Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.C(N(CC)CC)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1.Cl>O1CCCC1>[F:24][C:20]1[CH:19]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)[CH:3]=3)[NH:7][N:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.1 %

Procedure:
To a solution of 100 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26 and 0.1 ml of triethylamine in 5 ml tetrahydrofuran was added 55 mg of nicotinic acid chloride hydrochloride, and the mixture was stirred at room temperature for two days. After the completion of the reaction, the reaction mixture was treated with 5 N hydrochloric acid by the procedure of Production Example I-25-b, to give 62 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[CH:3]=[CH:4][N:5]=[CH:6][C:7]=2[C:8](=[O:10])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1ccncc1C(=O)O
Product: O=c1[nH]cnc2ccncc12
Yield: 47 %

Procedure:
Crude 4-amino nicotinic acid (2.72 g, 11.4 mmol) in formamide (20 mL) is heated to 170° C. for 12 h. The volatiles are distilled out under reduced pressure (0.8 mmHg). The residual solid is then purified on a medium pressure silica gel column, eluting with 10% MeOH in CHC3 to give 3H-pyrido[4,3-d]pyrimidin-4-one (780 mg, 47%) as a whitish yellow solid. 1H NMR (DMSO) δ 12.64 (1H, brs), 9.28 (1H, s), 8.83 (1H, d, J=5.5 Hz), 8.30 (1H, s), 7.58 (1H, d, J=5.8 Hz).
Reaction SMILES: [CH2:1]([C@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]1[C@H:42]2[C@H:38]([O:39][CH2:40][CH2:41]2)[O:37][CH2:36]1)[C@H:9]([OH:31])[CH2:10][N:11]([O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([S:12]([N:11]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:10][C@@H:9]([OH:31])[C@@H:8]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1cccc([N+](=O)[O-])c1)O[C@H]1CO[C@H]2OCC[C@H]21
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)OC2CCCCC2)c1
Reaction time: 16 h
Yield: 92.7 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(cyclohexyloxy)[(3-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (403 mg, 0.651 mmol) in absolute ethanol (12 mL) was combined with Palladium on carbon (10 wt %, 80 mg) and reduced under a Hydrogen atmosphere for 16 hours. The reaction mixture was filtered and evaporated in vacuo to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (356 mg, 93%) as a foam. A sample of the product (30 mg) was purified on a preparative TLC plate (20×20 cm, 500 uM) eluting with 95:5 dichloromethane:methanol. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate (18 mg) as a solid. H1-NMR (chloroform-D3): 1.26 (m, 6H), 1.64 (m, 5H), 2.07 (m, 2H), 2.93 (m, 4H), 3.14 (b, 1H), 3.69 (m, 2H), 3.87 (m, 4H), 3.94 (b, 2H), 4.19 (m, 1H), 4.83 (b, 1H), 5.03 (m, 1H), 5.64 (d, 1H), 6.89 (d, 1H), 7.06 (s, 1H), 7.21 (m, 7H). MS(ESI): 612(M+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]1[O:6][CH2:5]1.[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([OH:6])[CH2:5][S:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H]1CO1
Reactant: SCc1ccccc1
Product: COC(=O)[C@@H](O)CSCc1ccccc1
Yield: 92 %

