Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1)=[O:4].[N:30]1([CH2:35][CH2:36][NH2:37])[CH:34]=[CH:33][N:32]=[N:31]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>CO>[N:30]1([CH2:35][CH2:36][NH:37][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH2:18][C:16]3[N:17]=[C:13](/[CH:12]=[CH:11]/[C:8]4[CH:9]=[CH:10][C:5]([S:3]([C:2]([F:29])([F:1])[F:28])=[O:4])=[CH:6][CH:7]=4)[O:14][CH:15]=3)=[CH:21][CH:22]=2)[CH:34]=[CH:33][N:32]=[N:31]1
Reactant: O=Cc1ccc(OCc2coc(/C=C/c3ccc(S(=O)C(F)(F)F)cc3)n2)cc1
Reactant: NCCn1ccnn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CNCCn4ccnn4)cc3)co2)cc1)C(F)(F)F

Procedure:
A solution of 120 mg (0.28 mmol) 4-{2-[(E)-2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-benzaldehyde, 31 mg (0.28 mmol) (2-[1,2,3]triazol-1-yl-ethyl)-amine and 5 mg toluene-4-sulfonic acid in 10 ml methanol was stirred at room temperature for 1 hour, then 18 mg (0.28 mmol) sodium cyanoborohydride was added and the mixture stirred over night. After evaporation and chromatography on silica with ethyl acetate/methanolic ammonia 85:15, the title compound was isolated as light yellow solid melting at 111-113° C.; yield 89 mg (60%).
Reaction SMILES: [CH:1](=[N:10][NH:11][C:12]([NH2:14])=[S:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=O>>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:14]=[C:12]([NH:11][N:10]=[CH:1][CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[S:13][CH:16]=2)=[CH:24][CH:23]=1
Reactant: NC(=S)NN=CC=Cc1ccccc1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2csc(NN=CC=Cc3ccccc3)n2)cc1
Yield: 42 %

Procedure:
The compound is prepared according to the method described in Example 1B from cinnamaldehyde thiosemicarbazone (0.5 mmol) (Eur. J. Med. Chem. 25(7), 581-588, 1990) and from 2-bromo-4′-trifluoromethylacetophenone (0.5 mmol) (Tet., 59(8) 1317-1325, 2003). Yield 42%.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17]12([CH2:27][C:28](O)=[O:29])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N=C=NCCCN(C)C)C>>[NH2:12][C:11]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:7]([CH2:14][CH2:15][CH3:16])[C:8](=[O:9])[C:10]=1[NH:13][C:28](=[O:29])[CH2:27][C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Product: CCCn1c(N)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(=O)n(CCC)c1=O
Yield: 112.8 %

Procedure:
At first 2.00 g (8.85 mmol) of 1,3-dipropyl-5,6-diaminouracil and 2.06 g (10.6 mmol) of 1-adamantaneacetic acid were condensed according to the procedure of Example 1 using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide to afford 4.02 g (yield: 100%) of amorphous 6-amino-5-(adamantan-1-yl)acetylamino-1,3-dipropyluracil as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1N
Product: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Methyl 4-amino-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate (Intermediate 47) (2 g, 6.56 mmol) was dissolved in acetic anhydride (Aldrich, 6.75 mL, 92 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and the resulting precipitate was isolated by filtration and dried. The solid was triturated with methanol, filtered and dried to give the title compound methyl 4-acetamido-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate (2.05 g, 5.91 mmol, 90% yield) as beige solid. LCMS: (M+H)+=347; Rt=3.76 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:48][C@@H:49]([C:51]([O:53]C(C)(C)C)=[O:52])[CH3:50].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C@H:9]2[C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:48][C@@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](C)C(=O)O)cc2)cc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.04 g, 0.072 mmol) and N-methylmorpholine (0.022 g, 0.217 mmol) were dissolved in CH2Cl2 (4 ml). tert-Butyl D-alaninate hydrochloride (0.016 g, 0.087 mmol) and TBTU (0.030 g, 0.094 mmol) were added. After 2 h, the reaction mixture was purified on silica gel and eluted with EtOAc/CH2Cl2 (25/75). Pure fractions were collected and concentrated. The residue was dissolved in CH2Cl2 (3 ml) and TFA (2 ml). The hydrolysis was completed after 2 h. The reaction mixture was concentrated and MeOH (3 ml) and NABH4 (0.011 g, 0.290 mmol) were added. The mixture was stirred for 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (2 ml) and the solvent evaporated. The residue was purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions afforded the title compound (0.030 g, 66%) as a colourless solid. M/z: 624.2, (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 1.16 (d, 3H), 2.83-2.93 (m, 2H), 3.68-3.74 (m, 5H), 3.88-3.95 (m, 1H), 4.23-4.26 (m, 1H), 4.51 (s, 2H), 4.60-4.70 (m, 1H), 5.00-5.03 (m, 1H), 6.81-7.37 (m, 12H), 7.74-7.79 (m, 1H), 8.29-8.34 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](C3C=CC(Br)=CC=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14]C1C=CC=CC=1)=[O:12])C1C=CC=CC=1.[CH3:55][O:56][C:57]([C:59]1[CH:64]=[CH:63][C:62](B(O)O)=[CH:61][CH:60]=1)=[O:58]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[C:46]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:45]([C:62]3[CH:63]=[CH:64][C:59]([C:57]([O:56][CH3:55])=[O:58])=[CH:60][CH:61]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])[C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:10]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(Br)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: COC(=O)c1ccc(-c2ccc(CN(C(=O)CN(C)S(=O)(=O)c3ccc(C)cc3)c3ccc(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3)cc2-c2ccccc2)cc1

Procedure:
Aryl halide 5 was coupled to 4-(methoxycarbonyl)phenylboronic acid to give 39 on a 0.1 mmol scale via General Procedure H (59 mg, 47%): δH (400 MHz, CDCl3) 2.38 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.69 (s, 2H, CH2), 3.93 (s, 3H, CH3), 4.84 (s, 2H, CH2), 5.02 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.64 (s, 1H, CH), 6.70 (dd, J=8.4 and 1.6 Hz, 1H, CH), 7.20 (d, J=8.0 Hz, 2H, CH), 7.24-7.28 (m, 6H, CH), 7.30-7.33 (m, 5H, CH), 7.36-7.41 (m, 3H, CH), 7.54 (d, J=8.4 Hz, 2H, CH), 7.61 (d, J=8.4 Hz, 2H, CH), 7.64-7.73 (m, 6H, CH), 7.85 (d, J=8.4 Hz, 1H, CH). LRMS (ES+) calcd for [C52H46N2O8S+H] 881.29. found 881.39.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[OH:37])[CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[C:20]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[OH:37])[CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[C:20]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH:19]=2)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCNc1ccc(-c2ccc(C(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of methyl 4′-[[2-[(tert-butoxycarbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-ethyl]amino]-3-(cyclohexyloxy)-4-biphenylcarboxylate (125 mg) in methanol (1.750 ml) and tetrahydrofuran (0.900 ml) was added 1N aqueous sodium hydroxide solution (1.05 ml) and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added 1N aqueous sodium hydroxide solution (0.900 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and to the residue were added ethyl acetate (40 ml) and water (20 ml). The pH value was adjusted to 5.70 by addition of 0.1N hydrochloric acid and the separated organic layer was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation gave 4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-(cyclohexyloxy)-4-biphenylcarboxylic acid (123 mg) as a yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].[BH3-]C#N.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:35]3[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH:31]([CH3:30])[CH2:36]3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.52 mmol) and tert-butyl 2-methylpiperazine-1-carboxylate (311 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBH3CN (129 mg, 2.1 mmol) was added and the mixture was stirred for another 5 hours. Concentrated and the residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (70 mg, yield 24%). LC-MS (ESI) m/z: 570 (M+1)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:15]=[C:11]3[CH:10]=[C:9]([NH2:22])[N:8]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N1(C2N=C(N)C=C(N)N=2)CCCC[CH2:24]1>>[C:16]1([C:14]2[N:15]=[C:11]3[CH:10]=[C:9]([NH2:22])[N:8]=[C:7]([N:1]4[CH2:6][CH2:5][CH2:24][CH2:3][CH2:2]4)[N:12]3[CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Reactant: Nc1cc(N)nc(N2CCCCC2)n1
Product: Nc1cc2nc(-c3ccccc3)cn2c(N2CCCCC2)n1

