methylene chloride (1:1:3) to give the title compound as a white solid; MS (ES) m/z: 337.4 (M++H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].[N+]([O-])(O)=O>O.[OH-].[Na+]>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[O:14]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1[nH]c(-c2ccccc2)nc1C=O
Reaction time: 16 h

Procedure:
A 102.1 gm. portion of 5-methyl-2-phenyl-4-imidazolemethanol is dissolved in 765 ml. of concentrated HNO3. The solution is cooled in an ice bath and allowed to stand for 16 hours. The solution is heated on a steam bath for 30 minutes, diluted with 2.3 liters of water and neutralized with 50% NaOH while cooling in an ice bath. The solid is collected, dried, recrystallized from 200 ml. of ethanol and then from 1 liter of 1:2 ethanol:water giving the desired product, m.p. 102°14 115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.O.[C:23](OC(=O)C)(=O)[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[NH:21][C:23]([CH3:24])=[N:20][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc2nc(-c3ccncc3)c(-c3cccc(F)c3)nc2[nH]1
Temperature: 140 °C
Yield: 52 %

Procedure:
A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 300 mg, 1.07 mmol) in acetic anhydride (3 mL) was stirred and heated at 140° C. for 4 h. Then polyphosphoric acid was added (0.32 g) and allowed to react at the same temperature for 2 h. Upon cooling, water was added and the product extracted with ethyl acetate. The crude obtained was purified by silica column chromatography eluting with a gradient from CH2Cl2 to CH2Cl2/MeOH 95:5 to afford the title compound as a yellow solid (36 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36]>O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[CH3:34])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.07 g, 0.16 mmol) DCM (5 mL) were added Ac2O (0.018 mL, 0.19 mmol) and TEA (0.04 mL, 0.32 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM (2×15 mL). Combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)acetamide (20 mg, 26%), as an off white solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1 H), 8.08 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.4 Hz, 1 H), 7.74 (t, J=8.2 Hz, 1 H), 7.68 (d, J=8.2 Hz, 1 H), 7.64 (d, J=8.2 Hz, 2 H), 7.56 (t, J=8.5 Hz, 1 H), 7.48 (d, J=7.4 Hz, 2 H), 7.22 (d, J=7.5 Hz, 2 H), 7.08 (d, J=8.9 Hz, 2H), 5.42 (s, 2 H), 2.22 (s, 3 H), 1.58 (s, 6 H). MS: [M+Na]: m/z=501.3, [M+H]: m/z=479.3. HPLC: 95.9% (RT-2.32 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).