Procedure:
This reaction was performed as previously described by Deechongkit, S.; You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 497, using (S)-Methylglycidate 110a and Benzyl mercaptan. (R)-3-Benzylsulfanyl-2-hydroxy-propionic acid methyl ester 110b (7.41 g, 31.41 mmol, 92%) was isolated as a viscous oil: MS calcd. for C11H14O3S (M+H+) 227.1, found 227.3.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:18]3[C@@H:17]4[C@@H:21]([C:22]([O:24]CC)=[O:23])[C@@H:16]4[CH2:15][C:14]=3[CH:13]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:34].O.Cl>C1COCC1.CO>[CH3:3][C:4]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:18]3[C@@H:17]4[C@@H:21]([C:22]([OH:24])=[O:23])[C@@H:16]4[CH2:15][C:14]=3[CH:13]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:34]
Reactant: CCOC(=O)[C@H]1[C@@H]2Cc3cc(OCc4cccc(-c5c(C)cccc5C)c4C)ccc3[C@@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc3c(c2)C[C@H]2[C@H](C(=O)O)[C@@H]32)c1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide solution (0.69 ml, 10 N, 6.9 mmol) was added to a stirred solution of ester from Step E (0.98 g, 2.3 mmol) in THF (4 mL), methanol (4 mL), and water (2 mL) at rt under nitrogen. The mixture was stirred at 60° C. overnight. The solution was neutralized with conc. HCl (0.57 mL), concentrated to remove organic solvent. The residue was dissolved in ethanol/water (10 mL, 1:1) warmed to obtain a clear solution and then cooled in refrigerator to produce a precipitation. The solid was collected by filtration and dried in air to give the title compound as a white crystalline solid. 1H NMR (500 MHz, CDCl3): δ 7.44 (1H, d, J=7.5 Hz), 7.29 (2H, m), 7.20 (1H, dd, J=6.5, 8.5 Hz), 7.15 (1H, s), 7.14 (1H, d, J=7.5 Hz), 7.05 (1H, 7.5 Hz), 6.87 (1H, s), 6.85 (1H, dd, J=8.5, 2.0 Hz), 5.05 (2H, s), 3.31 (1H, dd, J=18, 6.5 Hz), 3.07 (1H, d, J=18 Hz), 3.00 (1H, d, J=6.5 Hz), 2.53 (1H, m), 1.99 (3H, s), 1.97 (6H, s), 1.25 (1H, t, J=2.5 Hz) ppm. MS: m/e 399 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2c(F)cccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1c(F)cccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.404 g, 6.27 mmol) was dissolved in MeOH (21 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.251 g, 6.27 mmol) dissolved in water (2.100 mL) was added over 8 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.384 mL, 6.27 mmol) was added over 6 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (32.3 mL, 193.76 mmol) and the mixture continued to stir at 80° C. for 25 min. The solvent was evaporated and the crude mixture was redissolved in DCM/water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.232 g, 55.8%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.94-2.04 (m, 2H), 2.08-2.16 (m, 2H), 2.63-2.73 (m, 1H), 2.81-2.91 (m, 1H), 2.98-3.09 (m, 1H), 3.24-3.37 (m, 4H), 3.88-3.99 (m, 1H), 4.41-4.54 (m, 1H), 5.81 (s, 1H), 6.82-6.92 (m, 2H), 7.16-7.26 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [OH:1][CH:2]([CH3:31])[CH2:3][NH:4][C:5](=[O:30])[CH2:6][CH:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:9]([N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[O:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:15]([N:11]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:10])[CH:8]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:5]([NH:4][CH2:3][C:2](=[O:1])[CH3:31])=[O:30])([CH3:16])[CH3:17]
Reactant: CC(O)CNC(=O)CC(c1ccccc1)C(C(=O)N(C(C)C)C(C)C)c1cccnc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)CNC(=O)CC(c1ccccc1)C(C(=O)N(C(C)C)C(C)C)c1cccnc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a cold (0° C.) suspension of N5-(2-hydroxypropyl)-N1,N1-diisopropyl-3-phenyl-2-pyridin-3-ylpentanediamide (20 mg, 0.047 mmol) in 1 mL dry CH2Cl2 was added solid Dess-Martin periodinane (24 mg, 0.056 mmol), and the reaction was stirred at 0° C. for 3.5 h. The cooling bath was then removed and stirred at room temperature for 1.5 h. More Dess-Martin periodinane was added (two 24 mg portions in 1.5 h interval). The reaction was quenched with saturated aqueous NaHCO3: saturated aqueous Na2S2O3 (1:1 v/v) and partitioned between CH2Cl2 and saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a white solid. This material was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:4][C:5](=O)[NH:6][C:7]=1[CH2:8][CH2:9][CH3:10].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[N:6]=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]([CH3:1])=[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:4]=1
Reactant: CCCc1[nH]c(=O)nc(-c2cccc(C(F)(F)F)c2)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1nc(Cl)nc(-c2cccc(C(F)(F)F)c2)c1C

