Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:21]([N:30]4[CH2:35][C@H:34]([CH3:36])[C@@H:33]([OH:37])[C@H:32]([NH:38]C(=O)OC(C)(C)C)[CH2:31]4)=[C:22]4[CH2:28][CH2:27][CH:26]([OH:29])[C:23]4=[N:24][CH:25]=3)=[O:18])[CH:14]=[CH:13][C:12]=2[F:46])=[C:6]([F:47])[CH:5]=1)[CH3:2].C(O)(C(F)(F)F)=O.O.CC#N>C(Cl)Cl>[NH2:38][C@H:32]1[C@H:33]([OH:37])[C@@H:34]([CH3:36])[CH2:35][N:30]([C:21]2[C:20]([NH:19][C:17]([C:15]3[CH:14]=[CH:13][C:12]([F:46])=[C:11]([C:7]4[C:8]([F:10])=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=4[F:47])[N:16]=3)=[O:18])=[CH:25][N:24]=[C:23]3[CH:26]([OH:29])[CH2:27][CH2:28][C:22]=23)[CH2:31]1
Reactant: CCOc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)[C@H](O)[C@@H](C)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (6 mg, 0.01 mmol) and 4.0 M TFA in DCM (2.0 mL) was stirred at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)), the diastereoisomers had the following properties:
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:11][C:12]=3[CH:13]=2)[NH:4][C:3]1=[O:22].[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][O:15][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:4][C:3](=[O:22])[N:2]([CH3:1])[C:14]4=[CH:13][C:12]=3[CH:11]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)O)cc3cc21
Reactant: NC1CCCCC1
Product: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)NC4CCCCC4)cc3cc21

Procedure:
This compound, m.p. 282°-284° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-1-methyl-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoic acid and cyclohexylamine.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:29]([CH3:28])(=[O:31])=[O:30])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: COC(=O)c1cn2c3c(c(O)c(F)cc3c1=O)CCN2C
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cn2c3c(c(OS(C)(=O)=O)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
304 mg of the compound (167) obtained in Example 44 was added to 2 ml of pyridine, and 120 mg of methane-sulfonyl chloride was added to the solution. The solution was stirred for 3 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain 260 mg of the subject compound (168).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].O.Cl>CCCCCC.C(OCC)(=O)C.[OH-].[K+]>[CH2:1]([S:3][CH2:4][CH:5]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CSCC)CC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCSCC(CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101.9 %

Procedure:
650 mg of ethyl 2-ethylthiomethyl-4-methylpentanoate was dissolved in 6 ml of an ethanol/water (10/1) solution, 8.9 ml of an ethanol/water (10/1) solution of 2N potassium hydroxide was added thereto. The solution was stirred at room temperature for 2.5 hours, and then, the reaction solution was distilled off under reduced pressure to obtain a suspension. To this suspension, 40 ml of water was added, and the reaction solution was adjusted to pH2 with 2N hydrochloric acid under cooling with ice, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 577 mg of 2-ethylthiomethyl-4-methylpentanoic acid as colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2[nH]ncc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ncc2c(Br)c(OC)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
A mixture of 4-bromo-5-methoxy-1H-indazole (8.57 g), ethyl bromoacetate (7.56 g), potassium carbonate (6.26 g) and N,N-dimethylformamide (30 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (4.65 g, yield 39%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 106-107° C. MS: 315 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([Br:13])[CH:9]=[CH:10][CH:11]=2)[C:6](C=O)=[CH:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([Br:13])[CH:9]=[CH:10][CH:11]=2)[C:6](=[O:24])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc(C=O)c2c(Br)cccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1CC(=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Acetyl-4-bromo-1H-indole-3-carbaldehyde (3.5 g, 13.2 mmol) was dissolved in CH2Cl2 (50 mL). 3-Chloroperbenzoic acid (3.9 g, 15.8 mmol) was added, and the reaction stirred 16 h at r.t. The solution was washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was stirred with K2CO3 (100 mg) in MeOH (50 mL) for 2 min. The solution was concentrated and purified by silica gel chromatography (100% CH2Cl2) to provide the title compound as a faintly blue solid (880 mg, 26%). MS (ES) [m+H] calc'd for C10H8BrNO2, 254, 256; found 254, 256.
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].Cl>CN1CCCC1=O.CO.[OH-].[Na+]>[CH3:12][C:11]1[C:2]([NH:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1cnc(F)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cc(C(=O)O)cnc1NCC(F)(F)F
Temperature: 220 °C
Reaction time: 2.5 h
Yield: 32 %

Procedure:
A mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol, Step-1 of Amine-36) and 2,2,2-trifluoroethanamine (9.37 g, 95 mmol) in N-methylpyrrolidone (24 mL) is stirred at 220° C. for 2.5 hours under microwave irradiation. The mixture is diluted with MeOH (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) is added to the mixture. After stirring at 50° C. for 1 hour, the mixture is acidified by 2 M hydrochloric acid, and extracted with EtOAc/hexane (100 mL×3). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is crystallized from diisopropyl ether to give 884 mg (32%) of the title compound as a pale pink solid.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](O)=[N:21]4)=[CH:16][CH:15]=3)[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH2:24][C:25]1[C:39]([O:40][CH3:41])=[CH:38][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][C@H:35]([OH:37])[CH3:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:24][C:25]5[C:39]([O:40][CH3:41])=[CH:38][C:28]6[CH2:29][CH2:30][N:31]([CH2:34][C@H:35]([OH:37])[CH3:36])[CH2:32][CH2:33][C:27]=6[CH:26]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:9]=2)(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Reactant: O=S(=O)(NC1CC1)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4cccc(S(=O)(=O)NC5CC5)c4)n3n1)CCN(C[C@@H](C)O)CC2

Procedure:
This compound as a yellow solid, was prepared following the same procedure as described for the synthesis of Example 522 by coupling N-Cyclopropyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. MP>150° C. (decomp.). LCMS (E/I+) 563.14 (M+H). 1H NMR (DMSO-d6) δ 9.00 (s, 1H), 8.60 (d, 1H, J=6.50 Hz), 8.20 (s, 1H), 7.95 (s, 1H), 7.85 (m, 2H), 7.70 (t, 1H, J=6.50 Hz), 7.20 (d, 1H, J=6.00 Hz), 7.00 (d, 1H, J=6.00 Hz), 6.80 (s, 1H), 4.30 (broad, 1H), 3.80 (s, 3H), 3.70 (broad, 1H), 2.80 (broad, 2H), 2.70 (broad, 2H), 2.60 (broad, 4H), 2.40 (broad, 2H), 2.10 (broad, 1H), 1.20 (broad, 1H), 1.10 (d, 3H, J=6.00 Hz), 0.50 (broad, 2H), 0.40 (broad, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8](Cl)=[N:7][C:6]=1[Cl:13])[CH3:2].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)#[N:16]>>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[N:7][C:6]=1[Cl:13])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: N#Cc1ccc(O)cc1
Product: CCOC(=O)c1cc(F)c(Oc2ccc(C#N)cc2)nc1Cl
Yield: 49.9 %

Procedure:
2,6-Dichloro-5-fluoro-nicotinic acid ethyl ester (3.5 g, 15.0 mmol) and 4-cyano-phenol (1.78 g, 15.0 mmol) were coupled using the procedure of Example 17(a) to afford 2.4 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (3H, t), 4.4 (2H, q), 7.58 (2H, d), 8.0 (2H, d), 8.4 (1H, d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:29][O:30][CH3:31])[C:20]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]#[C:25][CH3:26])=[O:21]>CN(C)C=O.O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:19]([CH2:29][O:30][CH3:31])[C:20]([NH:22][C:23]([CH3:28])([C:24]#[C:25][CH3:26])[CH3:27])=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1ccc2ncccc2c1
Temperature: 80 °C
Reaction time: 72 h
Yield: 29.5 %

Procedure:
6-Hydroxyquinoline (0.083 g), anhydrous potassium carbonate (0.087 g) and 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide (0.150 g) in dry N,N-dimethylformamide (3 ml) were stirred and heated to 80° C. for 5 hours then stored for 72 hours at ambient temperature. The yellow suspension was diluted with water, extracted with ethyl acetate and the organic phase was separated then washed with water, dried over magnesium sulphate and evaporated under reduced pressure to a gum. The gum was fractionated by chromatography (silica; ethyl acetate: hexane, 3:2 by volume) to give the required product (0.055 g) as a colourless gum.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:36])=[N:14][C:15]([CH3:35])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:36])=[N:14][C:15]([CH3:35])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:24])([CH3:25])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCC)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Yield: 84.6 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-ethoxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.013 g, 0.026 mmol) and LiOH (6.27 mg, 0.262 mmol) in 9:1 EtOH/H2O (1 ml) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-ethoxyphenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0105 g, 0.022 mmol, 86% yield) as solid. 1H NMR (500 MHz, CDCl3) δ 7.12-7.17 (m, 1H), 7.03-7.07 (m, 1H), 6.95-7.01 (m, 2H), 5.90 (br. s., 1H), 4.06-4.17 (m, 2H), 3.46-3.88 (m, 1H), 2.75-3.08 (m, 1H), 2.70 (s, 3H), 2.25 (s, 3H), 1.91-2.43 (m, 2H), 1.48 (t, J=7.0 Hz, 3H), 1.13-1.37 (m, 4H), 1.25 (s, 9H), 0.78 (br.s., 6H). LCMS (M+H)=469.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[OH:31])[C:21]([Cl:32])=[CH:20][N:19]=1.Cl.O1CCOCC1>CC(O)C>[Cl:32][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[OH:31])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4O)n3)cc2CC1
Temperature: 140 °C
Yield: 27.7 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (76 mg, 0.34 mmol) and trans-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanol (100 mg, 0.38 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (95 μL, 0.38 mmol, 1.1 eq) was added and the reaction was heated at 140° C. in a microwave for 2.5 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain trans-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexanol as a pink foam (42 mg, 28%). LCMS (m/e) 446 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.35-7.22 (m, 2H), 7.04 (d, 1H, J=8.1 Hz), 6.78 (s, 1H), 5.17 (d, 1H, J=7.1 Hz), 3.96-3.85 (m, 1H), 3.60-3.54 (m, 2H), 3.38 (s, 3H), 3.00-2.85 (m, 4H), 2.81-2.65 (m, 6H), 2.20-2.10 (m, 2H), 1.85-1.77 (m, 2H), 1.45-1.10 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a stirred solution of 2-bromo-5-chlorobenzoic acid (8 g, 34.0 mmole) in dichloromethane (35 mL) was added DMF (1 mL) and oxalyl chloride (3.54 mL, 37.4 mmol) drop wise at 0° C. After complete addition, the reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure to furnish 2-bromo-5-chloro-benzoyl chloride (8.5 g). The crude product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[C:34](Cl)=[N:35][CH:36]=[C:37]([CH:43]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:34]2[C:33]([Cl:32])=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=2)[CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)[CH3:22])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: COc1cccc([C@@H](C)N(CC2CCNCC2c2ccccc2)C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc(OC)c3)C(c3ccccc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a mixture of 119 mg of the crude tert-butyl[(1R)-1-(3-methoxyphenyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 62 mg of ethyl 5,6-dichloronicotinate, and 39 mg of potassium carbonate was added 1.0 mL of DMSO at room temperature, and the mixed solution was stirred at 100° C. overnight. After cooling to room temperature, to the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 132 mg of ethyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinate as a colorless foamy substance. FAB+: 608
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[OH:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2[O:72][N:71]=[C:70]([C:73](O)=[O:74])[CH:69]=2)=[CH:64][CH:63]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:73]([C:70]1[CH:69]=[C:68]([C:65]2[CH:66]=[CH:67][C:62]([OH:61])=[CH:63][CH:64]=2)[O:72][N:71]=1)=[O:74]
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)on1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccc(O)cc2)on1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 26.7 %

