Azzindani/Open_Reaction_Data huggingface dataset:
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][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].N1C=CC=CC=1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[S:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h
Yield: 84.9 %

Procedure:
In 50 ml of methylene chloride, methyl 18-hydroxyoctadecanoate (4.5 g, 14.3 mmoles) was dissolved. To the obtained solution was added pyridine (4.53 g, 57.2 mmoles), and then was gradually added p-toluenesulfonyl chloride (5.46 g, 28.6 mmoles) with ice-cooling over a period of 1 hour. Thereafter, reaction was carried out for 16 hours in a refrigerator. The reaction mixture was washed with a 10% aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water and aqueous sodium chloride solution in this order, dried, and then concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (eluent: benzene) to give methyl 18-tosyloxyoctadecanoate (5.69 g, 85%) having the following properties.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[CH:1]1[C:11]2[C:10](=[N:18][OH:19])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1c2ccccc2CSc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2ccccc2CSc2ccccc21

Procedure:
19.7 G. of dibenzo[b,e]thiepin-11(6H)-one and 14.6 g. of hydroxylamine hydrochloride in 350 ml. of pyridine are stirred under reflux conditions for 16 hours. After the addition of a further 7.3 g. of hydroxylamine hydrochloride, the mixture is stirred for a further 5 hours under reflux conditions. The mixture is evaporated and purified by chromatography over aluminum oxide using chloroform and chloroform/methanol (93:3) for the elution. The purified product is recrystallized from acetone. There is obtained dibenzo[b,e]thiepin-11(6H)-one-oxime of melting point 241°-243° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCC(=O)O)ccc2[nH]1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 5-carboxymethoxy-1H-indole-2-carboxylic acid ethyl ester (1.5 g, 5.7 mmol) and 1-1′-carbonyldiimidazole (1.11 g, 6.85 mmol) in dimethylformamide (15 mL) was stirred at room temperature for 30 mins. To the mixture was then added morpholine (1 mL) and the stirring was continued for overnight. The reaction was concentrated and the residue was dissolved in dichloromethane (200 mL), washed with 1N hydrochloric acid, saturated sodium bicarbonate and brine, dried and concentrated to give 1.6 g (85%) of 5-(2-morpholin-4-yl-2-oxo-ethoxy)-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+:18].[N+:19]([CH3:22])([O-:21])=[O:20]>CO>[N+:19]([CH2:22][CH:12]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)[O-:13])([O-:21])=[O:20].[Na+:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])CC([O-])c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 457.2 %

Procedure:
To a solution of 4-phenoxybenzaldehyde (1.5 g, 7.56 mmol) in methanol (12 mL) was added dropwise sodium methoxide (1.49 M methanol solution, 0.19 mL, 0.91 mmol) under nitrogen atmosphere at room temperature. Nitromethane (530 μL, 9.84 mmol) was added dropwise to the reaction solution on an ice bath (0° C.). Sodium methoxide (1.49 M methanol solution, 1.66 mL, 8.16 mmol) was added dropwise thereto at room temperature, and the solution was stirred for 30 minutes at room temperature. The precipitated solids were filtered and dried under reduced pressure, and the solids were dried azeotropically with toluene to obtain the title compound (1.17 g, 55%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([NH:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: NC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccccc1NCc1ccccc1

Procedure:
To a hot solution of 20 g NaOH in 1250 ml water was added 68 g 2-aminobenzamide followed by 58 ml benzyl chloride. The mixture was refluxed 20 minutes, cooled and the solid filtered and washed with water. The product was recrystallized from 95% alcohol to give 62 g, m.169-73.
Reaction SMILES: CC([O-])=O.[Na+].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=O)[CH2:17][S:16](=[O:21])(=[O:20])[N:15]([CH3:22])[C:14]=2[CH:23]=1)=[O:9].Cl.[NH2:25][OH:26]>CCO>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[N:25][OH:26])[CH2:17][S:16](=[O:21])(=[O:20])[N:15]([CH3:22])[C:14]=2[CH:23]=1)=[O:9]
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)N(C)S(=O)(=O)CC2=NO

