Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@@H:10]([NH:25]C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>ClCCl>[OH:40][C:34]([C:36]([F:39])([F:38])[F:37])=[O:35].[CH2:1]([O:8][C:9]([C@@H:10]1[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[N:25]1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2=N[C@H](C(=O)OCc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of (2S)2-tert-butoxycarbonylamino-5-(3,4-dimethoxy-phenyl)-5-oxo-pentanoic acid benzyl ester (10.46 g, 0.023 mol) in dichloromethane (150 ml) was cooled to 0° C. in an ice bath. TFA (40 ml) was slowly added to the stirring mixture and the reaction was allowed to warm to room temperature over two hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and the pH was adjusted to 7 with 1N NaOH. The organic extract was washed with brine (100 ml). The ethyl acetate extract was dried over anhydrous Na2SO4 and concentrated in vacuo to afford (2S)5-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid benzyl ester TFA salt (7.24 g, 0.021 mol, 91% yield). MS (LC-MS): Calculated for C20H21NO4 339.15, found 340.16 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
To a solution of 2-nitro-5-fluorophenol (1.0 g, 1 eq, 6.36 mmol) and ethyl 2-bromopropionate (0.91 ml, 1.1 eq, 6.99 mmol) in dry acetone (32 ml) was added anhydrous potassium carbonate (2.63 g, 3 eq, 19.08 mmol) and the reaction mixture was refluxed for 16 h. The reaction mixture was filtered through celite and then condensed on rotavapour. The residue was diluted with ethyl acetate and washed with water and brine to yield ethyl 2-(2-nitro-5-fluorophenoxy)propanoate as crude compound (1.6 g, yield 98%), which was used in step (ii).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)=[O:4].[BH4-].[Na+]>C(Cl)Cl>[F:1][C:2]([F:17])([F:18])[CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[OH:4]
Reactant: COc1ccc2cc(C(=O)C(F)(F)F)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2cc(C(O)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.1 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethanone (1 g, 3.9 mmol) and NaBH4 (312 mg, 7.8 mmol, 2 eq) in DCM (20 mL) was stirred at room temperature for 5 h. The reaction mixture was quenched with water (5 mL), washed with brine (10 mL*2), dried over Na2SO4 and concentrated to give 2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethanol (800 mg, yield: 80%) as a white solid. ESI-MS (M+1)+: 255.1. 1HNMR (400 MHz, CDCl3) δ: 7.80 (s, 1H), 7.72-7.68 (m, 2H), 7.46 (d, J=8.4 Hz, 1H), 7.13-7.07 (m, 2H), 5.09 (q, J=6.4 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.Cl.[NH2:42][C:43]1[C:51]([NH2:52])=[CH:50][CH:49]=[CH:48][C:44]=1[C:45]([NH2:47])=[O:46].C(O)(C)C>N1C=CC=CC=1.CN(C=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]3([C:25](=[O:26])[NH:52][C:51]4[CH:50]=[CH:49][CH:48]=[C:44]([C:45](=[O:46])[NH2:47])[C:43]=4[NH2:42])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCC1c2ccccc2-c2ccccc21
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: c1ccncc1
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)CCCCC2)c1N
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 1-(9H-fluoren-9-ylmethoxycarbonyl amino)-cyclohexanecarboxylic acid (0.326 g, 0.9 mmol) in pyridine (1 mL) and DMF (1 ml) was heated to 40° C. for 30 min. Carbonyl diimidazole (0.15 g, 0.9 mmol) was added and the mixture was stirred at 40° C. for 1 hour then treated with 2,3-diamino-benzamide dihydrochloride (prepared as described in WO0026192, 0.2 g, 0.9 mmol). After stirring for 1 hour at room temperature, isopropyl alcohol (3 ml) was added and the solution was cooled overnight at 0° C. The precipitated solid was filtered, dissolved in water (3 ml), treated with 50% aqueous NaOH (0.071 ml) then stirred for 3 hours at room temperature. The mixture was filtered and used immediately in Example 48B.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)C(=O)Cl
