Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:25][C:26]([O:28]C)=[O:27])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:25][C:26]([OH:28])=[O:27])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCCN1C(=O)C(CC(=O)OC)(c2ccc3c(c2)OCO3)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN1C(=O)C(CC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of methyl [3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetate (5.90 g, 15.0 mmol) in THF/water (2/1 v/v, 120 mL) was added lithium hydroxide monohydrate (1.26 g, 28.0 mmol). The mixture was stirred at ambient temperature overnight. Most THF was removed under vacuum and water (150 mL) was added. The solution was extracted with ethyl acetate/hexanes (1/3 v/v, 50.0 mL). The water layer was acidified with 1 N HCl solution until the pH value reached 2 and extracted with ethyl acetate (200 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound (5.00 g, 88%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.29 (td, 1H), 7.21 (dd, 1H), 7.05 (td, 1H), 6.87 (d, 1H), 6.76 (d, 1H), 6.72-6.64 (m, 2H), 5.90-5.86 (m, 2H), 3.65 (t, 2H), 3.43 (d, 1H), 3.11 (d, 1H), 1.70-1.55 (m, 2H), 1.36-1.22 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.2, 174.0, 148.0, 147.1, 143.4, 132.6, 131.4, 128.7, 124.4, 122.7, 119.8, 108.9, 108.2, 107.2, 101.2, 52.6, 41.5, 40.4, 29.0, 26.6, 22.3, 14.0; MS (ES+) m/z 404.0 (M+23), 382.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:23]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:10]=1[CH2:11][Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(CO)c1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(CCl)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound 4 (963 g, 3.56 mol) in anhydrous DCM (2000 mL) was added slowly SOCl2 (535 g, 4.5 mol) at 0° C. The mixture was stirred at 20° C. for 2 hours, then concentrated in vacuo to give compound 5 as an oil, which was used in the next reaction without further drying or purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12](CC4C=CC(OC)=CC=4)[CH:11]([CH2:24][F:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1>O.CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH:11]([CH2:24][F:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:28])[CH:3]=1
Reactant: COc1ccc(CN2CCc3oc4c(Cl)cc(S(=O)(=O)c5ccccc5)cc4c3C2CF)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)C(CF)NCC3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
A solution of ceric ammonium nitrate (800 mg, 1.46 mmol) in water (1 mL) was added to a solution of the product obtained in step C (90 mg, 0.18 mmol) in acetone (10 mL). The resulting red solution was stirred at ambient temperature for 1.5 h, diluted with ethyl acetate, washed sequentially with saturated aqueous NaHCO3 and brine then dried over anhydrous MgSO4. The solution was filtered and the filtrate concentrated in vacuo to give the crude product which was purified by flash column chromatography (SiO2, 9:1 to 1:1 hexanes/ethyl acetate) providing 