Procedure:
NaOAc (3.66 g, 44.5 mmol) was added to an EtOH (100 mL) solution of 1-methyl-2,2,4-trioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazine-7-carboxylic acid methyl ester (4.00 g, 14.8 mmol) and hydroxylamine hydrochloride (1.55 g, 22.3 mmol). After heating at reflux for 4 days, it was evaporated, diluted with CH2Cl2 (400 mL), washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo. Crystallization from MeOH provided the title compound. MS (−APCI, m/z): 283 (M−H)−.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].N(C(OCC)=O)=NC(OCC)=O.[OH:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]O>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:44][C:43]1[CH:42]=[C:41]([OH:40])[CH:48]=[CH:47][CH:46]=1
Reactant: Oc1ccccc1Cl
Reactant: OCc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1cccc(COc2ccccc2Cl)c1
Reaction time: 1 h
Yield: 50.9 %

Procedure:
At 0° C. to 616 mg (2.35 mmol) of triphenylphosphine and 400 μL (3.84 mmol) of 2-chlorophenol in 20 mL of methylene chloride was added 370 mL (2.35 mmol) of diethyl azodicarboxylate followed by dropwise addition of a solution of 233 mg (1.9 mmol) 3-hydroxybenzyl alcohol in 2 mL of tetrahydrofaran. The reaction mixture was stirred at 0° C. to ambient temperature for 1 h. The reaction mixture was quenched with water, extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (methylene chloride/hexane (2:1 to 4:1)) to provided 227 mg (44% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.39 (dd, 1H, J=1.6, 7.8 Hz), 7.25 (t, 1H), 7.15-7.21 (m, 1H), 6.88-7.01 (m, 4H), 6.79 (dd, 1 H, J=2.5, 8.1 Hz), 5.12 (s, 2H), and 4.97 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:11])[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH:9]([CH3:10])[C:8](=[O:11])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)CC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-methyl-3-oxopentanoate (5.0 g, 34.7 mmol) in chloroform at 0° C. was added bromine (1.79 mL, 34.7 mmol) in chloroform (10 mL) drop-wise. The resulting solution was stirred at rt for 16 h. The solution was washed with water, dried over sodium sulfate, and concentrated to give the title compound. 1HNMR (500 MHz, CDCl3), δ4.781-4.740 (dd, J=6.6 Hz, 1H), 4.140-4.098(dd, J=7.0 Hz, 1H), 3.770 (s, 3H), 1.797-1.783(d, J=6.6 Hz, 3H), 1.455-1.442 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=2)[O:3]1.Cl>C(O)C.O.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[C:6](=[O:7])[C:2]([CH3:1])([CH3:28])[O:3][C:4]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:19]([F:27])[CH:18]=2)=[CH:9][CH:10]=1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)c(F)c2)=C(c2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)c(F)c2)=C(c2ccc(N)cc2)C1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
To 200 mg of 2,2-dimethyl-4-(4-nitrophenyl)-5-{3-fluoro-4-(methylsulfonyl)-phenyl}-3(2H)-furanone (Example 287) in 7 ml ethanol and 1 ml water, were added 0.5 ml concentrated HCl and 0.2 g of iron powder. The mixture was stirred for 12 hours at 70° C. After the reaction mixture was cooled to room temperature, the unreacted iron was filtered off. The filtrate was concentrated in vacuo and the residue was neutralized with 1 N aqueous sodium hydroxide, which was followed by extraction with 30 ml dichloromethane. The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=1:1) to afford 102 mg of 4-(4-aminophenyl)-2,2-dimethyl-5-{3-fluoro-4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 199-200° C. NMR: δ1.54 (s, 6H), 3.24 (s, 3H), 3.80 (br s, 2H), 6.71 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 7.61 (dd, J=10.5, 1.8 Hz, 1H), 7.64 (dd, J=8.4, 1.8 Hz, 1H), 7.92 (dd, J=8.1, 7.2 Hz, 1H). IR (cm−1): 3468, 3374, 1694, 1517, 1386, 1320, 1159, 1147.
Reaction SMILES: C([Li])CCC.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:41]1([CH2:47][CH2:48][CH:49]=O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([CH2:47][CH2:48][CH:49]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][O:7]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=CCCc1ccccc1
Reactant: c1ccc([P+](CCCCCCCCOC2CCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=CCCc1ccccc1)CCCCCCCOC1CCCCO1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M solution in hexane, 20 ml) was added to a stirred solution of the product of step (a) (11.0 g) in dry tetrahydrofuran at -70° C. under nitrogen. The orange solution was stirred for 30 minutes at -70° C. then a solution of 3-phenyl-propionaldehyde (2.75 g) in tetrahydrofuran (7 ml) was added. The pale solution was allowed to warm to room temperature and then evaporated. The residue was extracted with ether and the extract again evaporated and the residue was chromatographed on silica-gel eluting with 1:1 ether:hexane to give the title compound as a pale oil.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]([C:34]3[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:33]=3[F:32])[OH:36])=[N:3][CH:4]=[C:5]([CH3:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1cccc(F)c1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(O)c1c(F)cccc1OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (158 mg, 0.33 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C. was added isopropylmagnesium chloride (2 M solution in THF, 0.4 mL, 0.8 mmol) via dropwise addition. The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-fluoro-6-methoxy-benzaldehyde (96.6 mg, 0.63 mmol) at −30° C. The mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with saturated aqueous NH4Cl solution (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to obtain 4-chloro-N-{2-[(2-fluoro-6-methoxyphenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (110 mg) as yellow syrup in 60% yield. ESMS m/z: 549 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][CH:50]=[CH:49][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([O:42][CH2:43][CH2:44][C:45]([O:47]C)=[O:46])[CH:36]=2)=[CH:13][CH:12]=1.C(OC(C)C)(C)C.P([O-])([O-])([O-])=O>CS(C)=O>[C:45]([CH2:44][CH2:43][O:42][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[CH3:41])[CH2:34][O:33][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:49]=[CH:50][CH:51]=[CH:52][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:19]1)([OH:47])=[O:46]
Reactant: COC(=O)CCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc(C)c(OCCC(=O)O)c2)cc1
Temperature: 35 °C
Reaction time: 120 h

