Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C-:21]#[N:22].[Na+].C1OCCOCCOCCOCCOCCOC1.Cl>CN(C)C=O>[CH2:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:4]2[C:3]([C:17]([F:20])([F:19])[F:18])=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:21]#[N:22])[CH2:9][CH2:10]1)[CH2:15][CH3:16]
Reactant: [C-]#N
Reactant: CCCN1CCC(c2cccc(F)c2C(F)(F)F)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(C#N)c2C(F)(F)F)CC1

Procedure:
Preparation according to Example 7: 4-[3-fluoro-2-(trifluoromethyl)phenyl]-1-propylpiperidine (0.81 g, 2.8 mmol), N,N-dimethylformamide (30 ml), sodium cyanide (0.5 g, 10 mmol) and 18-crown-6-ether (30 mg). Yield: 0.53 g (64%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 266-269° C. MS m/z (relative intensity, 70 eV) 296 (M+, 3), 268 (16), 267 (bp), 204 (3), 184 (3).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CC#N>[CH3:36][O:35][C:31](=[O:34])[CH:32]=[CH:33][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][CH2:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][CH:21]=1
Reactant: C=CC(=O)OC
Reactant: O=S(=O)(Oc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1)C(F)(F)F
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1

Procedure:
Prepared by Heck coupling 3b and methyl acrylate in accordance with the general method described in Example IV. Yield (94%); APcI m/z: 410 (M+H+CH3CN+, 100%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[CH:5]=[CH:4][C:3]=1[O:16][CH2:17][O:18][CH3:19].[CH:20]1[C:32]2[NH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:19][O:18][CH2:17][O:16][C:3]1[CH:4]=[CH:5][C:6]([C:8]([CH3:15])([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])=[CH:7][C:2]=1[N:31]1[C:32]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: COCOc1ccc(C(C)(C)CC(C)(C)C)cc1I
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCOc1ccc(C(C)(C)CC(C)(C)C)cc1-n1c2ccccc2c2ccccc21
Yield: 31.1 %

Procedure:
To 30 mL of dry toluene add 2-iodo-1-(methoxymethoxy)-4-(2,4,4-trimethylpentan-2-yl)benzene (1.50 g, 3.986 mmol), carbazole (0.633 g, 3.786 mmol), K3PO4 (1.71 g, 8.034 mmol), CuI (0.158 g, 0.830 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.158 g, 1.111 mmol). Reflux the reaction mixture for 48 hours, cool, filter, and concentrate to give material. Purify material by flash chromatography using 3% ethyl acetate in hexanes to give 0.49 g (29.6%) of 9-(2-(methoxymethoxy)-5-(2,4,4-trimethylpentan-2-yl)phenyl)-9H-carbazole as off-white powder. 1H NMR (400 MHz, CDCl3) δ 8.19-8.14 (m, 2H), 7.50-7.25 (m, 7H), 7.19-7.13 (m, 2H), 4.93 (s, 2H), 3.16 (s, 3H), 1.76 (s, 2H), 1.40 (s, 6H), 0.82 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 151.41 (s), 144.96 (s), 141.46 (s), 127.95 (s), 127.19 (s), 126.13 (s), 125.68 (s), 123.11 (s), 120.13 (s), 119.39 (s), 116.20 (s), 110.05 (s), 94.99 (s), 56.99 (s), 56.06 (s), 38.27 (s), 32.40 (s), 31.85 (s), 31.58 (s);
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:2]=1.S(Cl)([Cl:20])=O>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Cl:20])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCCCc1cnc2ccccc2c1
Solvent: ClCCl
Product: ClCCCCCCc1cnc2ccccc2c1
Yield: 98.5 %

