Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[OH-]>[Ni].C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCC1CCN(Cc2ccccc2)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCCCC1CCN(Cc2ccccc2)CC1
Yield: 78.6 %

Procedure:
A mixture of 3-(1-benzylpiperidin-4-yl)propanenitrile (0.5 g), Raney nickel (0.3 ml) and a conc. ammonia aqueous solution (1 ml) in ethanol (10 ml) was hydrogenated at atmospheric pressure for 6 hours. After Raney nickel was removed by filtration, the filtrate was evaporated in vacuo. The residue was chromatographed on alumina eluting with 2% methanol in chloroform and the fractions containing the object product were collected and evaporated to give 3-(1-benzylpiperidin-4-yl)propylamine (0.4 g) as an oil.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C.C(OC(C1C(NC(OCC2C=CC=CC=2)=O)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH2:19]([NH:18][C:16](=[O:17])[NH:15][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:8]1[C:6]([OH:7])=[O:5])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)NCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)NCc3ccccc3)C2C(=O)O)cc1

Procedure:
3-(3-Benzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (25 mg, 0.05 mmol) is reacted in the same manner as 3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester and purified by flash-chromatography, Dichloromethane/Methanol (9:1): Cal. 459.5 found (M−H)+ 458.2; 1H NMR (DMSO, 400 MHz), ppm: 7.79 (d, 2H), 7.30 (m, 2H), 7.20 (m, 3H) 7.02 (d, 2H), 5.60 (m, 1H), 5.50 (m, 1H) 4.3 (m, 3H), 4.00 (m, 1H), 3.93 (m, 3H), 2.81 (t, 2H), 2.35 (m, 2H), 2.05 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:26][O:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)([OH:24])=[O:23]
Reactant: COC(=O)CCCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 194.5 %

Procedure:
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(pyridin-3-yloxy)propanamide (12.3 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(6-carboxyhexyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (12.5 mg).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[CH:33][C:32]=2[Cl:39])=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:36]=[C:35]([Cl:37])[C:34]([OH:38])=[CH:33][C:32]=4[Cl:39])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)cc4Cl)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)cc4Cl)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-(cyclopropanecarbonyl)-6-(2,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (57 mg, 0.100 mmol) was reacted with TFA (2 mL) to afford the desired product (10.8 mg, 23%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.23 (s, 1H), 8.27 (d, J=1.6 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.87 (dd, J=8.7, 1.7 Hz, 1H), 7.48 (s, 1H), 7.12 (s, 1H), 4.27-4.14 (m, 1H), 3.27-3.18 (m, 1H), 2.95-2.82 (m, 1H), 2.34 (d, J=11.5 Hz, 2H), 2.14 (d, J=10.7 Hz, 2H), 1.72-1.59 (m, 2H), 1.59-1.48 (m, 2H), 1.26-1.16 (m, 2H), 1.16-1.07 (m, 2H); ESI MS m/z 470 [C25H25Cl2N3O2+H]+; HPLC 96.4% (AUC), tR=10.67 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
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: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 79.9 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (720 mg, 2.0 mmol), 4-(methanesulfonyl)phenylboronic acid (600 mg, 3.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (347 mg, 0.3 mmol) in dioxane (6 mL) was added 2 M sodium carbonate solution in water (4 mL, 8 mmol). The resulting mixture was subjected to microwave irradiation for 60 min at 110° C. The mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(4′-methanesulfonyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (696 mg, 80%) as a white solid: LC/MS m/e calcd for C25H25NO4S (M+H)+: 436.55, observed: 436.1.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:57])C(=O)C1>CC#N>[Br:57][C:36]1[N:37]2[C:12]3[N:13]4[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]5[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=5[C:30]5[CH:43]=[C:34]([C:35]=1[N:42]=[C:38]2[CH:39]=[C:40]([CH3:41])[C:11]=3[C@H:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[CH:33]=[CH:32][CH:31]=5)[CH2:15][CH2:14]4
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (50 mg, 0.074 mmol, 1 equiv) in MeCN (1.5 mL) was added NBS (13 mg, 0.074 mmol, 1 equiv). After 1 h, the reaction was concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (40 mg, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.16 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 6.97 (d, J=10.3 Hz, 1H), 6.85 (d, J=6.5 Hz, 1H), 4.58-4.37 (m, 2H), 3.82-3.66 (m, 4H), 3.64-3.55 (m, 1H), 3.46-3.38 (m, 1H), 2.47 (br. s., 3H), 2.30 (d, J=0.8 Hz, 4H), 1.98-1.69 (m, 8H), 1.66-1.48 (m, 4H), 1.31-1.26 (m, 7H), 1.24 (d, J=5.8 Hz, 8H), 1.15 (d, J=6.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[NH2:46][C:43]1[CH:44]=[CH:45][C:40]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=3)=[O:10])=[C:4]([C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[CH:3]=2)=[CH:41][CH:42]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)cc2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the Example 11, step (f), 30 mg, 0.060 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (14.4 mg, 0.066 mmol) and Pd(PPh3)4 (7 mg, 0.006 mmol) in 1 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (0.24 mL, 0.48 mmol). The resulting mixture was stirred at 80° C. for 3 h under Ar, and then cooled to RT. Treated with 50 μL of EtOAc, the mixture was washed with H2O (2×20 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20% EtOAc/hexane) gave 16 mg (85%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.76 (s, 1H), 8.37 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.43-7.47 (m, 3H), 7.35 (d, 1H, J=2.1 Hz), 6.84 (d, 2H, J=8.5 Hz), 5.97 (s, 2H), 5.89 (m, 1H), 3.67 (t, 2H, J=8.2 Hz), 2.25-2.34 (m, 4H), 1.77-1.90 (m, 4H), 0.98 (t, 2H, J=8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C29H35N5O2Si, 514.3 (M+H), found 514.1.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33]([C:27]5([OH:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:34])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1(O)CCCCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1(O)CCCCC1

Procedure:
The title compound, white solid (14.9 mg, 39.9%), MS (ISP) m/z=457.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 1-hydroxycyclohexanecarboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:14])=[N:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reaction time: 12 h
Yield: 47.7 %

Procedure:
To a solution of 3-[2-(3,3-dicyclohexylureido)-thiazol-5-yl]-acrylic acid ethyl ester (Example 257) (75 mg, 0.18 mmol) in methanol was added Pd/C (150 mg). The content was degassed and was placed under hydrogen atmosphere for 12 h. The mixture was filtered through celite, and the filtrate was concentrated. The residue was further purified by flash chromatography (silica, CH2Cl2-EtOAc 4:1 to give 3-[2-(3,3-dicyclohexylureido)-thiazol-5-yl]-propionic acid ethyl ester (35 mg) in 47% yield.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[C:13]1([C:19]2[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[O:22][CH2:23][C:24]=2[CH2:25][C:26]([OH:28])=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrCCCC.Cl>O1CCCC1.CCCCCC.CCCCC.O>[C:13]1([C:19]2[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[O:22][CH2:23][C:24]=2[CH:25]([CH2:8][CH2:9][CH2:10][CH3:11])[C:26]([OH:28])=[O:27])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [Li]CCCC
Reactant: O=C(O)CC1=C(c2ccccc2)c2ccccc2OC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCCCCC
Product: CCCCC(C(=O)O)C1=C(c2ccccc2)c2ccccc2OC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
3.1 ml (22 mmol) of diisopropylamine in solution in 20 ml of tetrahydrofuran are placed in a 250-ml reactor protected from moisture, and then 13.75 ml (22 mmol) of n-butyllithium in hexane (1.6 M) are added dropwise to this solution kept at 0° C. After stirring the reaction medium for 15 minutes at 0° C., 2.66 g (10 mmol) of 2-(4-phenyl-2H-3-benzo[b]-pyranyl)acetic acid are added dropwise to this solution kept at 0° C. The reaction medium is stirred for 2 hours at 0° C. and then 1.18 ml (11 mmol) of 1-bromobutane are poured into this solution kept at this temperature of 0° C. The reaction mixture is stirred for 72 hours at room temperature. After addition of water and hydrochloric acid (2 M), the reaction mixture is extracted with diethyl ether. The organic phase, after washing with water, is dried and then evaporated off. The oil obtained is chromatographed on a silica gel (eluent: methylene chloride). After evaporation of the solvent, the crystals obtained are dispersed in pentane and then drained. 1.7 g of the expected compound are thus obtained, that is to say a yield of 52.8%. This compound has a melting point of between 117 and 119° C.
Reaction SMILES: CO[C:3]([C:5]1[C:10](F)=[CH:9][CH:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O>[Cl:12][C:7]1[N:6]=[C:5]([CH2:3][OH:4])[C:10]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1nc(Cl)ccc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1nc(Cl)ccc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-chloro-3-fluoropyridin-2-carboxylic acid methyl ester (245 mg) in dimethylformamide (3 ml), 200 mg of phenol and 393 mg of potassium carbonate were added, and the reaction solution was stirred at 100° C. for 1.5 hours. The reaction solution was cooled, then 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a brown oil. To a solution of the crude product in toluene (5 ml), 9.9 ml of diisobutylaluminum hydride (1.0M hexane solution) was added at −78° C., and the reaction solution was stirred for 2 hours while increasing the temperature of the reaction solution to room temperature. To the reaction solution were added water and 10% aqueous citric acid sequentially, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50:50)) to afford the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH:5]=[CH:6][C:7]=1[F:8].Br>>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.5 %

Procedure:
(2R,4S)-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.7 g, 5.03 mmol) was dissolved in hydrobromic acid (33% in AcOH, 25 mL, 151.92 mmol) and stirred at room temperature for 20 h. The solvent was evaporated in vacuo. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. The compound was repurified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. 5-((2R,4S)-2-(3,4-difluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (0.923 g, 65.5%) was isolated as a white solid. 1H NMR (600 MHz, cd3od) δ 1.66-1.76 (m, 2H), 2.09 (d, 1H), 2.19 (d, 1H), 2.96-3.07 (m, 2H), 3.28-3.35 (omitted signals), 3.90-3.95 (m, 1H), 5.65 (s, 1H), 7.20-7.29 (m, 2H), 7.34-7.39 (m, 1H). HRMS Calcd for [C14H14F2N2O2+H]+: 281.1101. Found: 281.1106.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][C:20]1([NH:28]C(=O)OC(C)(C)C)[CH2:25][O:24]C(C)(C)[O:22][CH2:21]1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)OCC(NC(=O)OCCCC)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:28][C:20]([CH2:19][N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH2:15]1)([CH2:21][OH:22])[CH2:25][OH:24]
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4ccccc4)ccc3C2)COC(C)(C)OC1
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OCCCC)COC(C)(C)OC2)cc1
Product: NC(CO)(CO)CN1CCc2cc(OCc3ccccc3)ccc2C1
Yield: 71 %

Procedure:
When the product of Step E was substituted for tea-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 71% yield, as a creamy solid. 1H-NMR (CDCl3) 2.5-2.9 (m, 10H+H2O); 3.4-3.6 (m, 4H); 3.72 (s, 2H); 5.01 (s, 2H); 6.6-6.8 (m, 2H); 6.81-6.95 (m, 1H); 7.25-7.45 (m, 5H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]2[N:12]([N:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[C:13]([I:16])=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:11]2[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[C:13]([I:16])[N:12]2[N:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(I)n2nc(C(F)(F)F)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(I)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
The compound of Example 92 (4.57 g) was dissolved in tetrahydrofuran (50.0 mL). While this solution was chilled in an ice bath, 1.0 mol/L tetran-butyl ammonium fluoride/tetrahydrofuran solution (12.0 mL) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, water was added and the reaction mixture was extracted with ethylacetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (hexane:ethyl acetate=2:1) afforded the title compound as a pale yellow powder (3.26 g).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2N=N1.[Br:14][C:15]1[C:16]([CH3:25])=[C:17]([C:21]([OH:24])=[CH:22][CH:23]=1)[C:18](O)=[O:19].NC1C=CC=CC=1>C(Cl)Cl.C1COCC1.CCOC(C)=O>[Br:14][C:15]1[C:16]([CH3:25])=[C:17]([C:21]([OH:24])=[CH:22][CH:23]=1)[C:18]([NH:5][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1)=[O:19]
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1c(Br)ccc(O)c1C(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Br)ccc(O)c1C(=O)Nc1ccccc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
Step 3 Thionyl chloride (0.111 mL, 1.524 mmol) was added to a solution of benzotriazole (594 mg, 4.99 mmol) in DCM (8 mL) at rt and the mixture was stirred for 30 min. A solution of 3-bromo-6-hydroxy-2-methylbenzoic acid (320 mg, 1.385 mmol) in THF (8.00 mL) was added and the mixture was stirred at rt for 2 hrs. The mixture was filtered and the solid was washed with DCM (3 mL). The filtrate was concentrated, and the residue was dissolved in aniline (2 g, 21.48 mmol) and heated in a sealed tube by microwave irradiation at 150° C. for 10 min. The mixture was diluted with EtOAc (100 mL) and washed with 2 M hydrochloric acid (20 mL), water (10 mL) and brine (10 mL), dried and concentrated. The residue was triturated with DCM (4 mL) to give the 3-bromo-6-hydroxy-2-methyl-N-phenylbenzamide as light-colored solid (290 mg, 68%). Mass spectrum m/z 306, 308 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:24]1=[CH:25][C:26]2[C:27]([CH:32]([O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:34]1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C.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>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:24]1=[CH:25][C:26]2[C:27]([CH:32]([O:35][Si:36]([CH:40]([CH3:42])[CH3:41])([CH:43]([CH3:45])[CH3:44])[CH:37]([CH3:38])[CH3:39])[CH2:33][CH2:34]1)=[N:28][CH:29]=[CH:30][CH:31]=2
Reactant: CC(C)[Si](OC1CCC(OS(=O)(=O)C(F)(F)F)=Cc2cccnc21)(C(C)C)C(C)C
Reactant: OB(O)c1cccc(F)c1F
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: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC1CCC(c2cccc(F)c2F)=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 80 °C
Yield: 41.5 %

Procedure:
The mixture of 2,3-difluorophenylboronic acid (0.936 g, 5.93 mmol), sodium carbonate (4.57 mL, 9.14 mmol), (E)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridin-6-yl trifluoromethanesulfonate (2.3 g, 4.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.285 g, 0.247 mmol) in toluene (30 mL) and MeOH (6 mL) was heat to 80° C. under N2 for 3 hours. LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed with water one time. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column by ethyl acetate in hexane from 0 to 25% afforded the desired product (0.8797 g, 54%). MS(ESI)[M+H+]=430.43.