Procedure:
A mixture of 5-methyl-6-propyl-4-(3-trifluoromethylphenyl)-1H-pyrimidin-2-one (64 mg) and phosphorus oxychloride (3 mL) was stirred and heated at reflux for 24 h, then allowed to cool and poured onto a mixture of ice/ether (20 mL). The ether layer was separated, washed with saturated sodium carbonate solution (10 mL) and water (10 mL), dried over sodium sulphate, and evaporated at reduced pressure to afford 2-chloro-5-methyl-4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine as an oil (64 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][S:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: ClCCCCCCSc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCSc2ccccc2)CC1
Yield: 42.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.5 g) as starting compound and 6-phenylthiohexyl chloride (2.76 g) were reacted and treated in the same manner as in Example 168 to give 1.40 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-phenylthiohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5](=[O:14])[CH:4]=1.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19]>C(O)C>[CH2:15]([NH:20][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5](=[O:14])[CH:4]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC1=CC(=O)C(=O)c2ccccc21
Reactant: CCCCCN
Solvent: CCO
Product: CCCCCNC1=CC(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a stirred suspension of 650 mg (3.45 mmol) of 4-methoxy-1,2-naphthoquinone in 20 mL of ethanol was added 0.80 mL (6.90 mmol) of pentylamine. The reaction mixture was stirred at room temperature for 60 min. The resulting red precipitate was collected by filtration and then triturated with 20 mL of ethyl acetate to afford 411.7 mg (49%) of 4-pentylamino-1,2-naphthoquinone, which was recrystallized from ethyl acetate: mp>215° C.; 1H NMR (300 MHz, CDCl3, TMS) δ 8.21 (dd, J=7.5, 1.6 Hz, 1H), 7.69 (td, J=7.7, 1.6 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 5.86 (s, 1H), 5.76 (br s, 1H), 3.4-3.3 (m, 2H), 1.8-1.7 (m, 4H), 1.5-1.4 (m,4H), 0,95 (t, J=7 Hz, 3H); 13C NMR (75.5 MHz, d6 -DMSO, TMS) δ 182.0, 174.7, 154.8, 134.1, 131.2, 130.8, 127.8, 123.3, 98.0, 43.1, 28.7, 27.4, 21.8, 13.9. Analysis calculated for C15H17NO2 : C=74.04, H=7.06, N=5.7; Found: C=73.88, H=7.01, N=5.73.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:31][C:32]2([CH2:36][OH:37])[CH2:35][O:34][CH2:33]2)[C:5]=1[O:21][CH3:22]
Reactant: OCC1(CBr)COC1
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 38.1 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (135.7 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C1CCCCO1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]2)[CH:20]=[N:19][CH:18]=1.[ClH:37].CC(O)C>>[ClH:37].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:17]1[N:22]=[C:21]([N:23]2[CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][CH2:28]2)[CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Agent: Cl
Solvent: CC(C)O
Product: NC1CCN(c2cncc(-c3n[nH]c4ccc(Br)cc34)n2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A glass scintillation vial containing tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate 1e (0.338 g, 0.606 mmol) and HCl, 5-6N in IPA (12 mL, 60.0 mmol) was stirred vigorously at 50° C. for 4 h. The reaction mixture was cooled to RT and the solvent was removed in vacuo. The residue was concentrated to dryness to give a yellow solid that was used in the next step without further purification. MS (ESI, pos. ion) m/z: 373 (M+1).
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=[O:14])[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.[Br:15]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5](=[O:14])[CH:4]3[CH2:3][CH2:2][CH2:1][CH:13]3[C:12]=2[CH:11]=1
Reactant: O=C1Nc2ccccc2C2CCCC12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Br)cc2C2CCCC12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (374 mg, 2.0 mmol) in DMF (10 ml) is mixed with N-bromosuccinimide (356 mg, 2.0 mmol). After 15 minutes of stirring at room temperature, the batch is heated for 15 minutes to 100° C., diluted with water and extracted with methyl-tert-butyl ether. The combined extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue is purified on silica gel with ethyl acetate-hexane: 470 mg (88%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15](C([O-])=O)[CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:19]C(OCC(Cl)(Cl)Cl)=O)=[CH:4][CH:3]=1.ClC(OCC(Cl)(Cl)Cl)=O>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[OH:19])=[CH:6][CH:7]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)OC1C(c2ccc(Br)cc2)CC2CCC1N2C(=O)[O-]
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: OC1C2CCC(CC1c1ccc(Br)cc1)N2