Procedure:
The mixture of 0.527 g of benzyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[3-(2-methoxycarbonylethoxy)-4-methylbenzyloxy]piperidine-1-carboxylate, 20 ml of diisopropyl ether, 0.20 ml of dimethyl sulphoxide and 100 ml of pH 7.0 phosphate buffer is admixed with 15 ml of Novozyme 398 (Novo Nordisk) and stirred at 35° C. over 120 hours. The reaction mixture is extracted repeatedly with tetrahydrofuran and the organic phases are concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (1:1 EtOAc-heptane); Rt=5.57.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2cc(O)ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-1H-indole-3-carboxylic acid (1.05 g) in N,N-dimethylformamide (11.0 mL) were added sodium carbonate (722 mg) and benzyl bromide (0.775 mL), followed by stirring at room temperature overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain benzyl 6-hydroxy-1H-indole-3-carboxylate (1.04 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[N:15]1[CH:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[N:17][CH:16]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:19]2[CH:20]=[N:21][C:22]3[C:18]2=[N:17][CH:16]=[N:15][CH:23]=3)[CH3:13])[CH2:11][O:10]1
Reactant: c1ncc2[nH]cnc2n1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnc2cncnc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 47.7 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (1.03 g) and purine (500 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(9H-9-purinyl)ethyl]oxirane (600 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([N:12]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[N:15][N:14]=[N:13]2)[CH:3]=1.Cl.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:37][C@H:36]3[N:32]([CH2:33][CH2:34][CH2:35]3)[C:31]([CH3:39])([CH3:38])[CH2:30]2)[C:25]([F:40])=[CH:24][N:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH:17]1([C:16]2[N:12]([C:4]3[CH:3]=[C:2]([NH:1][C:22]4[N:27]=[C:26]([NH:28][C@@H:29]5[CH2:37][C@H:36]6[N:32]([CH2:33][CH2:34][CH2:35]6)[C:31]([CH3:38])([CH3:39])[CH2:30]5)[C:25]([F:40])=[CH:24][N:23]=4)[CH:11]=[CH:10][C:5]=3[O:6][CH2:7][CH2:8][OH:9])[N:13]=[N:14][N:15]=2)[CH2:19][CH2:18]1
Reactant: Nc1ccc(OCCO)c(-n2nnnc2C2CC2)c1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(-n4nnnc4C4CC4)c3)ncc2F)C[C@@H]2CCCN21
Yield: 64.6 %

