Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.B(OC(C)C)(OC(C)C)OC(C)C.Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[ClH:34].C(=O)([O-])[O-].[Na+].[Na+].[NH2:41][C:42]1[C:43]([C:49]([NH:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:50])=[N:44][C:45](Br)=[CH:46][N:47]=1>O1CCCC1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:34].[NH2:41][C:42]1[C:43]([C:49]([NH:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:50])=[N:44][C:45]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:46][N:47]=1
Reactant: Nc1ncc(Br)nc1C(=O)NCCN1CCOCC1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(S(=O)(=O)N3CCCC3)cc2)nc1C(=O)NCCN1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
n-Butyllithium (1.6 mL, 2.6 mmol) was added dropwise over 10 min to a cooled solution (−78° C.) of triisopropyl borate (0.6 mL, 2.6 mmol), and 1-[(4-bromophenyl)sulfonyl]pyrrolidine (0.251 g, 0.86 mmol) in anhydrous tetrahydrofuran (10 mL) under an atmosphere of nitrogen. The resulting mixture was stirred at −78° C. for 1 h and the mixture was allowed to warm up to room temperature. Aqueous HCl (3 M, 1.4 mL, 4.3 mmol) was added and the mixture was stirred for 10 min followed by the addition of sodium carbonate (0.9 g, 8.6 mmol) and the stirring was continued for another 20 min. 3-Amino-6-bromo-N-(2-morpholin-4-ylethyl)pyrazine-2-carboxamide (0.20 g, 0.61 mmol), and tetrahydrofuran (4 mL) were added followed by addition of Pd(dppf)Cl2 (28 mg, 0.03 mmol) and the resulting mixture was heated at 65° C. for 17 h. The mixture was allowed to return to room temperature and the solvent was evaporated. The resulting residue was suspended in methanol, silica was added, and the solvent was evaporated. Purification by column chromatography on silica using methylene chloride/methanol/triethyl amine, (95:5:0.1), as the eluent gave the free base that was subsequently dissolved in hot methanol and treated with HCl (1 M in diethyl ether). The formed precipitate was filtered off and dried in vacuo to give 72 mg (26% yield) of the title compound as a yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.24 (br s, 1H), 9.28 (m, 1H), 8.98 (s, 1H), 8.49 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 2H), 3.97 (m, 2H), 3.87 (d, J=12 Hz, 2H), 3.78 (m, 2H), 3.55 (d, J=12 Hz, 2H), 3.15 (m, 6H), 1.65 (m, 4H); MS (ES) m/z 461 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[C:5]([CH3:14])=[C:4]([Cl:15])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[OH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:4]1[C:5]([CH3:14])=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:7]=[C:2]([C:27]2[CH:28]=[C:23]([OH:22])[CH:24]=[CH:25][CH:26]=2)[N:3]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Cc1c(Cl)nc(Cl)nc1N[C@@H]1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(Cl)nc(-c2cccc(O)c2)nc1N[C@@H]1CCOC1
Temperature: 100 °C
Reaction time: 14 h
Yield: 107.5 %

Procedure:
To a solution of (R)-2,6-dichloro-5-methyl-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine (1.8 g, 7.3 mmol) in degassed dioxane and H2O (4/1, 21 mL) was added Na2CO3 (1.5 g, 14.5 mmol); Pd(PPh3)4 (296 mg, 0.36 mmol) and 3-hydroxy-phenylboronic acid (1.21 g, 8.8 mmol). The system was purged with nitrogen stream and then stirred at 100° C. for 14 h., cooled down to room temperature, diluted with water (30 mL) and the resulting mixture extracted with EtOAc (30 mL×2). The combined organic layer were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (EtOAc/petroleum ether, gradient elution, from 1/10 to 2:1) to give (R)-3-(4-chloro-5-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenol (2.4 g, 33%) as a white solid. ESI-LCMS (m/z): 306.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>C(O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1ccnc(-c2cc([N+](=O)[O-])ccc2F)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccnc(-c2cc(N)ccc2F)c1
Reaction time: 0.58 h