6-chloro-1-(fluoromethyl)-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (8 mg, 12%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.14 (d, J=1.5 Hz, 1H), 7.98-7.95 (m, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.57-7.48 (m, 3H), 5.72-5.54 (m, 1H), 3.68-3.58 (m, 1H), 3.42-3.28 (m, 2H), 3.26-3.18 (m, 1H), 3.13-3.00 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1[CH2:16][N:15]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:14]C1.F[P-](F)(F)(F)(F)F.CNC>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:15]([CH3:16])[CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C(=O)Cc1ccc(Br)cc1
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a suspension of 4-bromophenylacetic acid (2.0 g, 9.3 mmol) and PyBOP (4.8 g, 9.3 mmol) in DMF (15 mL) was added dimethylamine (2 M solution in THF, 12 mL, 24 mmol). The solution was stirred overnight, then diluted with ether and washed with 1 M HCl, saturated aqueous NaHCO3 and brine to give 1.15 g 2-(4-bromophenyl)-N,N-dimethylacetamide.
Reaction SMILES: FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](OCC=C)CN2C(OC(C)(C)C)=O)OC(=O)N1.[F:32][C:33]1[CH:34]=[C:35]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:36][C@H:37]1[C@@H:41]([C@H:42]2[CH2:47][O:46][CH2:45][CH2:44][N:43]2[CH:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:40][C:39](=[O:61])[NH:38]1.FC1C=C(C=C(F)C=1)C[C@@H]([C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O)C(O)=O.C(=O)([O-])[O-].[K+].[K+].BrC(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[F:32][C:33]1[CH:34]=[C:35]([CH:62]=[C:63]([F:65])[CH:64]=1)[CH2:36][C@H:37]1[C@@H:41]([C@H:42]2[CH2:47][C@H:45]([OH:46])[CH2:44][N:43]2[CH:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:40][C:39](=[O:61])[NH:38]1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2COCCN2C(c2ccccc2)c2ccccc2)O1
Agent: BrC(c1ccccc1)c1ccccc1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: C=CCO[C@@H]1C[C@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Solvent: CC#N
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
Step D (7): (4S,5S)-4-(3,5-Difluorobenzyl)-5-((R)-4-benzhydrylmorpholin-3-yl)oxazolidin-2-one. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-(morpholin-3-yl)oxazolidin-2-one (step D (6), 180 mg, 0.6 mmol) in acetonitrile (5 mL) were added potassium carbonate (248 mg, 1.8 mmol) and bromodiphenylmethane (296 mg, 1.2 mmol). This mixture was stirred at 100° C. for 1.5 h. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 65% EtOAc/Hexane step gradient) to give 85 mg of the title compound (29% yield): 1H NMR (CDCl3, 500 MHz) δ 2.14 (1H, m), 2.76 (2H, d, J=15 Hz), 2.98 (1H, d, J=5 Hz), 3.15 (1H, m), 3.52 (1H, m), 3.67 (1H, m), 3.87-3.94 (3H, m), 5.23 (2H, d, J=10 Hz), 5.31 (1H, m), 6.56 (2H, d, J=5 Hz), 6.70 (1H, m), 7.16 (1H, d, J=5 Hz), 7.21-7.37 (7H, m), 7.41 (2H, d, J=10 Hz). MS (ESI) (M+H)+ 465.14.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F-:13].[K+].O>S1(CCCC1)(=O)=O>[F:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Yield: 92.5 %