Procedure:
Similarly, 2-(4-amino-2-(5-cyclopropyl-1H-tetrazol-1-yl)phenoxy)ethan-1-ol (67 mg, 0.26 mmol) was used in a similar displacement reaction using (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (95 mg, 0.28 mmol) and pTsOH.H2O (98 mg, 0.51 mmol) in IPA (5 mL) at reflux to give the product (88 mg, 66% yield) after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]Br)=[N:6][CH:7]=1.[C-:10]#[N:11].[K+]>CCO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]#[N:11])=[N:6][CH:7]=1
Reactant: BrCc1ccc(Br)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a stirred solution of 5-bromo-2-(bromomethyl)pyridine (0.70 g, 2.12 mmole), in EtOH (50 mL) at 60° C. was added KCN (0.21 g, 3.18 mmole) in H2O (3 mL). After 1.5 h, the reaction contents were cooled to RT and concentrated under vacuum. The aqueous residue was dissolved in EtOAc and washed with H20, and dried over Na2SO4. Concentration under vacuum and purification on silica (EtOAc) afforded the title compound (0.38 g, 65%) as light yellow solid: LC-MS (ES) m/e 277 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:16][C:15]([CH3:17])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:16][C:15]([CH3:17])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:28]=[O:29])[CH:8]=2)[S:3]1
Reactant: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)s1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C=O)cc32)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cold (−78° C.) solution of 2,2-dimethyl-4(2-methyl-thien-5-yl)-6-bromo-thiochrom-3-ene (Compound T, 430 mg, 1.2 mmol) in THF (12 mL) was added n-BuLi in hexane (1.6 M solution, 1 mL). The mixture was gradually warmed to ambient temperature over 1 hour and recooled to −78° C. To this solution was added DMF (220 mg, 3 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by adding water (10 mL) and ethy lacetate (100 mL). The organic layer was washed with brine (10 mL), dried and the solvent was removed by distillation to obtain the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[H-].[Na+].[CH2:32](Br)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>CN(C=O)C>[CH2:32]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:9]2[C:10]([F:12])([F:13])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:15][CH:16]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(F)(F)C(c1ccc(O)cn1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2(F)F)nc1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
10 mmol of 1,8,8-trifluoro-7-(5-hydroxypyridin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 7.55 mmol of 7-[5-(octyloxy)pyridin-2-yl]-1,8,8-trifluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:36])C(=O)C1>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:36][C:9]1[N:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:11]2[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:20])=[O:21])[C:13]=3[N:14]=[CH:15][C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CCCCC4)n23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C4CCCCC4)n23)cc1
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.27 g, 0.67 mmol, prepared using Q from Preparation #13, Lawesson's reagent, and mercury(II) acetate) in THF (10 mL) at about 0° C. was added a solution of NBS (0.12 g, 0.672 mmol) in THF (2 mL). After about 30 min, the reaction mixture was diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with EtOAc:DCM:heptane (1:1:2) to provide 3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.27 g 83%) as a tan solid: LC/MS (Table 1, Method a) Rt=3.12 min; MS m/z 473, 475 (1:1) (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[CH3:18][Mg]Br>O1CCCC1.[Cu]I>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH:9]([C:12]#[N:13])[C:10]#[N:11])[CH3:18])=[CH:14][CH:15]=1
Reactant: N#CC(C#N)=Cc1ccc(OC(F)(F)F)cc1
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(c1ccc(OC(F)(F)F)cc1)C(C#N)C#N
Yield: 60 %

Procedure:
Using 1.19 g of (4-(trifluoromethoxy)benzylidene)malononitrile 20 ml of tetrahydrofuran, a catalytic amount of copper (I) iodide, and 12.5 ml of a solution of methyl magnesium bromide in tetrahydrofuran (about 1 M, available from Tokyo Kasei Kogyo Co., Ltd), and according to the process described in Reference Production Example 2, there was obtained 0.76 g of (1-(4-(trifluoromethoxy)phenyl)ethyl)malononitrile (the intermediate (10)).