Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([CH2:12][CH2:13][P:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:42]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH2:50])=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([C:9](=[O:11])[NH:50][CH2:49][CH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:43][CH:44]=1)[CH2:12][CH2:13][P:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(CCP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Reactant: NCCc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC(CCP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)NCCc1ccc(-c2ccccc2)cc1

Procedure:
A solution of the compound of Example 77 (770 mg, 1.67 mmol) in anhydrous DMF (2 mL) was treated with DIEA (1.5 mL), 4-biphenylethyl amine (672 mg, 3.34 mmol), and TBTU (775 mg, 2.34 mmol). The reaction mixture was stirred for 24 h at room temperature after which HCl (1M, excess) was added. The mixture was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed with 50% ethyl acetate in hexanes and the desired product was obtained as a white solid. 1H NMR (CDCl3, 400 MH: 1.41(s, 9H); 1.61–1.87(m, 4H); 2.15, 2.59(2dd, J1=16.4 Hz. J2=4.2 Hz, 2H); 2.67(m, 1H); 2.80(m, 2H); 3.49(m, 2H); 4.96(m, 4H); 6.35(t, J=5.6 Hz); 7.32(m, 13H); 7.42(m, 2H); 7.55(m, 4H); 31P NMR(CDCl3, 400 MHz): 33.05.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.O1CCCC1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:1]([NH:4][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCN
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
First, 10 g of propylamine, 26 g of triethylamine, and 200 mL of tetrahydrofuran (THF) were put in a 500 mL three-neck flask, and stirred. This mixed solution was cooled in ice, and a mixed solution of 24 g of benzoyl chloride and 50 mL of THF was dripped, and then, the temperature was increased to room temperature and the mixture was stirred for 2 hours. After the stirring, chloroform was added to this mixture, the mixture was washed with water and then a saturated aqueous solution of sodium hydrogen carbonate, and anhydrate magnesium sulfate was added for drying. The mixture after the drying was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with hexane, so that 25 g of N-propylbenzamide was prepared as a white solid with a yield of 92%. The synthetic scheme of Step 1 is shown by (a-15).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8]>N.CO>[NH2:11][CH2:10][C:4]1[C:5](=[O:9])[NH:6][C:7]([CH3:8])=[C:2]([F:1])[C:3]=1[CH3:12]
Reactant: Cc1[nH]c(=O)c(C#N)c(C)c1F
Agent: N
Solvent: CO
Product: Cc1[nH]c(=O)c(CN)c(C)c1F
Yield: 41 %

Procedure:
A solution of 0.05M 5-fluoro-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (731 mg, 4.4 mmol) in 1.75M NH3/MeOH (87 ml) was passed through the H-Cube flow hydrogenator at 80° C. and 50 bar at a flow rate of 1 ml/min. The resulting solution was concentrated in-vacuo. The resulting solid was split into 2 batches and 350 mg of the crude product was purified by column chromatography (25 g SNAP cartridge, Isolera, 0-25% MeOH (containing 10% NH4OH):CH2Cl2) to give the title compound (307 mg, 20%) as an off white solid and a 1:1 mixture of product:starting material. LC-MS (ELS) 100%, m/z=170.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 3.79 (s, 2H) 2.31 (d, J=2.84 Hz, 3H) 2.25 (d, J=2.05 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[N:13]([CH3:24])[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]2[N:13]([CH3:24])[C:12]3[CH:25]=[CH:26][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41](=[O:48])[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(N)c3)ccc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(NC(=O)c4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To [5-(2-amino(4-pyridyloxy))-1-methylbenzimidazol-2-yl] (4-chlorophenyl)amine (1 eq) in tetrahydrofuran added EDC (2 eq) and HOAT (1 eq) and N,N-disopropylethylamine (4 eq) and benzoic acid (1 eq) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was then dried with sodium sulfate and concentrated and purified by preparative chromatography to give N-[4-({2-[(4-chlorophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]benzamide. MS: MH+=470.9.
Reaction SMILES: N1([C:10]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)=[O:11])C2C=CC=CC=2N=N1.CCOCC.[Mg+2].[Br-].[Br-].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH2:38][C:10]([CH:12]2[CH2:13][C:14]([CH3:20])([CH3:21])[O:15][C:16]([CH3:18])([CH3:19])[CH2:17]2)=[O:11])=[CH:33][CH:32]=1
Reactant: CC1(C)CC(C(=O)n2nnc3ccccc32)CC(C)(C)O1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC1(C)CC(C(=O)CC(=O)c2ccc(Cl)cc2)CC(C)(C)O1
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a mixture of benzotriazol-1-yl-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-methanone (1.00 g, 3.13 mmol), magnesium bromide diethyl etherate (1.62 g, 6.26 mmol), and 1-(4-chloro-phenyl)-ethanone (0.39 mL, 2.98 mmol) in 10 mL of DCM at RT was added dropwise DIEA (1.74 mL, 9.40 mmol). The mixture was stirred overnight and then diluted with 50 mL of DCM and washed with 1N HCl (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, concentrated, and the residue purified by flash chromatography on silica gel to give 0.70 g (69%) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:30]([C:27]1[CH:26]=[CH:25][C:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)(=[O:32])=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCc1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CCCCCCCCCCCCCc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Yield: 81 %

Procedure:
N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4-biphenylsulfonamide was prepared, in the same manner as described in Example 2b, from 5-amino-4-tridecyl-3-trifluoromethyl-isoxazole and 4-biphenylsulfonyl chloride in 81% yield. Purification was achieved by recrystallization from methanol/water to give an off white solid, m.p. 115-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]1[O:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][CH2:18][CH:17]([OH:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: Cc1ccccc1C1CO1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNCC(O)c2ccccc2C)cc1OC

Procedure:
Similarly a mixture of 13.6 g. (0.0753 mol) of 3,4-dimethoxyphenethylamine and 10.1 g. (0.753 mol) of o-methylstyrene oxide is stirred at 100° C. under argon for 16 hours to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(2-methylphenyl)ethylamine, m.p. 91°-94° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=2[CH3:29])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.CNC>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]([C:20]3[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH:32][CH3:31])=[CH:22][C:21]=3[CH3:29])[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(=O)O)cc1C
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(=O)NC)cc1C
Yield: 55.1 %

Procedure:
4-(2-(3-Ethoxy-3-oxopropyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (44 mg) was treated with TBTU (42 mg), DPPA (10 μL) and dimethylamine HCl (14 mg) in DCM (4 mL) over 8 h at room temperature. The reaction mixture was diluted with EtOAc (15 mL), washed with 0.5 N HCl (8 mL), saturated NaHCO3 (8 mL), and Brine (8 mL). After removal of solvents, the residue was purified by flash silcal gel chromatography to afford ethyl 3-(5-(4-methoxyphenyl)-1-(2-methyl-4-(methylcarbamoyl)phenyl)-1H-pyrrol-2-yl)propanoate (25 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH2:49][CH2:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[Cl:66])[CH2:55][CH2:54]1)=[O:52]>CN(C=O)C.O>[Cl:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[NH:59][CH:56]1[CH2:55][CH2:54][N:53]([C:51](=[O:52])[CH2:50][NH:49][C:13]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[NH:12][N:11]=2)=[O:15])[CH2:58][CH2:57]1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)[nH]n1
Reactant: NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccc(O)cc2)[nH]n1
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a stirred solution of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid (0.1 g, 0.00049 mol) in DMF (5 mL) was added DIPEA (0.253 g, 0.00196 mol), HOBt (0.0827 g, 0.00061 mol) and EDCI.HCl (0.117 g, 0.00061 mol) at ambient temperature. After 5 minutes 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone dihydrochloride (0.164 g, 0.00054 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and recrystallized from ethyl acetate to afford 0.092 g (41%) of 5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 426.16 (M+1)+, 91.47%, 1H NMR (DMSO-d6): δ 13.5 (s, 1H), 9.7 (s, 1H), 8.0 (s, 1H), 7.58 (d, 2H), 7.1 (m, 2H), 6.8 (m, 4H), 6.56 (m, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.8 (m, 11H), 3.6 (m, 11H), 3.1 (m, 1H), 2.7 (m, 1H), 1.9 (m, 2H), 1.3 (m, 2H)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4o3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-benzoxazole.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([N:13]=[C:14]=S)[N:6]=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH2:24][CH2:25][C@@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([NH:13][C:14]1[O:34][C@:26]3([CH2:25][N:24]=1)[CH:31]1[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]1)[CH2:27]3)[N:6]=[CH:7]2