Procedure:
A solution of 7.8 g of 3-quinolinehexanol in 35 ml of dry dichloromethane was treated dropwise with a solution of 6.07 g of thionyl chloride in 15 ml of dichloromethane. The reaction mixture was heated to reflux for 1 hour and evaporated to dryness. The residue was dissolved in dichloromethane, washed successively with water, saturated sodium bicarbonate solution and brine, dried over potassium carbonate and evaporated to give 8.3 g of crude 6-(3-quinolinyl)hexylchloride. A suspension of 8.3 g of 6-(3-quinolinyl)hexylchloride, 12.6 g of potassium phthalimide, and 0.50 g of potassium iodide in 60 ml of dimethylformamide was heated to a bath temperature of 130° C. for one hour. The cooled mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with water, dried over potassium carbonate and evaporated. The crude solid was crystallized from ethyl acetate-hexane to give 9.9 g (82%) of 2-[6-(3-quinolinyl)hexyl]-1H-isoindole-1,3-(2H)-dione, mp 90°-91° C. An analytical sample was obtained from toluene, mp 95.5°-96.5° C.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]1.[N:17]#[N:18].C([O-])(O)=O.[Na+].BrN1C(=O)CCC1=O>CC(C)=O.O.C1COCC1>[N:17]1[CH:5]=[CH:4][CH:3]=[C:2]([C:6]2([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7]2)[N:18]=1
Reactant: N#N
Reactant: CC(C)(C)OC(=O)NC1(c2ccco2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2cccnn2)CC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-(furan-2-yl)cyclopropylcarbamate (2.15 g, 9.64 mmol, 1.0 eq) in acetone (86 ml) and water (86 ml) was purged N2 and cooled to −20° C. NaHCO3 (1.62 g, 19.28 mmol, 2.0 eq) and N-bromosuccinimide (2.23 g, 12.52 mmol, 1.3 eq) were added to the mixture at −20° C. which was stirred at the same temperature for 2 hr. To the reaction mixture at −20° C. was added THF (4.3 ml) and the temperature raised to 0° C. over 30 min. Acetone was removed from the reaction mixture by a stream of N2 and to the residue at 0° C. was added isopropanol (86 ml) followed by hydrazine hydrate (12.9 ml). The reaction mixture was stirred at r.t. overnight. Product formation was confirmed by LCMS. After removal of the solvent by vacuum, the residue was diluted with water and extracted with EtOAc. The organic was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent. Yield: 0.8 g (36%). 1H NMR (400 MHz, CDCl3): δ 8.95 (d, J=3.6 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.39 (m, 1H), 5.45 (bs, 1H), 1.82 (m, 2H), 1.46 (s, 9H) 1.24 (m, 2H). LCMS: (ES+) m/z=236.2 (M+H)+
Reaction SMILES: [O:1]=[C:2]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH2:24](O)[CH2:25][OH:26].C([O-])([O-])OC>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][C:2]2([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[O:26][CH2:25][CH2:24][O:1]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCCCC(=O)CCCCc1ccccc1
Reactant: OCCO
Agent: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCCCCCCC1(CCCCc2ccccc2)OCCO1
Reaction time: 0.67 h
Yield: 91.9 %

Procedure:
Methyl 9-oxo-13-phenyl-tridecanoate (1.8 g, 5.65 mmol) was dissolved in toluene (5.0 mL), and ethylene glycol (0.935 mL, 16.8 mmol), methyl orthoformate (1.85 mL, 16.8 mmol), and p-toluenesulfonic acid monohydrate (53.0 mg, 0.279 mmol) were then added in order at room temperature. The mixture was stirred for 40 minutes, and then quenched with a saturated aqueous solution (30 mL) of sodium bicarbonate, and 10% methanol/ethyl acetate (100 mL) was then added. The mixture was separated. The organic layer was washed with a mixture of water (10 mL) and a saturated aqueous solution (30 mL) of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 1.88 g (5.19 mmol, yield 92%) of methyl 8-[2-(4-phenyl-butyl)-[1,3]dioxolan-2-yl]-octanoate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:15])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:15])[C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(I)c(OC)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(I)cc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Methyl 3-cyano-5-iodo-4-methoxybenzoate (8.00 g) was dissolved in tetrahydrofuran (100 mL) and water (50 mL), and lithium hydroxide monohydrate (423 g) was added to the solution, and then the mixture was stirred at room temperature for 4 hours. The organic solvent was distilled off under reduced pressure and the aqueous layer was washed with n-hexane. The aqueous layer was acidified with 2N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (7.26 g) as a colorless crystal.
Reaction SMILES: C1([O:6][C:7](=O)[C:8]2[C:13]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][C:11]([Cl:20])=[N:10][C:9]=2[CH3:21])CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[Na+]>O1CCCC1>[Cl:20][C:11]1[N:10]=[C:9]([CH3:21])[C:8]([CH2:7][OH:6])=[C:13]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:12]=1
Reactant: Cc1nc(Cl)cc(OC2CCCC2)c1C(=O)OC1CCCC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(OC2CCCC2)c1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the 6-chloro-4-cyclopentyloxy-2-methyl-nicotinic acid cyclopentyl ester (7.4 g, 22.8 mmol) in anhydrous tetrahydrofuran (250 mL) under nitrogen cooled to 0° C., lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 45.8 mL, 45.8 mmol) is added over period of 15 minutes. The reaction is stirred for 3 hours at ambient temperature, after which a saturated solution of sodium potassium tartarate (300 mL) is slowly added and the mixture is stirred for additional 1 hour. The organic layer is separated and the aqueous solution is extracted with methylene chloride (2×100 mL). The combined organic extracts are washed with washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue is dissolved in a mixture of hexane and ethyl acetate (1:1, 150 mL) and filtered over a small pad of silica gel (30 g) which is subsequently rinsed with additional 200 mL of the same mixture of hexane and ethyl acetate. The obtained solution is concentrated in vacuo to give (6-chloro-4-cyclopentoxy-2-methyl-pyridin-3-yl)-methanol as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11][CH3:12])=[O:10]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][CH:6]1[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13][CH2:14][NH:15]1
Reactant: COC(=O)c1ccnc(Cc2ccc(F)c(F)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2ccc(F)c(F)c2)C1
Reaction time: 0.75 h
Yield: 103.3 %