Procedure:
(eee) In an analogous manner to that described in Example 12(c)-(d), cleavage of the N-methyl group from (1RS,2RS,3RS,5SR)-3-(4-bromo-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-2-ol, obtained analogously to the 4-chlorophenyl derivative [J.Org.Chem. 35, 802 (1970)], was effected by firstly synthesizing (1RS,2RS,3RS,5SR)-3-(4-bromo-phenyl)-2-(2,2,2-trichloro-ethoxycarbonyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate by reaction with 2,2,2-trichloroethyl chloroformate and subsequently reacting with zinc in glacial acetic acid to give (1RS,2RS,3RS,5SR)-3-(4-bromo-phenyl)-8-aza-bicyclo[3.2.1]octan-2-ol. Subsequent introduction of the BOC group analogously to Example 1(f) gave tert-butyl (1RS,2RS,3RS,5SR)-3-(4-bromo-phenyl)-2-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylate, palladium-catalyzed carbonylation of which with carbon monoxide in methanol analogously to Example 22(d) yielded tert-butyl (1RS,2RS,3RS,5SR)-2-hydroxy-3-(4-methoxycarbonyl-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate. Subsequent reduction with lithium borohydride analogously to Example 22(e) gave tert-butyl (1RS,2RS,3RS,5SR)-2-hydroxymethyl-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate, reaction of which with trityl chloride analogously to Example 22(h) gave tert-butyl (1RS,2RS,3RS,5SR)-2-hydroxy-3-(4-trityloxymethyl)-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate. Further reaction with 2-bromomethyl-naphthalene analogously to Example 1(g) gave tert-butyl (1RS,2RS,3RS,5SR)-2-(naphthalen-2-ylmethoxy)-3-(4-trityloxymethyl-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate. In an analogous manner to that described in Example 86(u)(b), by cleavage of the trityl group with a mixture of trifluoroacetic acid and trifluoroacetic anhydride there was obtained tert-butyl (1RS,2RS,3RS,5SR)-3-(4-hydroxymethyl-phenyl)-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate, alkylation of which with benzyl 3-bromopropyl ether analogously to Example 44(e) gave tert-butyl (1RS,2RS,3RS,5SR)-3-[4-(2-benzyloxy-propoxymethyl)-phenyl]-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:20])[CH2:13][NH:14][S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH:8][CH:7]=2)=[CH:2]1>[Pd].C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([CH3:20])[CH2:13][NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:11]=2)=[CH:2]1
Reactant: C=CS(=O)(=O)NCC(C)c1ccc(-c2ccsc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCC(C)c1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A solution of 0.024 g (0.078 mmol) of material from Example 130 and 5 mg 5% palladium on carbon in 5 mL ethyl acetate was degassed three times under a hydrogen balloon and stirred at room temperature for 4 hr. The mixture was filtered and concentrated in vacuo. The residue was recrystallized from ether and hexane to afford 0.024 g (99%) of the title compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][CH2:15][CH:16](O)[CH2:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[C:22]([CH3:28])[NH:23]2)([CH3:13])([CH3:12])[CH3:11].C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N.C(O)(=O)/C=C/C(O)=O.C(O)(=O)/C=C/C([O-])=O>CN(C)P(=O)(N(C)C)N(C)C.CC(C)=O.CO.CCOCC>[C:1]([O:9][CH:16]([CH2:15][NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[C:22]([CH3:28])[NH:23]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(OCC(O)CNC(C)(C)C)cccc2[nH]1
Reactant: O=C(O)c1ccccc1
Agent: N
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Solvent: CC(C)=O
Product: Cc1cc2c(OCC(CNC(C)(C)C)OC(=O)c3ccccc3)cccc2[nH]1
Reaction time: 20 h

Procedure:
26 g of Benzoic acid are dissolved, while heating, in 50 cc of hexamethylphosphoric acid triamide and 3.5 g of 1-tert.butylamino-3-(2-methyl-indole-4-yloxy)-2-propanol are added. After cooling, 3.0 g of benzoic acid anhydride are added and stirring is effected for 20 hours at room temperature. The resulting clear, yellow solution is poured onto ice, 0.5 liters of ether are added and stirring is effected for 2 hours. After making the liquid alkaline with concentrated ammonia, the ether phase is separated, shaken out with tartaric acid, made alkaline with caustic soda solution while cooling with ice and extracted with methylene chloride. After evaporating the solvent, the residue is crystallised with 1 mol of fumaric acid from methanol and acetone. M.p. of hydrogen fumarate form: 189°-191°.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:17][CH:16]=1>C(O)C>[C:3]([CH:2]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: Clc1ccc(CCCCCBr)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCCCc1ccc(Cl)cc1)C(C)=O
Reaction time: 0.25 h

Procedure:
A solution of 6.0 g (46 mmol) of ethyl acetoacetate in 6 ml of absolute ethanol is added drop by drop, with stirring, to a solution of 23 mmol of sodium ethylate in 18 ml of ethanol. Stirring is continued for another 15 minutes to complete the salt formation, and then a solution of 6.0 g (23 mmol) of 5-(4-chlorophenyl)pentyl bromide in 6 ml of absolute ethanol is added. The mixture is then heated for 3 hours with refluxing, and then completely concentrated by evaporation. Water is added to the concentrate and the mixture is neutralized with 2N hydrochloric acid. Then the organic components are extracted with ether, the combined extracts are dried, and are concentrated by evaporation. The concentrate is chromatographed on silica gel with a mixture of n-heptane and butanone. Yield: 5.8 g (81% of theory) of ethyl 2-acetyl-7-(4-chlorophenyl)heptanoate, a colorless oil.