Procedure:
The title compound was prepared in analogy to 5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (Example 63, Step 1) from 2-piperidin-1-yl-pyrimidine-4,6-diamine. MS (m/e)=294.2 [M+H+].
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:16]2[CH:15]=[C:14]([O:17]C)[C:13]([O:19]C)=[C:12]([C:21]([NH:23][CH2:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:22])[C:11]=2[CH:10]=[C:9]([CH3:33])[C:8]=1[C:34]1[C:43]([CH3:44])=[CH:42][C:41]2[C:40]([C:45]([NH:47][CH2:48][CH:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH3:50])=[O:46])=[C:39]([O:57]C)[C:38]([O:59]C)=[CH:37][C:36]=2[C:35]=1[O:61]C.Cl>C(Cl)Cl>[OH:6][C:7]1[C:16]2[CH:15]=[C:14]([OH:17])[C:13]([OH:19])=[C:12]([C:21]([NH:23][CH2:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:22])[C:11]=2[CH:10]=[C:9]([CH3:33])[C:8]=1[C:34]1[C:43]([CH3:44])=[CH:42][C:41]2[C:40]([C:45]([NH:47][CH2:48][CH:49]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH3:50])=[O:46])=[C:39]([OH:57])[C:38]([OH:59])=[CH:37][C:36]=2[C:35]=1[OH:61]
Reactant: COc1cc2c(OC)c(-c3c(C)cc4c(C(=O)NCC(C)c5ccccc5)c(OC)c(OC)cc4c3OC)c(C)cc2c(C(=O)NCC(C)c2ccccc2)c1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1cc2c(C(=O)NCC(C)c3ccccc3)c(O)c(O)cc2c(O)c1-c1c(C)cc2c(C(=O)NCC(C)c3ccccc3)c(O)c(O)cc2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
0.45 mL of BBr3 solution (1.18 g, 4.73 mmol) was added dropwise into a solution of compound 8 (310 mg, 0.40 mmol) in 20 mL of anhydrous CH2Cl2 at −78° C. Stirring was continued at −78° C. for 1 h, 0° C. for 1 h, and ambient temperature for 1 h. 50 grams of ice containing 10 mL of 6M HCl was added to the mixture and stirred for 1 h at room temperature. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layer was washed with water, brine and dried over MgSO4. The solvent was concentrated in vacuo and the residue was purified using C-18 column chromatography (H2O/Acetonitrile) to give 200 mg of compound 10 (72%) as white-yellow solid. 1H NMR (600 MHz, CD3OD) δ 7.56 (d, J=6.6 Hz, 2H), 7.39 (t, J1=6.0 Hz, J2=3.0 Hz, 4H), 7.35 (t, J1=6.0 Hz, J2=6.6 Hz, 4H), 7.23 (t, J1=6.0 Hz, J2=6.6 Hz, 2H), 7.06 (s, 1H), 6.99 (s, 1H), 3.76 (dd, J1=6.6 Hz, J2=11.4 Hz, 1H), 3.68 (m, 3H), 3.22 (m, 2H), 1.90 (s, 3H), 1.89 (s, 3H), 1.43 (m, 6H). HRMS calcd for C42H40N2O8 701.2857 (M+H), found 701.2853. 150 mg of compound 10 was further purified using a CHIRALCEL OD-RH 5 μM 250 mm×10 mm reverse phase chiral column to give 50 mg of compound 13 and 58 mg of compound 14, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C([NH:24][C@@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(OC(C)(C)C)=O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]2[NH:1][C:33](=[O:34])[C@@H:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=2[CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=N[C@@H]1Cc1ccccc1
Reaction time: 120 h