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: S=C=Nc1cc2c(Cl)c(Cl)ccc2cn1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Clc1ccc2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cc2c1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To 5,6-dichloro-3-isothiocyanatoisoquinoline (0.11 g, 0.431 mmol) in DMF (10 mL) was added cesium carbonate (0.351 g, 1.078 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.100 g, 0.435 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with DMF (10 mL) and N,N′-diisopropylcarbodiimide (0.202 mL, 1.293 mmol). The reaction was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5,6-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.084 g, 0.218 mmol, 50.6% yield) as a yellow powder. 1H NMR (500 MHz, CDCl3) δ ppm 9.09 (s, 1 H), 8.93 (s, 1 H), 7.63-7.82 (m, 2 H), 7.40 (d, J=8.55 Hz, 1 H), 3.99 (d, J=9.16 Hz, 1 H), 3.78 (d, J=8.85 Hz, 1 H), 3.51 (d, J=14.65 Hz, 1 H), 3.30 (d, J=14.65 Hz, 1 H), 2.90-3.23 (m, 4 H), 2.33-2.48 (m, 1 H), 2.29 (s, 1 H), 1.83-1.94 (m, 1 H), 1.62-1.83 (m, J=42.12 Hz, 2 H). MS (LC/MS) R.T.=1.57; [M+H]+=377.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:25].C(OCC)(=O)C>O1CCCC1.O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]([C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:25])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C(C)c2nccn2C(=O)Oc2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 1 (100 mg, 0.5 mmol) in anhydrous tetrahydrofuran (2 ml) was added triethylamine (0.08 ml, 0.6 mmol), followed by 4-fluorophenyl chloroformate (0.26 ml, 2.0 mmol). The reaction mixture was then stirred at room temperature, under nitrogen, for 1 h. To the mixture was added ethyl acetate (10 ml) and water (10 ml) and the two layers were separated. The aqueous layer was washed with ethyl acetate (10 ml) and the combined organic phases were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:19])=[C:6]([C@@:8]([C:14]#[C:15][CH:16]2[CH2:18][CH2:17]2)([C:10]([F:13])([F:12])[F:11])[OH:9])[CH:7]=1.[C:20](Cl)(Cl)=[O:21].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:19][C:20](=[O:21])[O:9][C@:8]([C:14]#[C:15][CH:16]3[CH2:17][CH2:18]3)([C:10]([F:12])([F:13])[F:11])[C:6]=2[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
(S)-5-Chloro-α-(cyclopropylethynyl)-2-amino-α-(trifluoromethyl)benzenemethanol (15.7 kg, 54.3 mol) was dissolved in a mixture of heptanes (32 kg) and THF (52 kg) below -10° C. Phosgene (~8.0 kg, 80 mol) was directly fed below the surface over about 1 h, keeping the temperature below 0° C. The resulting slurry was warmed to 20-25° C. and held 1 hour. Methanol (6.5 kg, 203 mol) was added and the solution stirred about 30 min. Heptanes (97 kg) was added and ~140 L of solvent was distilled under reduced pressure. Heptanes (97 kg) and THF (22 kg) were added and the solution washed with 5% aqueous sodium bicarbonate (15 L), followed by water (15 L). The solution was warmed to 50° C. and filtered into a clean reactor, followed by a 40 kg heptanes rinse. The solution was concentrated under reduced pressure, diluted with heptanes (22 kg) and cooled below -10° C. The product was filtered, washed with heptanes (37 kg) and dried in vacuo at 90-100° C. to give 16.0 kg (95%) as an off-white to slightly pinkish solid. HPLC: 99.8 area %: mp 139-141° C.; [a]25D -94.1° (c 0.300, MeOH); 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J 32 2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19F NMR (282 MHz, DMSO-d6) δ -81.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1Cc2cc(-c3ccccc3)ccc2N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 77.3 %

Procedure:
5-Bromo-2-oxindole (5 g, 23.5 mmol) was dissolved in 110 mL of toluene and 110 mL of ethanol with stirring and a little heating. Tetrakis(triphenylphosphine)-palladium(0) (1.9 g, 1.6 mmol) was added followed by a 2M aq. solution of sodium carbonate (40 mL, 80 mmol). To this mixture benzene boronic acid (3.7 g, 30.6 mmol) was added and the mixture was heated in a 100° C. oil bath. After 12 h, the reaction was diluted with ethyl acetate (500 mL), washed with saturated aq. sodium bicarbonate (200 mL), water (200 mL), 1N HCl (200 mL) and brine (200 mL). The organic layer was dried with magnesium sulfate and concentrated to afford a brown solid. Trituration with dichloromethane and filtering afforded 3.8 g (77%) of a tan solid.
Reaction SMILES: N[C@H](C=O)CCSC.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18].Cl>O1CCCC1>[OH:33][C:30]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:31][CH2:32][CH:27]([CH2:26][CH2:25][C@H:22]2[CH2:21][CH2:20][C@H:19]([CH2:16][CH2:17][CH3:18])[CH2:24][CH2:23]2)[CH2:28][CH2:29]1
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Reactant: Brc1ccccc1
Agent: CSCC[C@H](N)C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](CCC2CCC(O)(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Metal magnesium in an amount of 11.6 g was suspended in 100 ml of tetrahydrofuran (hereinafter referred to as THF) under nitrogen gas stream, and a solution prepared by dissolving 69 g of bromobenzene in 200 ml of THF was added dropwise in the suspension and then stirred at room temperature for 1 hour. A solution prepared by dissolving 100 g of 4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexanone in 300 ml of THF was added dropwise thereto and stirred at room temperature for 1 hour. After finishing of the reaction, 500 ml of dilute hydrochloric acid was added thereto and extracted with 1 l of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 119 g of (1-hydroxy-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzene.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1Br.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[C:24](=[O:34])[NH:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]>>[NH2:1][C:2]1[C:3]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:25][C@@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])=[O:34])=[C:18]([F:17])[CH:19]=2)=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: C[C@@H](NC(=O)c1ccc(B(O)O)cc1F)c1ccccc1
Reactant: CN1CCC(c2cnc(N)c(Br)c2)CC1=O
Product: C[C@@H](NC(=O)c1ccc(-c2cc(C3CCN(C)C(=O)C3)cnc2N)cc1F)c1ccccc1

Procedure:
Following Step 6 in Scheme 47, using (+/−)-4-(6-amino-5-bromopyridin-3-yl)-1-methylpiperidin-2-one and (R)-(3-fluoro-4-((1-phenylethyl)carbamoyl)phenyl)boronic acid, 4-(2-amino-5-(1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-2-fluoro-N—((R)-1-phenylethyl)benzamide was obtained as a diastereomeric mixture (inseparable) (34%). LCMS (m/z): 447.3 (MH+), 0.58 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.85 (m, 1H), 7.72 (m, 2H), 7.41-7.20 (m, 6H), 7.18 (m, 1H), 5.17 (m, 1H), 3.51-3.29 (m, 3H), 3.13-2.98 (m, 1H), 2.88 (s, 3H), 2.60-2.48 (m, 1H), 2.48-2.30 (m, 1H), 2.10-1.85 (m, 2H), 1.58-1.38 (m, 3H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), 100 mL/min, IPA+0.1%, DEA=40%, 5 ml/min). The polar diastereomer, 4-(2-amino-5-((R)-1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-2-fluoro-N—((R)-1-phenylethyl)benzamide was obtained at Rt=1.67 min. LCMS (m/z): 447.3 (MH+), 0.64 min. The less polar diastereomer, 4-(2-amino-5-((S)-1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-2-fluoro-N—((R)-1-phenylethyl)benzamide was obtained at Rt=2.37 min. LCMS (m/z): 447.2 (MH+), 0.64 min. The absolute stereochemistry for both diastereomers was assigned arbitrarily.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[CH:6][CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:28].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:28].[ClH:28].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:12][OH:13])[CH2:14][OH:15])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(NC(CO)CO)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(NC(CO)CO)cc1

Procedure:
The 2-(4-nitrophenylamino)propane-1,3-diol (15) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.