Procedure:
18.6 g (0.1 mol) of 4-chloro-3-nitrobenzaldehyde and 8.7 g (0.15 mol) of potassium fluoride in 100 ml of sulpholane are stirred for 1 hour at 180° C. The mixture is stirred with 300 ml of water and the aldehyde is extracted with methylene chloride. After the customary working-up , 17.1 g of 92% strength 4-fluoro-3-nitrobenzaldehyde are obtained.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[C-]#N.[Na+].C(C1C=CC=CN=1)#N.[NH:19]1[C:29]2[C:23](C=[CH:25][CH:26]=[C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]3=2)=[CH:22][CH:21]=[CH:20]1>>[O:6]=[C:7]1[C:23]2[CH:22]=[CH:21][CH:20]=[N:19][C:29]=2[C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[CH:26]=[CH:25]1
Reactant: COS(=O)(=O)OC
Reactant: C1=CNC2=c3ccccc3=CC=CC2=C1
Agent: [C-]#N
Agent: [Na+]
Solvent: N#Cc1ccccn1
Product: O=c1ccc2ccccc2c2ncccc12

Procedure:
In a process described in U.S. Pat. No. 3,326,924, 3-(2-phenethyl)-2-cyanopyridine is prepared by reacting 3-(2-phenethyl)pyridine-1-oxide with dimethylsulfate and then with aqueous sodium cyanide. A process to convert the cyanopyridine to an aza-dibenzocycloheptene by cyclizing to give the 5-keto-aza-dibenzocycloheptene, then reacting with a Grignard reagent, e.g., 1-methyl-4-piperidinyl magnesium chloride, to give a 5-(1-methyl-4-piperidinyl)aza-dibenzocycloheptene-5-ol, which is dehydrated to give the exocyclic 5-(1-methyl-piperidylidenyl) compound, e.g., azatadine, is also described in U.S. Pat. No. 3,326,924.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[NH3:18]>O1CCOCC1.O>[C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8]([NH2:18])(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
2-Phthalimidoethanesulfonyl chloride (2.0 g) was added portion wise to a solution of 0.5 M of ammonia in dioxane (15 ml) and the solution obtained this way was stirred at room temperature. After 48 hours the reaction mixture was poured in water (50 ml) causing the title compound to precipitate. The product was collected by filtration. Yield: 1.52 g (83%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 7.92-713 (m, 4H), 7.06 (s, 2H), 6.88-3.93 (m, 2H), 3.37-3.30 (m, 2H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])=[CH:10][CH:9]=1>C(Cl)Cl>[C:20]([NH:19][C:17]1[S:18][C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=2)=[C:15]([CH3:23])[N:16]=1)(=[O:22])[CH3:21]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1
Solvent: ClCCl
Product: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To chlorosulfonic acid (25 ml, excess), cooled at −10° C., is added portionwise a suspension of N-[5-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 31a) (1.0 g, 3.8 mmol) in DCM (10 ml). The temperature is kept below 0° C. throughout the addition. The reaction mixture is left to warm up to room temperature. After 2 hours, the reaction mixture is poured carefully onto ice (500 ml). Once the ice is melted, the aqueous layer is extracted with DCM (3×200 ml). The combined organic layers are washed with brine (150 ml), dried over MgSO4, filtered and concentrated to afford 5-(2-acetylamino-4-methyl-thiazol-5-yl)-2-methoxybenzene-sulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](I)[C:5]=2[S:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[C:38](#[N:41])[CH:39]=[CH2:40]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:7]1[C:6]2[C:2]([Br:1])=[CH:3][S:4][C:5]=2[C:10](/[CH:40]=[CH:39]/[C:38]#[N:41])=[CH:9][N:8]=1
Reactant: Nc1ncc(I)c2scc(Br)c12
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#C/C=C/c1cnc(N)c2c(Br)csc12
Temperature: 77 °C
Yield: 88.5 %

Procedure:
To a solution of 3-bromo-7-iodothieno[3,2-c]pyridin-4-ylamine (430 mg, 1.21 mmol), triphenylphosphine (128 mg, 0.48 mmol) and sodium carbonate (257 mg, 2.42 mmol) in N,N-dimethylformamide (6 ml) was added acrylonitrile (0.32 ml, 4.84 mmol) followed by palladium(II) acetate (56 mg, 0.24 mmol). The reaction was heated at 77° C. for 18 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate as the mobile phase to give the title compound (300 mg, 88%) as an off-white solid used directly in the following Suzuki coupling step. LCMS (Conditions g); 2.28; MS: MH+ 280.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:25]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:15][C:6]2[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=2)=[CH:24][CH:23]=3)=[O:26])[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc4[nH]c(C(=O)O)cc4c3)c2cc1OC
Reactant: COc1cccc(N)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(NC(=O)c2cc3cc(Oc4ccnc5cc(OC)c(OC)cc45)ccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(6,7-dimethoxy-quinolin-4-yloxy)-1H-indole-2-carboxylic acid (0.1 g, 0.27 mmol, from step b), 3-methoxy-phenylamine (68 mg, 0.55 mmol) and DIEA (0.1 mL, 0.55 mmol) in 3 mL of DMF was added PyBOP (0.29, 0.55 mmol, Aldrich) at RT. The reaction was stirred at RT for 16 h. The mixture was diluted with 50 mL of EtOAc, and the resulted solution was washed with 30 mL of satd. NaHCO3 followed by 30 mL of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (50% to 100% EtOAc/hexane) to afford off-white solid as desired product. MS (ESI pos. ion) m/z: 470 (M+H). Calc'd Exact Mass for C27H23N3O5: 469.49.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[N:23]=[C:22]([CH:24]=O)[CH:21]=[CH:20][CH:19]=1.CS(O)(=O)=O>>[CH:1]1([N:6]2[C:10]3=[N:11][C:24]([C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[N:23]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: Cc1cccc(C=O)n1
Agent: CS(=O)(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(C)n3)nc(=O)c1-2
Yield: 53.3 %

Procedure:
1-Cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9.0 mmol), 6-methyl-2-pyridinecarboxaldehyde (2.2 g, 18.0 mmol), methanesulfonic acid (0.5 ml) and xylenes (80 ml) were combined and heated to reflux for 24 hours. The solvents were removed in vacuo, ethanol was added and the solvents were removed in vacuo. The residue was partitioned between 10% K2CO3 and chloroform, the organic layer was separated and the aqueous layer was extracted with chloroform (3×200 ml). The combined organic layers were concentrated in vacuo, redissolved in dichloromethane and combined with silica gel (40 g). The slurry was air dried for 3 hours, and placed on a silica gel column (150 g). Elution with ether and concentration of the solvent in vacuo and drying the residue at 40° C. in high vacuum for 6 hours afforded 1.55 g (53%) of 1-cyclopentyl-3-ethyl-6-(6-methyl-2-pyridyl) -pyrazolo-[3,4-d]pyrimidin-4-one.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([F:11])=[C:9]([Br:12])[C:8]([CH3:13])=[C:7]([C:14]#[N:15])[C:6]=1[NH2:16])(=O)[CH3:2].O.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1>C1(C)C=CC=CC=1>[Br:12][C:9]1[C:10]([F:11])=[C:5]2[O:4][C:1]([CH:2]3[CH2:19][CH2:18]3)=[N:16][C:6]2=[C:7]([C:14]#[N:15])[C:8]=1[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)Oc1c(N)c(C#N)c(C)c(Br)c1F
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N

Procedure:
2-Amino-5-bromo-3-cyano-6-fluoro-4-methylphenyl acetate (I-76) (7.95 g, 25.38 mmol) was dissolved in toluene (80 ml), p-toluenesulfonic acid monohydrate (1.60 g, 20 wt. %) was added, followed by stirring under reflux for 19 hours.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]=[N:14][N:15]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[C:19]([F:30])[CH:18]=2)[CH:16]=1)=O)C>C1COCC1>[F:23][C:21]1[CH:22]=[C:17]([N:15]2[CH:16]=[C:12]([CH2:10][OH:9])[N:13]=[N:14]2)[CH:18]=[C:19]([F:30])[C:20]=1[N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cn(-c2cc(F)c(N3CCSCC3)c(F)c2)nn1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of lithium aluminum hydride (161 mg, 4.24 mmol) in dry THF (10 mL) was added a solution of 1-(3,5-difluoro-4-thiomorpholin-4-yl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (1.0 g, 2.8 mmol), obtained in Preparation 22, in THF (10 mL) at 0° C. and stirred for 0.5 h. The reaction mixture was then quenched with saturated solution of sodium sulfate and filtered. The residue was washed with ethyl acetate and the combined filtrate was concentrated to yield the title alcohol (0.7 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.[C:32](C1C=CC(CCl)=CC=1)([CH3:35])([CH3:34])[CH3:33].COC1C=CC(CCl)=CC=1>>[C:32]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH:19]([OH:30])[CH2:18][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:10]([NH:9][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=3[CH3:8])=[O:31])[CH2:13][CH2:14]2)=[CH:27][CH:26]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: COc1ccc(CCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1
Agent: COc1ccc(CCl)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CCc2ccc(C(C)(C)C)cc2)CC1

Procedure:
Compound 19 was prepared in a manner similar to that of compound 16 substituting 4-t-butylbenzyl chloride for 4-methoxybenzyl chloride. (M+1)=452.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C@@:9]34[C@H:17]5[N:18]([C:19]([CH2:21][C@@H:22]6[O:23][CH2:24][CH:25]=[C:26]7[CH2:27][NH+:12]([C@H:13]3[CH2:14][C@@H:15]7[C@H:16]56)[CH2:11][CH2:10]4)=[O:20])[C:6]2=[CH:5][C:4]=1[O:28][CH3:29]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C@@:9]34[C@@H:13]5[CH2:14][C@H:15]6[C:26]([CH2:27][N:12]5[CH2:11][CH2:10]3)=[CH:25][CH2:24][O:23][C@H:22]3[CH2:21][C:19](=[O:20])[N:18]([C@H:17]4[C@@H:16]63)[C:6]2=[CH:5][C:4]=1[O:28][CH3:29]
Reactant: COc1cc2c(cc1OC)[C@@]13CC[NH+]4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Solvent: CC#N
Product: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Yield: 100 %