Procedure:
DIPEA (65 mg, 0.51 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt. (87 mg, 0.20 mmol) in DMF (1 mL). HOBT (28 mg, 0.20 mmol) and EDCI.HCl (39 mg, 0.20 mmol) were then added at room temperature. After 2 minutes, 5-(4-hydroxyphenyl)-isoxazole-3-carboxylic acid (35 mg, 0.17 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 23 mg (26.7% yield) of 5-(4-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.77%, HPLC Purity: 90.43%, 1H NMR (DMSO-d6): δ 10.1-10.0 (s, 1H), 8.6-8.5 (s, 1H), 8.0-7.6 (m, 5H), 7.5 (bs, 1H), 7.1 (s, 1H), 6.8 (d, 2H), 4.2-4.1 (d, 2H) 3.8-3.7 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 3.2-3.1 (m, 2H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([C:11]1[C:16]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[C:15]([O:22][CH3:23])[C:14]([O:24][CH3:25])=[CH:13][C:12]=1[N+:26]([O-])=O)#[N:10].[OH-].[Na+]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:9]([C:11]1[C:16]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[C:15]([O:22][CH3:23])[C:14]([O:24][CH3:25])=[CH:13][C:12]=1[NH2:26])#[N:10]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(OC2CCC2)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(N)c(C#N)c(OC2CCC2)c1OC
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
A solution of sodium dithionite (27.6 g, 0.144 mol) in water (100 ml ) was added to a solution of 2-cyano-3-cyclobutyloxy-4,5-dimethoxynitrobenzene (4.0 g, 0.0143 mol) and tetra-n-butylammonium chloride (2.33 g, 0.0084 mol) in dichloromethane (100 ml ) and the reaction stirred vigorously for 90 minutes. 2N aqueous sodium hydroxide solution (100 ml) and dichloromethane (100 ml ) were then added and stirring continued for 5 minutes. The aqueous phase was extracted with further dichloromethane (400 ml) and the combined organic extracts dried (MgSO4), filtered and concentrated under reduced pressure to a volume of 50 ml. Ethereal hydrogen chloride was added and the resulting precipitate filtered and washed with diethyl ether. The solid was then partitioned between 2N aqueous sodium hydroxide (50 ml) and dichloromethane (100 ml) and the organic layer dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a yellow oil (2.99 g, 86%). Rf 0.75 (ethyl acetate). MS m/z 266 (MNH4)+.
Reaction SMILES: [CH2:1]([S:3][C:4]([O:6][Si](C)(C)C)=[CH2:5])[CH3:2].[CH2:11]([O:18][CH2:19][CH:20]=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.CO>C1(C)C=CC=CC=1>[CH2:11]([O:18][CH2:19][CH:20]([OH:21])[CH2:6][C:4](=[O:5])[S:3][CH2:1][CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C(O[Si](C)(C)C)SCC
Reactant: O=CCOCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCSC(=O)CC(O)COCc1ccccc1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 21.5 mg (0.05 mmol) of (R)-1 in 3 ml of toluene were added 176 mg (1 mmol) of 1-ethylthio-1-(trimethylsilyl)oxyethene and 150 mg (1 mmol) of α-benzyloxyacetaldehyde at 0° C. After stirring for 2 hours at that temperature, the resultant mixture was poured into 10 ml of a buffer (pH 7) at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give a crude product in a silylated form. The crude product was poured into 10% hydrochloric acid-methanol, and the mixture was purified by silica gel chromatography (eluent: hexane/ethyl acetate=20/1 by volume) to obtain S-ethyl 4-benzyloxy-3-hydroxybutanethioate in a yield of 84%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[C:14](=[O:15])[N:13]3[C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[NH:17][C:18](=[O:19])[C:12]3=[C:11]([CH3:25])[CH:10]=2)[CH:5]=[CH:4][N:3]=1>C(O)(=O)C.[Cu].[Zn]>[CH3:25][C:11]1[CH:10]=[C:9]([S:8][C:6]2[CH:5]=[CH:4][N:3]=[CH:2][N:7]=2)[C:14](=[O:15])[N:13]2[C:16]3([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[NH:17][C:18](=[O:19])[C:12]=12
Reactant: Cc1cc(Sc2ccnc(Cl)n2)c(=O)n2c1C(=O)NC21CCCCC1
Agent: [Cu]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc(Sc2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 6′-((2-chloropyrimidin-4-yl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (6, 0.3 g, 0.80 mmol) in acetic acid (4 mL) is added zinc copper couple (0.5 g). The reaction is stirred at reflux for 4 h. The resulting mixture is cooled to room temperature, filtered and concentrated. The crude is purified via column chromatography to afford 8′-methyl-6′-(pyrimidin-4-ylthio)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 210).