Procedure:
To a solution of 2-(2-fluoro-5-nitrophenyl)-4-methylpyridine (0.6 g, 2.6 mmol) in ethanol (50 ml) was added platinum(IV) oxide (100 mg) and the mixture stirred for 35 min under hydrogen (40 psi). The catalyst was filtered off and the solution evaporated to dryness to give 4-fluoro-3-(4-methylpyridin-2-yl)phenylamine as a brown oil: δH (400 MHz, CDCl3) 8.55 (1H, d, J 5), 7.59-7.62 (1H, m), 7.27 (1H, dd, J 6 and 3), 7.06-7.09 (1H, m), 6.95 (1H, dd, J 11 and 9), 6.64-6.68 (1H, m), 2.60-3.20 (2H, br), 2.41 (3H, s); m/z (ES+) 203 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:28][CH2:29][C:30]([CH3:33])([CH3:34])[CH2:31][CH2:32]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([O:26][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](O)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-(4,4-Dimethyl-cyclohexyl)-3-[(cis-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.25 g, 4.60 mmol) in 23 ml of CH2Cl2 was added at 0° C. methanesulfonyl chloride (1.05 g, 9.20 mmol) followed by triethylamine (1.28 ml, 9.20 mmol). The reaction mixture was stirred at room temperature for 24 h and treated with water. The aqueous Layer was extracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduce pressure to give 5-(4,4-Dimethyl-cyclohexyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.56 g, 98%)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C1CCCCC1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:5][CH2:4][CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: CN1CCCNCC1
Reactant: ClCCCBr
Solvent: C1CCCCC1
Product: CN1CCCN(CCCCl)CC1
Reaction time: 8 h
Yield: 42 %

Procedure:
A round-bottom, 250 milliliter, three-necked flask was equipped with a mechanical stirrer, a Claisen adapter, equipped with a thermocouple and a dry-ice condenser with a gas inlet, and a pressure-equalizing dropping funnel. This apparatus was baked in an oven overnight at 125° C., assembled hot, and purged with argon until cool. The reaction flask was charged with 1-bromo-3-chloropropane 15.75 grams, (0.10 moles, 1 equivalent) and cyclohexane 8.68 grams, (0.10 moles, 1 equivalent). The reaction mixture was stirred with a magnetic stir bar. 1-Methylhomopiperizine 22.64 grams, (0.20 moles, 2 equivalents) was added dropwise via the addition funnel over a period of thirty-three minutes. A hexane/dry ice cooling bath was applied as needed to maintain a reaction temperature no greater than 35° C. After addition was complete, samples of the reaction mixture were removed periodically, washed with saturated sodium bicarbonate solution, and assayed for unreacted 1-bromo-3-chloropropane by gas chromatography (GLC). The reaction was allowed to stir until 1-bromo-3-chloro-propane was consumed. Next, 75 milliliters of saturated sodium bicarbonate solution and 25 milliliters of distilled water were added to the reaction flask. The reaction mixture was then transferred to a separatory funnel (homogeneous mixture). The mixture was extracted 2×75 milliliters with ethyl ether. The resulting organic layer was then dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator, to afford a slightly hazy solution with a yield=42%; (GC assay=98.3%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(N(CC)CC)C.IC>O1CCOCC1>[CH3:6][N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CI
Solvent: CCN(CC)CC
Product: CN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5.00 g (13.3 mmol) 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester in a 4 N solution of hydrochloric acid in dioxane was stirred at room temperature for 16 hours. The precipitate that has formed was filtered off and the filtrate was evaporated to dryness. This residue was dissolved in 20 ml DMF and 2.6 ml (18.5 mmol) triethylamine and 0.6 ml (9.7 mmol) iodomethane were added. The reaction mixture was stirred for 16 hours at room temperature. The precipitate that had formed was filtered off and the filtrate was evaporated in vacuo. The residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on a silica gel column with toluene/ethylacetate as eluent yielding 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine as colourless crystals; HPLC-MS: 1.29 min, [M+H] 292.
Reaction SMILES: [C:1]1([C:7]2[C:12](C3C=CC=CC=3)=[C:11]([C:19](OCC)=[O:20])[CH:10]=[CH:9][C:8]=2[C:24](OCC)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:10]([C:10]1[C:11]([CH2:19][OH:20])=[C:12]([C:2]2[CH:1]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([CH2:24][OH:25])[CH:9]=1)[CH2:9][CH2:8][CH2:7][CH2:12][CH3:11]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(-c2ccccc2)c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1cc(CO)c(-c2ccccc2)c(-c2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.3 %

Procedure:
A solution of diethyl 2,3-diphenyl-1,4-benzenedicarboxylate (21.1 g, 46.0 mmol) in anhydrous THF (175 mL) was added dropwise with stirring over a 0.5 hour period to a suspension of lithium aluminum hydride (7.89 g, 208 mmol) in 350 mL of anhydrous THF at 0° C. This solution was stirred at room temperature for 1 hour and refluxed for 24 hours. The solution was then cooled and treated with: 1) 8 mL of water, added dropwise and stirred carefully for 0.25 hour, 2) 24 mL of 15% NaOH with stirring for an additional 0.25 h, and 3) 24 mL of water with additional stirring for 0.25 hour. The THF was evaporated and the resulting mixture was stirred for 12 hours with a 10% (v/v) H2SO4 solution. The product was filtered and recrystallized from aqueous ethanol to give a white solid (12.6 g, 73% yield): mp 136-7° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=[C:6]([NH:22][CH2:23][C@H:24]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]2)[C:5]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 97.9 %

Procedure:
A mixture of benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (647 mg, 1.98 mmol), tert-butyl (3R)-3-aminomethyl-1-pyrrolidinecarboxylate (preparation 80), (398 mg, 1.98 mmol) and triethylamine (830 ml, 5.95 mmol) in ethyl acetate (25 ml) was heated under reflux for 18 hrs. The cooled mixture was washed consecutively with water, 1N citric acid solution, brine, then dried over MgSO4, and evaporated under reduced pressure to give the desired compound as a gum, (952 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]([C:29]1[S:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[CH:11]=1)(=[O:9])=[O:8].[Br:40][C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=1I.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.C(O)(C)(C)C.O1CCOCC1>[Br:40][C:41]1[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[CH:43][C:42]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:17]=1[CH:18]=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]1[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=1[O:2][CH3:1])[C:29]1[S:33][N:32]=[CH:31][N:30]=1)(=[O:9])=[O:8])=[CH:11]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(B4OC(C)(C)C(C)(C)O4)cccc3c2)c(OC)c1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)cccc3c2)c(OC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
A reaction vessel was charged with N-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2 sulfonamide (Intermediate E) (4 g, 7.05 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (4.95 g, 14.10 mmol) and Pd(dppf)Cl2 DCM (1.151 g, 1.410 mmol). Dioxane (35.2 mL) and t-butanol (35.2 mL) were added to the reaction mixture followed by sodium carbonate in water (1.9 M) (11.13 mL, 21.15 mmol). The reaction vial was then swept with nitrogen and sealed with a screw cap. The resulting mixture was then heated to 50° C. and stirred for 4 hours. LC/MS indicated that the product was formed. The resulting mixture was transferred to a separatory funnel containing water and the aqueous layer was washed three times with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to a dark oil which was purified by MPLC using 120 g silica gel column eluting with 0 to 70% EtOAc in heptane) to afford 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (3.27 g, 4.92 mmol) as a white solid. m/z (ESI) 685.8 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][C:3]=1[F:24].Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][C:3]=1[F:24]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(Cl)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
(2R,4S)-Methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (446 mg, 1.26 mmol) was dissolved in hydrogen bromide (33% in AcOH, 6.8 mL, 38.97 mmol) and stirred at room temperature for 20 h. The solvent was then evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-chloro-3-fluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (266 mg, 71%). 1H NMR (600 MHz, dmso) δ 1.31 (q, 1H), 1.44 (dq, 1H), 1.82-1.89 (m, 1H), 1.94-2.00 (m, 1H), 2.70 (dt, 1H), 2.84 (tt, 1H), 3.06-3.12 (m, 1H), 3.66 (dd, 1H), 5.72 (s, 1H), 7.23 (dd, 1H), 7.38 (dd, 1H), 7.49 (t, 1H). HRMS Calculated for [C14H14ClFN2O2+H]+: 297.0806. Found: 297.0795
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][N:23]=1)([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3](=O)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O.C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][C:2]([C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][N:23]=1)([C:3]1[NH:34][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: [NH4+]
Reactant: CSc1ccc(C(C)(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)nc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(C)(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 145.1 %