Procedure:
Methyl 2-(3,4-difluorobenzyl)isonicotinate (7.7 g, 29.25 mmol) was dissolved in acetic acid (75 mL) and platinum(IV) oxide (0.332 g, 1.46 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 4 h 45 min. More platinum(IV) oxide (0.166 g, 0.73 mmol) was added and the hydrogenation continued at 5 bar for 2 h. More platinum(IV) oxide (0.166 g, 0.73 mmol) was added and the hydrogenation continued at 5 bar for 1 h 20 min. The catalyst was filtered off and washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The organic layer was washed with brine, passed through a phase separator and evaporated to yield crude methyl 2-(3,4-difluorobenzyl)piperidine-4-carboxylate (8.133 g, 103%) as a brown oil. MS m/z 270 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:17][C:18]1[CH:19]=[C:20](I)[CH:21]=[C:22]([Cl:24])[CH:23]=1.C(N1CCOCC1)C.Cl>CN(C)C=O.C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)c1cccc(Nc2cc(Cl)cc(Cl)c2)c1
Reaction time: 120 h
Yield: 3 %

Procedure:
A mixture of 3-amino-N-phenyl-benzamide (2.0 g, 9.4 mmol), 3,5-dichloroiodobenzene (2.65 g, 9.7 mmol), N-ethylmorpholine (1.1 g, 9.5 mmol), and copper(II) acetate (0.1 g, 0.6 mmol) in N,N-dimethylformamide (6 mL) was stirred under an inert atmosphere and heated to reflux. After 120 hours, the mixture was allowed to cool and was stirred into water (300 mL) and acidified with concentrated hydrochloric acid. The mixture was extracted with dichloromethane (300 mL) and the extract separated and washed successively with 2N hydrochloric acid, water, 0.5 M aqueous potassium carbonate, water, and saturated aqueous sodium chloride, then dried over MgSO4. The solution was filtered and stripped of solvent under reduced pressure to leave a solid residue which was subjected to chromatography on a column of silica gel in chloroform to afford the product (0.1 g); m.p. 164-165° C. after recrystallization from ethyl alcohol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](Cl)=[O:12])=[CH:3]1.[Br:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH3:31])=[CH:25][CH:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH3:31])[C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[O:12])=[CH:25][CH:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: Cn1cc(C(=O)Cl)c2ccccc21
Reactant: CNCc1ccc(-c2ccc(OC)c(Br)c2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc(CN(C)C(=O)c3cn(C)c4ccccc34)cc2)cc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
1-methyl-1H-indole-3-carbonyl chloride (16.3 mmol), prepared in the previous step, in 50 mL of methylene chloride was added under nitrogen dropwise to a solution of N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N-methylamine (5.00 g, 16.3 mmol), prepared in step 5 of Example 6, and triethylamine (2.3 mL, 16.3 mmol) in 200 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 20 h. The reaction was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give N-[(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methyl]-N,1-dimethyl-1H-indole-3-carboxamide (7.4 g, 98%) as a white solid foam, MS (ESI) m/z 463 [M+H]+. Elemental Analysis for C25H23BrN2O2. Calc'd: C, 64.80; H, 5.00; N, 6.05 Found: C, 62.88; H, 4.92; N, 5.61
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Br)cc1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To a solution of 4-bromo-2-hydroxybenzonitrile (2 g, 10 mmol) in DMF (15 mL) and was added iodomethanel (2.87 g, 20.2 mmol) and potassium carbonate (2.79 g, 20.2 mmol) at room temperature. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 4-bromo-2-methoxybenzonitrile (2.08 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.0 Hz, 1H), 7.10 (dd, J=8.4, 1.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>>[ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(C2(O)CCN(Cc3ccccc3)C2)c1
Agent: Cl
Product: Cc1cccc(C2=CN(Cc3ccccc3)CC2)c1
Yield: 100 %