Procedure:
To 2.3 liters acetonitrile was added 99.6 g (0.342 mol) of title product of the preceding Example and 147.0 g (0.342 mol) brucine dihydrate. The mixture was brought to reflux to effect almost complete solution of the reagents and slightly hazy particulate matter was removed by filtration of the hot solution. The filtrate was allowed to cool to 23° C. and after 20 hours, 96.5 g of white solid; m.p. 184°-187° C., [alpha]D25 =+11° (CH3OH, C=1) was collected by filtration. The mother liquors were set aside for recovery of the 2S,4S enantiomer and racemate and the entire batch of white solid was taken up in 1.5 liters acetonitrile at reflux to give a clear solution. The volume was reduced to 1.2 liters by boiling off acetonitrile, the solution was allowed to cool to 23° C. and after 20 hours partially purified title product recovered by filtration, 65 g of white crystals; m.p. 191°-195° C.; [alpha]D25 =+30° (CH3OH, C=1). This latter material was dissolved in 1.4 liters acetonitrile at reflux, the solution was allowed to cool to 23° C. and after 20 hours there was isolated by filtration 52.7 g of purified title product, white crystals; m.p. 193°-197° C.; [alpha]D25 =+36° (CH3OH, C=1). The absolute 2R,4Rstereochemistry of this compound was shown by X-ray crystallographic analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:18])[C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)/C=C/C(O)=O>CCOC(C)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:18])[C:9]([CH3:10])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccn1)C(N)c1cccc(F)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(c1ccccn1)[C@H](N)c1cccc(F)c1

Procedure:
(R)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine is prepared starting from racemic 1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. The free base was dissolved in EtOAc and a solution of fumaric acid (1.0 eq) in MeOH is added. The solvent is removed in vacuo and the residue is triturated with Et2O/hexanes (1:1), collected by filtration and air-dried. 1HNMR (300 MHz, DMSO-d6) δ 1.19 (s, 3 H), 1.31 (s, 3 H), 4.48 (s, 1 H), 6.55 (s, 2 H), 6.85-6.95 (m, 2 H), 7.01 (t, J=8.9 Hz, 1 H), 7.18-7.34 (m, 3 H), 7.64-7.77 (m, 1 H), 8.59 (d, J=3.8 Hz, 1 H). MS: m/z 245.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[OH:12])[CH2:5][CH2:4]1.C(OC(=O)C)(=O)C.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[ClH:1].[NH2:2][CH:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([N+:21]([O-:23])=[O:22])[C:10]=2[OH:12])[CH2:5][CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c2c1CCC2N
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5.75 Grams of 1-amino-7-hydroxy-4-methylindane hydrochloride was suspended in 40 ml of acetic acid, then 3.27 ml of acetic anhydride and a solution consisting of 2.59 ml of concentrated nitric acid and 10 ml of acetic acid were added thereto, and the whole mixture was stirred at a room temperature for 6 hours. The solvent was removed by evaporation, the residue was washed with acetone and recrystallized from ethanol to obtain 2 g of 1-amino-7-hydroxy-4-methyl-6-nitroindane hydrochloride in the form of yellow needle-like crystals. Melting point: 200°-230° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([S-:13])[CH3:12].[Na+].C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:11]([S:13][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:12]
Reactant: N#Cc1cc(F)ccc1Br
Reactant: CC[S-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ccc(F)cc1C#N
Yield: 40 %

Procedure:
(Step 1) A mixture of 2-bromo-5-fluorobenzonitrile (5.0 g), sodium ethanethiolate (2.31 g), Pd2(dba)3 (114 mg), Xantphos (145 mg) and N,N-diisopropylethylamine (6.46 g) was stirred in toluene (100 ml) at 90° C. for 9 hr under a nitrogen atmosphere. The reaction mixture was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19) to give 2-(ethylsulfanyl)-5-fluorobenzonitrile (1.81 g) as a solid.