Procedure:
To a solution of 5-methyl-5-[5-(methylsulfanyl)pyridin-2-yl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (60.7 mg) in acetic acid (1 mL) was added ammonium acetate (181 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (84.0 mg, yield 82%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([CH3:18])[C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:2]3[CH:7]=[CH:6][C:5]([O:28][CH3:25])=[CH:4][CH:3]=3)[CH:15]=2)[N:10]([CH3:18])[C:9]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 3-benzyl-5-bromo-1-methyl-2-phenyl-1H-indole (1.525 g, 4.053 mmol) was reacted with aqueous 2M K2CO3 (4.1 ml), 4-methoxyphenylboronic acid (0.862 g, 5.674 mmol) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.099 g, 0.122 mmol) in dioxane (41 ml) to give the product (0.766 g, 1.898 mmol, 47%) as an off-white solid, mp 122-125° C. 1H NMR (DMSO-d6) δ 3.62 (s, 3H), 3.77 (s, 3H), 4.04 (s, 2H), 6.98 (d, J=8.6 Hz, 2H), 7.07-7.11 (m, 3H), 7.18 (t, J=7.8 Hz, 2H), 7.42 (dd, J=1.5, 8.6 Hz, 1H), 7.45-7.55 (m, 9H); [ESI(+)], m/z 405 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[C:4]([CH3:20])=[N:3]1.S(Cl)([Cl:23])=O>>[CH3:1][N:2]1[C:6]([C:7]([Cl:23])=[O:8])=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[C:4]([CH3:20])=[N:3]1
Reactant: O=S(Cl)Cl
Reactant: Cc1nn(C)c(C(=O)O)c1Nc1ccccc1[N+](=O)[O-]
Product: Cc1nn(C)c(C(=O)Cl)c1Nc1ccccc1[N+](=O)[O-]

Procedure:
2.6 g of 1,3-dimethyl-4-[(2-nitrophenyl)amino]pyrazole-5-carboxylic acid and 10 ml of thionyl chloride are stirred at 80° C. for 3 hours; the solution is concentrated; 10 ml of toluene are added, and the mixture is re-concentrated, this procedure being carried out 3 times. 2.9 g of 1,3-dimethyl-4-[(2-nitrophenyl)amino]pyrazole-5-carboxylic acid chloride are thus obtained as an orange-colored oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:17]#[N:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])C.[H][H]>CO.[Ni]>[CH3:1][O:3][C:4]([C:6]1([CH2:17][NH2:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:7]1)=[O:5]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C#N)CN(C(=O)OC(C)(C)C)C1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1(CN)CN(C(=O)OC(C)(C)C)C1

Procedure:
3-Cyano-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (7.75 g; 30.5 mmol) in methanol (1000 ml) is combined with wet RaNi (˜28 g) and hydrogenated at room temperature under 1 atm of hydrogen for 2 hours. The reaction mixture is filtered and evaporated to dryness to yield the title compound as light brown resin, which crystallizes slowly (6.8 g; 91%).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)([C:11](OCC)=[O:12])[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)([CH2:6][OH:7])[CH2:11][OH:12])(=[O:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCC(CO)(CO)NC(C)=O)cc1
Reaction time: 1 h

Procedure:
A solution (100 ml) of diethyl 2-acetamido-2-[2-(4-octylphenyl)ethyl]malonate (11.55 g) in anhydrous tetrahydrofuran was dropwise added to a solution (260 ml) of lithium aluminum hydride (3.0 g) in anhydrous tetrahydrofuran under ice-cooling. The mixture was stirred for 1 hour under ice-cooling and then at room temperature for 2 hours. A saturated aqueous solution of sodium sulfate was dropwise added under ice-cooling to decompose lithium aluminum hydride, which was then filtered off. The resultant mixture was extracted with ethyl acetate and the ethyl acetate layer was washed and dried. The solvent was distilled away and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give crystals of 2-acetamido-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol, melting point 66°-68° C. The obtained compound was dissolved in pyridine (40 ml) and acetic anhydride (30 ml) was added thereto under ice-cooling. The mixture was left standing at room temperature overnight. The reaction mixture was poured into a 10% aqueous hydrochloric acid solution (500 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous potassium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1) to give 8.25 g of the subject compound yield 71%