Procedure:
A mixture of 8 parts of 3-(3-methylphenyl)-1-(phenylmethyl)-3-pyrrolidinol hydrochloride and 150 parts of a hydrochloric acid solution 6 N was stirred and refluxed for 3 hours. After cooling, the reaction mixture was evaporated, yielding 7.4 parts (100%) of 2,3-dihydro-4-(3-methylphenyl)-1-(phenylmethyl)-1H-pyrrole hydrochloride as a residue (intermediate 47).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:12]1[CH:11]=[CH:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][N:13]=1
Reactant: COc1cccc(-c2ccc(=O)[nH]c2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2ccc(Cl)nc2)c1

Procedure:
In the manner described in Example 26, a mixture of 5-(3-methoxyphenyl)-2(1H)-pyridinone and phosphorus oxychloride yields the product of the Example.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C:3]1=[O:10].CC=CCCCC(=O)C.[BH4-].[Na+]>CO>[Cl:1][C:2]1([Cl:11])[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C@H:3]1[OH:10]
Reactant: O=C1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Agent: CC=CCCCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1[C@@H]2CCC=C[C@@H]2C1(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.0 g of (1S,6R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one, the compound of formula (XXXIX), prepared as shown in Preparation 22, is dissolved in 120 ml of methanol and treated at 0° C. with 1.2 g of sodium borohydride, and the mixture is stirred at 25° C. for 1 hour. The solvent is removed under reduced pressure and the residue partitioned between methylene chloride and water. The extract is dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue is recrystallized from hexane to give (1S,6R,7R)-8,8-dichlorobicyclo[4.2.0]oct-2-en-7-ol, [α]D =+214.4°, (C=0.5, CHCl3).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.CC(O)C.C(O)C.[OH-].[Li+]>O1CCCC1>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)nc2)C2CCCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 3-{[(5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}pyridin-2-yl)carbonyl](methyl)amino}propanoate (9.31 g) synthesized in Example A59(3) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase: hexane/2-propanol (700/300-200/800), flow rate: 60 mL/min-50 mL/min, column temperature: room temperature). The fraction containing an optically active form having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (4.52 g, 99.9% ee). To a mixture of the obtained amorphous form, ethanol (20 mL) and tetrahydrofuran (20 mL) was added 1N lithium hydroxide aqueous solution (20 mL), and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (4.12 g, 98%, 99.9% ee) as a white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[CH2:20][C@@H:21]([OH:23])[CH3:22])[CH:13]=1.C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][C@H:21]([CH2:20]/[CH:19]=[CH:18]/[C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[C@H](O)C/C=C/c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)C/C=C/c2cccnc2)cc1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
Under a nitrogen atmosphere, p-toluenesufonyl chloride (7.01 g, 36.77 mmol) was added to a stirring solution of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol (3.00 g, 18.38 mmol) in dry triethylamine (20 mL) at 0° C. After stirring and warming to ambient temperature over 18 h, the mixture was stirred with cold, saturated NaHCO3 solution (50 mL) for 1 hour and extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation to afford a thick, dark-brown mass (˜7 g). The crude product was purified by column chromatography on silica gel, eluting with chloroform-acetone (98:2, v/v) to afford 4.00 g (68.6%) of a light-brown syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[C:28](NC(C4CNC4)=O)[CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:27]=3)(=[O:24])=[O:25])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)C3CNC3)c2)cc(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(S(C)(=O)=O)c2)cc(OC)c1

Procedure:
N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-sulfamoyl)phenyl)azetidine-3-carboxamide (125 mg, 0.23 mmol), prepared using procedures similar to those described in Example 372, was dissolved into 5 mL DCE in a mL round-bottom flask. DIEA (1.17 mmol, 5.0 equiv.) was then added with stirring followed by acid chloride (0.47 mmol, 2.0 equiv.). The reaction was then stirred at room temperature for 1 hour or until complete as indicated by LCMS. The solvent was subsequently removed under reduced pressure on a rotary evaporator. The crude material was then redissolved in methanol. Purification of the final product was accomplished by preparatory reverse-phase HPLC with the eluents 25 mM aqueous NH4OAc/CAN. A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C18, OCD 5 μM, 30×70 mm column and running a 5-100% gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification.