Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][OH:12])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) solution of 4-tert-butylcyclohexane-carboxylic acid (3.00 g, 16.3 mmoles) in THF (30 mL) is slowly added a THF solution of borane-THF complex (1.0M, 21.2 mL, 21.2 mmoles). The solution is stirred at room temperature for 18 hours, then quenched with 2N HCl solution (30 mL), and extracted with EtOAc. The organic layer is isolated, washed with 1N NaOH, dried over sodium sulfate, and concentrated to yield the title compound as a clear oil. 1H NMR (300 MHz, CDCl3): δ 2.06 (d, 2H), 1.82 (m, 4H), 1.52 (m, 2H), 0.88 (m, 4H), 0.83 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:25]=[CH:24][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].ClC1C=C(NC2C=CC(F)=CC=2F)C=C[C:39]=1[C:40](C1C=C(C2N=NN(CC(O)=O)C=2)C=CC=1C)=[O:41].Cl.N1CCOCC1>>[Cl:1][C:2]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:25]=[CH:24][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([N:21]3[CH2:39][CH2:40][O:41][CH2:23][CH2:22]3)=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCNC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Agent: Cl
Solvent: C1COCCN1
Product: Cc1ccc(-c2cn(CC(=O)N3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 112, using compound 111 (0.12 mmol) and morpholine hydrochloride (0.12 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 5:95 as the eluent to afford the title compound as almost yellow syrup. 13C NMR (CDCl3) δ 196.0, 163.5, 147.9, 147.3, 139.8, 138.0, 135.3, 133.7, 131.9, 129.2, 128.0, 127.7, 126.5, 124.4 (dd), 124.2 (dd), 121.4, 116.3, 112.8, 111.6 (dd), 104.9 (dd), 66.6, 66.4, 50.9, 45.9, 42.6, 20.2
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[N-:14]=[N+:15]=[N-:16].[Na+].C(OCC)C>CN(C1C=CN=CC=1)C.O>[CH2:1]([N:14]=[N+:15]=[N-:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=NCc1ccccc1
Reaction time: 6 h

Procedure:
2.07 ml of benzyl alcohol (20 mmole), 2.99 g of DMAP (1.2 eq) and 1.86 ml of MeSOCl2 (1.2 eq) were sequentially added to 25 ml of DMF. After stirring the mixture for 6 hours, 3.96 g of NaN3 (3 eq) was added thereto, and the mixture was stirred for 12 hours. The reaction mixture was treated with a mixture of diethyl ether and water, the ether extract was dried under MgSO4, ether was removed under a reduced pressure, and the resulting residue was subjected to column chromatography (silica gel 60, 230˜400 meshes, Merck) to obtain the title compound as a pale yellow liquid. The chromatography was conducted using a mixture of hexane and CH2Cl2 as an eluting solution whose mix ratio was gradually varied from 2:1 to 1:1 (v/v).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:39]=[C:40]=[O:41])(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][N:11]1[C:40]([NH2:39])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: c1ccc(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: NC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1ccccc1
Yield: 46.9 %

Procedure:
A solution of 400 mg (0.86 mmol) (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine in 15 ml CH2Cl2 with 0.3 ml (2.2 mmol) trimethylsilylisocyanate and a catalytic amount of DMAP was stirred over night. The reaction was extracted with aqueous 10% KHSO4/EtOAc (3×) and the organic phase was dried over Na2SO4. Crystallization (CH2Cl2/MeOH/Et2O) gave 205 mg (47%) (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid amide, MS: 509 (MH+).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][CH2:33][CH2:34][CH3:35])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[N:38]1.C1(N=C=NC2CCCCC2)CCCCC1.N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC3N(NC(=O)C)N=NN=3)CS[C@H]12>O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][CH2:33][CH2:34][CH3:35])/[C:27]([O:29][N:37]2[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[N:39]=[N:38]2)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: C1CCOC1
Product: CCCCO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-n-butoxyiminoacetic acid (1.6 g, 3.29 mmol) and 1-hydroxybenzotriazole (0.49 g, 3.62 mmol) in tetrahydrofuran (16 ml) was added N,N'-dicyclohexylcarbodiimide (0.75 g, 3.62 mmol) and the mixture was stirred at room temperature. Then the mixture was treated in a manner similar to that descirbed in Example 6, (b) to give colorless needles of 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-n-butoxyiminoacetate (1.50 g, 75.7%), mp 100°-102° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH:12]([CH3:13])[CH3:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NC(C)C)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
2-Isopropylamino-cyclopent-1-enecarboxylic acid ethyl ester (2.44 g, 12.38 mmol) was dissolved in glacial acetic acid (30 mL) and sodium triacetoxyborohydride (7.87 g, 37.13 mmol) was added at 0° C. The solution was allowed to warm to 25° C. and stirred for 3 h. The acetic acid was removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution followed by saturated aqueous brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product, 2-isopropylamino-cyclopentanecarboxylic acid ethyl ester (1.5 g, 7.53 mmol, 60.8%), as a yellowish oil. LC-MS (ESI) calcd for C11H21NO2 199.16, found 200.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[H-].[Na+]>CN(C)C=O>[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:11][C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[N:6]([CH3:12])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4]3)=[CH:29][CH:28]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CNC(=O)OC(C)(C)C)cc3)c2n1C
Yield: 74.1 %

Procedure:
The reaction was carried out in a manner similar to Example 196 a) except for using 0.44 g (1.74 mmol) of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate, 0.66 g (2.58 mmol) of 4-(tert-butoxycarbonylaminomethyl)-benzyl chloride, 0.07 9 (1.74 mmol) of 60% sodium hydride and 20 ml of dimethylformamide. Thus, 0.61 g (73.1%) of ethyl 7-[4-(tert-butoxycarbonylaminomethyl)benzyloxy]-4-chloro-1-methyl-2-indolecarboxylate was obtained.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([CH3:38])[N:31]=3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:50])C=1>C(Cl)Cl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([CH3:38])[N+:31]=3[O-:50])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: ClCCl
Product: COc1ccc(C)[n+]([O-])c1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methylpyridin-2-yl)-5-(trifluoromethyl) benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 174) (7.6 mg, 0.0128 mmol) in CH2Cl2 (1.3 mL) was added m-CPBA (5.8 mg, 77% purity, 0.0256 mmol). The reaction was stirred at room temperature for 1 hour and then diluted with CH2Cl2 (10 mL), washed with aq. NaHSO3, saturated K2CO3, and brine (5 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (50% Et2O/CH2Cl2) afforded the title compound. Rf=0.23 (50% Et2O/CH2Cl2). LCMS=609.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.70 (s, 2H), 7.62 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.04 (d, J=9.2 Hz, 1H), 5.74 (d, J=8.3 Hz, 1H), 4.88 (d, J=14.8 Hz, 1H), 4.11-3.96 (m, 1H), 3.88 (d, J=14.9 Hz, 1H), 3.86 (s, 3H), 2.49 (s, 3H), 0.65 (d, J=6.6 Hz, 3H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][NH2:21]>C1COCC1>[CH3:20][NH:21][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(N)c(N)c2)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nccc(Oc2ccc(N)c(N)c2)n1
Temperature: 80 °C

Procedure:
To a solution of 4-(2-methanesulfonyl-pyrimidin-4-yloxy)-benzene-1,2-diamine (Step B, 400 mg, 1.4 mmol, 1.0 eq) in anhydrous THF (4 mL) was added 1 mL of 2 M CH3NH2 in THF (2 mmol, 1.4 eq). The solution was heated to 80° C. for 1 h. The THF was removed under reduced pressure. The crude was purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) to yield 4-(2-methylamino-pyrimidin-4-yloxy)-benzene-1,2-diamine.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:5])C.[CH2:41]([NH2:43])[CH3:42]>CO.C1COCC1>[CH2:41]([NH:43][C:4]([C:6]1[C:7](=[O:40])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:20]=3)=[N:10][C:9]=2[N:29]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[CH2:36][CH2:35][CH2:34]3)[CH:30]=1)=[O:5])[CH3:42]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Reactant: CCN
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 8-indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 27 (b), 20 mg, 0.037 mmol) in 1 mL methanol was added a solution of ethylamine in THF (2N, 2 mL). The mixture was stirred at 80° C. for 16 hours. The solvent was removed by vacuum to leave a yellow solid (12.7 mg, 64%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.60 (br, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 7.75 (s, 1H), 7.60 (br, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.20 (m, 2H), 7.12 (d, J=7.6 Hz, 1H), 6.87 (br, 2H), 3.69 (br, 4H), 3.42(q, J=7.1 Hz, 2H), 3.01 (t, J=7.3 Hz, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.65 (br, 2H), 2.49 (br, 6H), 2.17 (m, 2H). 1.08 (t, 7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H34N6O3: 539.27 (M+H), Found 539.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O-:33])=[O:32])=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([OH:33])=[O:32])=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:4]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 57.4 %

Procedure:
To a solution of Methyl (1RS, 2RS, 3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (80 mg, 0.12 mmol) in dioxane (2 mL) was added 1M aqueous NaOH (0.3 mL, 0.3 mmol). The resulting mixture was heated to reflux for 48 h, then concentrated under reduced pressure. The residue was partitioned between dilute aqueous HCl and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4 anhydrous). The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane containing 5% of acetic acid) to afford the title compound (36 mg, 46%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6](OC)=[O:7])#[N:2].[BH4-].[Li+].O1CCCC1>O1CCOCC1>[CH:13]1([C:12]2[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(C2CCCCC2)c(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#Cc1cc(CO)ccc1C1CCCCC1
Temperature: 0 °C
Yield: 72 %

Procedure:
To a solution of methyl 3-cyano-4-cyclohexylbenzoate (299.0 mg, 1.229 mmol) in 1,4-dioxane (30 mL) was added 2 M lithium borohydride solution in tetrahydrofuran (1.23 mL, 2.46 mmol). The mixture was heated under reflux for 2.5 h. The mixture was cooled to 0° C. and quenched with 1 N aqueous HCl solution slowly to pH 5. After the addition of brine solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to provide the title compound as a white solid (190.5 mg). LCMS m/z=216.5 [M+H]+; NMR (400 MHz, CDCl3) δ ppm 1.23-1.33 (m, 1H), 1.41-1.52 (m, 4H), 1.76-1.83 (m, 1H), 1.84-1.92 (m, 4H), 2.90-3.05 (m, 1H), 4.70 (d, J=5.81 Hz, 2H), 7.36 (d, J=8.21 Hz, 1H), 7.53 (dd, J=8.27, 1.71 Hz, 1H), 7.61 (d, J=1.39 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C=O)ncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(CO)ncn1
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a stirred solution of the crude tert-butyl 6-formylpyrimidin-4-ylcarbamate (4.6 g, 0.020 mol) in MeOH (100 mL) was added sodium borohydride (0.74 g, 0.020 mol) in four portions at room temperature. After addition, the resulting mixture was stirred for 1 hour and then water (50 mL) was added. The solvent was removed under reduced pressure and the resulting aqueous residue was extracted with EtOAc (3×100 mL). The combined organic extract was washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography, eluting with DCM/MeOH (30:1) to give the desired product (1.4 g, 30% yield). LCMS (ESI) m/z: 226.0 [M+H+].
Reaction SMILES: [C@H:1]12[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]1[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:2]2.[CH:25]1([Mg]Br)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1COCC1.[NH4+].[Cl-]>[Cu]I>[C:11]([O:10][C:8]([NH:7][C@H:1]1[C@H:6]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2]1)=[O:9])([CH3:14])([CH3:13])[CH3:12].[C:11]([O:10][C:8]([NH:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2][C@@H:1]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: Br[Mg]C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@@H]21
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C[C@@H]1C1CCCCC1
Temperature: -40 °C
Reaction time: 0.13 h
Yield: 23 %

Procedure:
(1R,6S)-3-benzyl 7-tert-butyl 3,7-diazabicyclo[4.1.0]heptane-3,7-dicarboxylate (220 mg, 0.663 mmol), CuI (25 mg, 0.2 equiv), and a stirring bar were put in a 100-mL flask. The flask was evacuated and backfilled with N2 gas (3×). Dry THF (5 mL) was added and the mixture was cooled to −40° C. 1 M Cyclohexylmagnesium bromide in THF (2.0 mL, 3 equiv) was added slowly. After 8 min, the reaction mixture was allowed warmed slowly to rt. After 20 min, the reaction mixture turned into black. After stirring a further 2 h, LC-MS showed the reaction was complete. Satd aq NH4Cl solution (5 mL) was added to quench the reaction. The reaction mixture was partitioned between EtOAc (50 mL) and satd aq NH4Cl solution (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined EtOAc layers were washed with water (15 mL) and brine (15 mL), and dried over Na2SO4. After concentration, the residue was purified by preparative HPLC to afford (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-cyclohexylpiperidine-1-carboxylate (62.3 mg, 23% yield) and (3S,4S)-benzyl 4-(tert-butoxycarbonylamino)-3-cyclohexylpiperidine-1-carboxylate (15 mg). LC-MS (3 min) tR=2.33 min., m/z 439 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=C[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.ClCl.[CH:24]([Cl:27])(Cl)[Cl:25].CO.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[ClH:25].[Cl:27][C:24]1[NH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:12]=1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: ClC(Cl)Cl
Agent: ClCl
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2nc(Cl)[nH]c2-c2ccc(OC)cc2)cc1
Product: Cl
Yield: 100 %

Procedure:
A suspension of 4,5-bis(4-methoxyphenyl)-1H-imidazole (10.0 g, 0.036 mol) in 200 ml of carbon tetrachloride was treated with chlorine until no starting material was evidenced by tlc (chloroform-methanol-acetic acid, 17:1:2). The resulting solid was collected by filtration, washed with carbon tetrachloride, and dried in vacuo to yield 12.5 g (100%) of the title compound, m.p. 129°-132° (dec.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:19]1[NH:23][N:22]=[C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[C:34]([Cl:36])[N:33]=[CH:32]3)=[C:27]([O:37][CH3:38])[CH:26]=2)[N:20]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[Cl:36][C:34]1[N:33]=[CH:32][N:31]([C:28]2[CH:29]=[CH:30][C:25]([NH:24][C:21]3[N:20]=[C:19]4[CH:6]([C:7]5[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:16])([F:18])[F:17])=[CH:9][CH:8]=5)[CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[N:22]=3)=[CH:26][C:27]=2[O:37][CH3:38])[CH:35]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)(F)F)cc3)n2)ccc1-n1cnc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(OCC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1
Yield: 14.9 %

Procedure:
A solution of 5-(5-chloro-1-(4-(2,2,2-trifluoroethoxy)phenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.02 g, 3.54 mmol), sodium iodide (2.65 g, 17.7 mmol), and diisoproplylethylamine (0.618 mL, 3.54 mmol) in acetone (25 mL) was heated in a sealed vessel at 100° C. for 4 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 281 mg (15% yield) of the titled compound as an off-white solid. LC-MS (M+H)+ 533.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.51 (d, J=1.5 Hz, 1H), 7.41 (d, J=2.4 Hz, 1 H), 7.14 (m, J=8.9 Hz, 2 H), 7.09 (d, J=8.5 Hz, 1 H), 7.02 (d, J=1.5 Hz, 1 H), 6.95 (m, J=8.9 Hz, 2 H), 6.84 (dd, J=8.5, 2.1 Hz, 1 H), 6.66 (s, 1 H), 4.36 (q, J=8.1 Hz, 2 H), 4.20-4.27 (m, 3 H), 3.80 (s, 3 H), 2.16-2.29 (m, 1H), 2.05-2.13 (m, 1 H), 1.92-2.03 (m, 2 H), 1.83-1.90 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]2[N:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:16]=[CH:15][C:13]=2[N:14]=1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=[O:39].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:36][C:37]([F:42])([CH3:41])[C:38]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]2[N:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]3)[CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:39]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Nc4ccccc4N)nc(N4CCOCC4)c3n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)C(=O)Nc1ccccc1Nc1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
2-(1-((2-(2-aminophenylamino)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol was reacted with 2,2-difluoropropanoic acid (2 eq), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.5 eq) and DIPEA (4 eq) in DMF (4 mL) for 1 hr (hour). The reaction mixture was extracted with EtOAc and bicarbonate solution and the organic layer was dried with Magnesium sulfate, filtered, evaporated and purified via flash column chromatography to get 50 mg of 2,2-difluoro-N-(2-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-ylamino)phenyl)propanamide. This intermediate was reacted with acetic acid (1.6 mL) over one week to yield 4.1 mg of 120 following reverse phase HPLC purification. MS (Q1) 552.3 (M)+