Procedure:
The procedure of Example 1 was carried out using 2-amino-5-chlorobenzophenone (2.32 gm, 0.01 mol), Boc-D-Phenylalanine (2.65 gm, 0.01 mol), and DCC (10 ml of 1.0 M solution in CH2Cl2) in CH2Cl2 (10 ml). After filtration and evaporation, the crude solid was deprotected and cyclized by the procedure of Example 2. After stirring 5 days, the mixture was evaporated in vacuo, treated with H2O (50 ml), and extracted with EtoAc (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness in vacuo. Chromatogaphy on silica gel eluted with 7.5% (v/v) Et2O in CH2Cl2 gave a white foam which was crystallized from Et2O. The solid was dried in vacuo at 65° C.: (m.p. 154°-7° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][S:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:37][CH2:36][CH2:35][CH2:34][S:33][CH3:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CSCCCN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: CSCCCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 52.2 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 48 (200 mg, 0.44 mmol) and 3-(methylthio)propylamine (231 mg, 2.2 mmol) were reacted to afford the title compound 108 mg (52%). LC-MS: 471.2 (MH+, m/z), 2.37 (Rt, min).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[N:21]=[CH:22][CH:23]=3)[CH2:18][O:17][C:15]=2[CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[N:21]=[CH:22][CH:23]=3)[CH2:18][O:17][C:15]=2[CH:16]=1
Reactant: CC(=O)Nc1nccc2c1COc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nccc2c1COc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
To a stirred solution of (S)-tert-butyl(1-((4-acetamido-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.329 mmol) in CH2Cl2 (10 mL) at room temperature was added TFA (0.025 mL, 0.329 mmol) and the solution was stirred at room temperature for 3 h. The solution was concentrated under reduced pressure and the sample was purified by preparative HPLC (0.1% TFA in water and methanol) yielding (S)-N-(8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-4-yl)acetamide (40 mg, 0.113 mmol, 33% yield for three steps) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=5.3 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.58 (d, J=5.4 Hz, 1H), 6.77 (m, 1H), 6.63 (d, J=2.4 Hz, 1H), 4.94 (s, 2H), 4.03 (m, 1H), 3.85 (m, 1H), 3.33 (m, 1H), 2.21 (s, 3H), 1.81 (m, 1H), 1.43 (m, 2H), 0.99 (m, 6H); LCMS (ESI) m/e 356.2 [(M+H)+, calcd for C20H26N3O3 356.2]; LC/MS retention time (Method C): tR=1.26 min; HPLC retention time (method A): tR=8.02 min; HPLC retention time (method B): tR=9.08 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1>>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[CH:24][N:23]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cn1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 5-amino-2-methoxypyridine (35 mg, 0.288 mmol) similar to Example 180 and was isolated as a solid (30 mg, 45%). 1H NMR (CDCl3): 9.65 (brs, 1H), 8.72-8.69 (m, 2H), 8.26 (d, J=2.7 Hz, 1H), 7.71 (d, J=6.9 Hz, 1H), 7.44-7.40 (m, 2H), 6.86 (d, J=9.0 Hz, 1H), 6.74 (s, 1H), 3.98 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:39][N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:34])([F:36])[F:35])=[CH:17][N:16]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
2-(2-(2-(2-((4-(piperazin-1-ylmethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (25) (11 mg, 0.022 mmol) was dissolved in methanol (1 mL). 37% Formaldehyde solution (7 μL) was added followed by sodium triacetoxyborohydride (24 mg, 0.11 mmol). The mixture was stirred vigorously at room temperature for two hours then concentrated. The residue was suspended in 10% sodium hydroxide (1 mL) and brine (2 mL) then extracted with ethyl acetate (5×2 mL). The combined ethyl acetate phases were washed with brine, dried over sodium sulfate, evaporated and the residue evaporated from DCM to give the title compound (36) (10.3 mg, 94% yield) as an off-white solid; 1H NMR (400 MHz, d4-MeOD) δ 8.46 (d, J=0.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.20 (d, J=8.6 Hz, 2H), 7.18-7.13 (m, 1H), 7.13-7.07 (m, 3H), 3.57 (s, 2H), 3.46 (s, 2H), 3.06 (qd, J=6.8, 3.1 Hz, 2H), 3.01-2.94 (m, 2H), 2.54 (s, 8H), 2.29 (s, 3H). LCMS Method C, 4.70 min; m/z 513.2 [M+H]+; m/z 511.0 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=[CH:17][CH:16]=2.S(Cl)([Cl:29])=O>O1CCCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([Cl:29])=[O:26])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.1 g (0.0147 mole) of 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionic acid and 7.0 g (0.059 mole) of thionyl chloride in 200 ml tetrahydrofuran is stirred for 18 hours at room temperature. The solvent is then removed in vacuo to give 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionyl chloride.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(NCC#CCO)C(O)(c1ccccc1)C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NCC#CCCl)C(O)(c1ccccc1)C1CCCCC1

Procedure:
Thionyl chloride (4.8 ml) was added dropwise to a mixture of N-(4-hydroxy-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (6.56 g) and N,N-dimethylformamide (5 drops) in dry chloroform (145 ml) at 0° C. and the reaction mixture was refluxed for 1 hour. The mixture was washed successively with water, 1N aqueous sodium hydroxide solution, and sodium chloride, aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give N-(4-chloro-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide as white powder (6.7 g).