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Methyl chloro(oxo)acetate (0.842 mL) was added to a stirred solution of methyl [trans-4-(4-aminophenyl)cyclohexyl]acetate (1740 mg) and pyridine (0.689 mL) in DCM (50 mL) at 0° C. After the addition was complete the mixture was allowed to warm to ambient temperature and stirred for 64 hours. The solution was diluted with DCM (100 mL), washed with water (50 mL) and brine (50 mL), then dried and concentrated in vacuo to give the title compound (2267 mg) as a solid; 1H NMR δ 7.60 (2H, d), 7.18 (2H, d), 3.83 (3H, s), 3.58 (3H, s), 2.58-35 (1H+DMSO, m), 2.21 (2H, d), 1.75 (5H, m), 1.43 (2H, m), 1.12 (2H, m); MS m/e MH− 332.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][CH3:14])=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=2.[F:16][C:17]([F:22])([F:21])[C:18](O)=O.[OH-].[NH4+]>Cl>[CH3:14][N:13]1[C:12]2[C:11]3[CH:10]=[C:9]([CH3:15])[CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:2]=[C:18]1[C:17]([F:22])([F:21])[F:16]
Reactant: CNc1c(N)cnc2ccc(C)cc12
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2ncc3nc(C(F)(F)F)n(C)c3c2c1

Procedure:
A mixture of 4.5 g (0.0201 mole) of 3-amino-6-methyl-4-(methylamino)quinoline hydrochloride (from Example 32), 9.1 g (0.080 mole) of trifluoroacetic acid and 100 ml of 4 N hydrochloric acid was heated at its reflux temperature for three hours. The solution was cooled and basified with ammonium hydroxide. The precipitate was separated by filtration and washed with water. Recrystallization from isopropanol provided 1,8-dimethyl-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline, m.p. 220°-223° C. Analysis: Calculated for C13H10F3N3 : %C, 58.9; %H, 3.8; %N, 15.8; Found: %C, 58.6; %H, 3.7; %N, 16.2.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:30])([CH3:29])[C:14]([O:16][CH2:17][O:18][C:19](ON1C(=O)CCC1=O)=[O:20])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][C:13]([CH3:30])([CH3:29])[C:14]([O:16][CH2:17][O:18][C:19]([CH:10]([NH2:11])[C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:20])=[O:15]
Reactant: CC(C)(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)C(N)[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]methyl 2,2-dimethylpropanoate (547 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 6 (476 mg, 76% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 2H), 1.13 (s, 9H), 1.17-1.38 (br. m, 3H), 1.64-1.72 (br. m, 2H), 1.82-1.91 (br. m, 2H), 2.09 (tt, J=12.0, 3.6 Hz, 1H), 2.78-2.87 (br. m, 2H), 5.61 (s, 2H), 7.54 (t, J=5.6 Hz, 1H), 11.98 (br. s, 1H). MS (ESI) m/z 316.11 (M+H)+; 314.01 (M−H)−.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)=[N:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)=[N:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1O
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nnc(-c3cc(OC)nc(C4CCCC4)c3)o2)cc(C)c1OC[C@@H](O)CO
Temperature: 70 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-phenol (100 mg, 264 μmol) and (S)-3-chloro-propane-1,2-diol (244 mg, 2.64 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at 70° C. for 48 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (86 mg) as a white solid; LC-MS**: tR=0.83 min, [M+H]+=454.12; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.65-1.80 (m, 2H), 1.83-1.96 (m, 4H), 2.05-2.15 (m, 2H), 2.42 (s, 3H), 2.78 (q, J=7.3 Hz, 2H), 3.19-3.30 (m, 1H), 3.82-3.99 (m, 4H), 4.02 (s, 3H), 4.15-4.23 (m, 1H), 7.22 (s, 1H), 7.48 (s, 1H), 7.84 (s, 1H), 7.86 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:30][CH:29]([O:31][CH2:32][CH:33]=[CH2:34])[CH2:28][C@H:24]1[C:25](O)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:35]([O:39][C:40](=[N:46][NH:47][C:48]([NH2:50])=[O:49])[CH2:41][CH:42]([NH2:45])[CH:43]=[O:44])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40](=[N:46][NH:47][C:48]([NH2:50])=[O:49])[CH2:41][C@H:42]([NH:45][C:25](=[O:26])[C@@H:24]1[CH2:28][C@@H:29]([O:31][CH2:32][CH:33]=[CH2:34])[CH2:30][N:23]1[C:21](=[O:22])[C@H:17]([CH:18]([CH3:19])[CH3:20])[NH:16][C:14](=[O:15])[C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2])[CH:43]=[O:44])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(CC(N)C=O)=NNC(N)=O
Reactant: C=CCOC1C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(C)=O)C(C)C)C1
Product: C=CCO[C@@H]1C[C@@H](C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C)N(C(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(C)=O)C(C)C)C1
Yield: 20 %

Procedure:
N-Acetyl-tyrosinyl-valinyl-(4-allyloxyproline) methyl ester (770 mg, 1.57 mmol) was dissolved in 20 ml of tetrahydrofuran and 4 ml of methanol. Lithium hydroxide (145 mg, 3.46 mmol) was added to the mixture and stirred at room temperature. After two hours, 1 ml of 10% hydrogen chloride was added and the mixture evaporated in vacuo to give a solid residue then partitioned between Sml of water and 50 ml of ethyl acetate and the organic layer separated and evaporated in vacuo to give 430 mg of the acid that waa used immediately in the next step. N-Acetyl-tyrosinyl-valinyl-4-allyloxyproline (420 mg, 0.88 mmol) and 3-amino-4-oxobutyric acid tert-butyl ester semicarbazone (184 mg, 0.8 mol, Graybill et al., Int. J. Protein Res., 44, pp. 173-82 (1994)) to give 100 mg (20%) of the title compound as a white amorphous solid: 1H NMR (CD3OD) δ7.24-7.2 (1H, m), 7.04-6.97 (2H, d), 6.73-6.65 (2H, d), 5.98-5.86 (1H, m), 5.35-5.24 (1H, d), 5.17-5.12 (1H, m), 4.12-3.98 (2H, m), 3.72-3.67 (1H, m), 2.98-2.92 (3H, m), 2.38-2.32 (1H, m), 2.1-2.02 (2H, m), 1.92 (3H, s), 0.98-0.89 (6H, 2×d).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=1[NH:10]2.C1C=[N:22]C2N(O)N=NC=2C=1.C(Cl)CCl.N>C1COCC1.O.CCOC(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:22])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=1[NH:10]2
Reactant: On1nnc2cccnc21
Reactant: O=C(O)c1ccc(Br)c2c3c([nH]c12)CCCC3
Agent: N
Solvent: O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CCCC3
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-bromo-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (Intermediate 46-3, 70% purity, mixed with Intermediate 47-3 from an incomplete reaction done according to the procedure used to prepare Intermediate 47-1; 3 g, 7.14 mmol) in THF (80 mL) and DCM (20 mL) was treated with HOAT (1.166 g, 8.57 mmol) and EDC (1.642 g, 8.57 mmol). The mixture was stirred at rt for 2.5 h, then was treated with anhydrous ammonia gas for ca. 2 min, forming a very thick slurry. The mixture was stirred for 30 min, then was treated again with ammonia gas for ca. 1 min. After stirring for another hour, the mixture was diluted with water and EtOAc (dissolving the solid). The layers were separated and the aqueous phase was extracted again with EtOAc. The combined organic layers were washed twice with 0.1 M aqueous sodium hydroxide, then with 1 M hydrochloric acid and brine, dried and concentrated to provide 5-bromo-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a pale orange-tan solid (2.47 g, 84%, including the product from the incomplete reaction yielding the starting material). 1H NMR (400 MHz, DMSO-d6) δ 10.95 (1H, s), 8.02 (1H, br. s.), 7.44 (1H, d, J=7.9 Hz), 7.38 (1H, br. s.), 7.14 (1H, d, J=8.1 Hz), 2.99 (2H, br. s.), 2.75 (2H, br. s.), 1.78 (4H, br. s.). Mass spectrum m/z 293, 295 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[CH3:11][NH:10][C:8]([C:4]1[CH:3]=[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[CH:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1)=[O:9]
Reactant: Nc1ccc(O)cc1
Agent: CNC(=O)c1cc(Cl)ccn1
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[NH:13][C:12](=S)[C@:11]([F:16])([CH3:15])[CH2:10][C:9]2([F:18])[F:17])[CH:7]=1.CO.[NH3:23]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[N:13]=[C:12]([NH2:23])[C@:11]([F:16])([CH3:15])[CH2:10][C:9]2([F:18])[F:17])[CH:7]=1
Reactant: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)NC1=S
Reactant: N
Solvent: CO
Product: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)N=C1N
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (750 mg, 2.44 mmol) was dissolved in 7M ammonia in methanol (36 ml, 252 mmol). The reaction mixture was stirred in a sealed vial at 60° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethyl-3,4,5,6-tetrahydropyridin-2-amine (708 mg, 2.448 mmol, 100% yield) as a pale yellow solid that was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:38][C@H:39]1[NH:45][CH2:44][C@@H:43]([CH3:46])[CH2:42][NH:41][C:40]1=[O:47]>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:45]1[CH2:44][C@@H:43]([CH3:46])[CH2:42][NH:41][C:40](=[O:47])[C@H:39]1[CH3:38])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CNC(=O)[C@@H](C)NC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC#N
Product: C[C@H]1CNC(=O)[C@@H](C)N(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 120 mg, 0.36 mmol) in acetonitrile (10 mL) was added HOBT (60 mg, 0.43 mmol) and EDC (75 mg, 0.4 mmol). The reaction was stirred at room temperature for 1 h and then treated with (3R,6R)-hexahydro-3,6-dimethyl-2H-1,4-diazepin-2-one (Intermediate 23, 50 mg, 0.35 mmol). The reaction was stirred at room temperature overnight. After removal of solvent, the crude product was purified by flash chromatography on a Biotage® system (silica, 6% methanol in dichloromethane) to yield the title compound as white solid. MS (M+1−Boc): 358.0
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:20][C:21]1[C:28]([F:29])=[C:27]([C:30]([F:33])([F:32])[F:31])[C:26]([F:34])=[C:25]([F:35])[C:22]=1[CH2:23]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH:14]1([C:12]([O:11][C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:23][C:22]3[C:25]([F:35])=[C:26]([F:34])[C:27]([C:30]([F:31])([F:33])[F:32])=[C:28]([F:29])[C:21]=3[F:20])=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc(OC(=O)C2CCCCC2)c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1OC(=O)C1CCCCC1
Yield: 49 %

Procedure:
According to the similar procedure in Synthesis Example (14-4), by using 5-amino-2-cyclohexanecarbonyloxybenzoic acid (1.03 g, 3.95 mmole) which was prepared from Synthesis Example (16-2), DMF (15 ml), TEA (0.10 ml), tetrabutyl ammonium iodide (10 mg), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.01 ml, 5.92 mmole), 0.95 g (49.0% yield) of was obtained 2-cyclohexanecarbonyloxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[NH:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[NH:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CCl
Reactant: CC1NC(=O)NN=C1c1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.00 g of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-5-methyl-1,2,4-triazin-3(2H)-one [prepared as described in Example 2(a)] were added, whilst ice-cooling, to a stirred suspension of 364 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 30 ml of anhydrous dimethylformamide. The mixture was then stirred at room temperature for 30 minutes, after which 0.89 ml of ethyl chloroacetate was added, and the mixture was stirred at 105°-110° C. (bath temperature) for 1.5 hours. The dimethylformamide used as the solvent was removed by evaporation under reduced pressure, and water and ethyl acetate were added to the resulting residue. The crystals which precipitated were collected by filtration, washed with ethyl acetate and dried to give the title compound as a pale yellowish-brown powder melting at 187°-189° C. (with decomposition). The ethyl acetate layer of the filtrate was separated, washed with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure to give crystals, which were collected by filtration, washed with ethyl acetate and dried to give more of the title compound. The total yield was 2.11 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.Br[CH:15]1[CH2:20][CH2:19][CH:18]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1>[Zn].[Ni](Cl)Cl.O1CCCC1>[CH2:27]([C@H:24]1[CH2:25][CH2:26][C@H:21]([C@H:18]2[CH2:19][CH2:20][C@H:15]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[CH2:16][CH2:17]2)[CH2:22][CH2:23]1)[CH2:28][CH3:29]
Reactant: CCC[C@H]1CC[C@H](C2CCC(Br)CC2)CC1
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(S(F)(F)(F)(F)F)cc3)CC2)CC1

Procedure:
A mixture of 18.3 g of 4-bromophenyl-sulfur pentafluoride and 50 ml of tetrahydrofuran is added to a mixture of the organozinc compound prepared from 28.7 g of 1-bromo-4-(trans-4-propylcyclohexyl)-cyclohexane and 7 g of zinc, 13 g of nickel(II) chloride and tetrahydrofuran, and the mixture is heated at the boil for 5 hours. Working up in the customary manner gives 4-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-phenyl-sulfur pentafluoride.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH:29]([OH:41])[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[C:27]([CH:42]([CH3:44])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:47])[CH2:22][C:23]([CH3:46])([CH3:45])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@H:29]([OH:41])[C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:34][CH:35]=3)=[C:27]([CH:42]([CH3:43])[CH3:44])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:47])[CH2:22][C:23]([CH3:45])([CH3:46])[O:24]3)=[CH:15][CH:14]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
140 μl (800 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 4.45 mg (30 μmol) of (1R,2S)-1-aminoindan-2-ol in 5 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 100 mg (200 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 24A) in 5 ml of tetrahydrofuran is then slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) gives the diastereomerically pure target compounds.