Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[C:10](C#CC(O)(C)C)[N:9]=[C:8]2[C:4]=1[N:5]=[C:6]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27](F)[CH:26]=1)[N:7]2[C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=1.Cl.[CH2:33](N)C#CC>>[ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[C:6]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:1])[CH:26]=1)[N:7]2[C:18]1[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH3:33])[CH:23]=1
Reactant: CC(C)(O)C#Cc1nc(N)c2nc(-c3cccc(F)c3)n(-c3ccc(=O)[nH]c3)c2n1
Reactant: CC#CCN
Agent: Cl
Product: Cn1cc(-n2c(-c3cccc(Cl)c3)nc3c(N)ncnc32)ccc1=O

Procedure:
The title compound was synthesized in the same manner as in Example 1 (2), (3) and (4), and Examples 2 and 5.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:9]([N+:20]([O-:22])=[O:21])=[CH:8][N:7]=1.NCC1CCC(C[NH:36][C:37]2C([N+]([O-])=O)=CN=C(NCC3C=CC=CC=3Cl)[N:38]=2)CC1>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:37]([NH2:38])=[NH:36])[CH2:18][CH2:19]2)[C:9]([N+:20]([O-:22])=[O:21])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2Cl)nc1NCC1CCNCC1
Reactant: NCC1CCC(CNc2nc(NCc3ccccc3Cl)ncc2[N+](=O)[O-])CC1
Product: N=C(N)N1CCC(CNc2nc(NCc3ccccc3Cl)ncc2[N+](=O)[O-])CC1

Procedure:
This compound was prepared in an analogous fashion to Example 9 using N2-(2-Chloro-benzyl)-5-nitro-N4piperidin-4-ylmethyl-pyrimidine2,4-diamine (Example 11) as a starting material in place of N4-(4-Aminomethyl-cyclohexylmethyl)-5-nitro-N2-(2-chloro-benzyl)-pyrmidine-2,4-diamine, m/z calculated for C18H23ClN8O2: 418.0 found: 419.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[ClH:19]>C(OCC)(=O)C>[ClH:19].[CH2:8]([O:6][C:5](=[O:7])[C@H:2]([CH2:3][SH:4])[NH2:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCCCCCCCCCO
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOC(=O)[C@@H](N)CS

Procedure:
L-Cysteine 157.4 g was added to 250 ml of decyl alcohol saturated with dry HCl. The mixture was heated to 150° for 6 h. The solution was cooled and was mixed with equal volume of ethyl acetate. The solution was cooled in a dry ice bath to give crystals. The crystals were filtered and were recrystallized from ethyl acetate, mp 96°-99° C., yield 100 g, IR (KBr) 1745 cm-1 ; NMR (CDCl3) δ.
Reaction SMILES: [N:1]1([C:13]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][C@H:23]([CH2:25][C:26]([O-:28])=[O:27])[C:22](=[O:29])[N:21]([CH3:30])[CH2:20][C:19]=3[CH:31]=2)=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(C(O)=O)(F)(F)F.N1(C(C2C=CC3N[C@@H](CC([O-])=O)C(=O)N(C)CC=3C=2)=O)CCC(C2CCNCC2)CC1>O.C(#N)C>[N:1]1([C:13]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][C@H:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22](=[O:29])[N:21]([CH3:30])[CH2:20][C:19]=3[CH:31]=2)=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CN1Cc2cc(C(=O)N3CCC(C4CCNCC4)CC3)ccc2N[C@H](CC(=O)[O-])C1=O
Agent: CN1Cc2cc(C(=O)N3CCC(C4CCNCC4)CC3)ccc2N[C@@H](CC(=O)[O-])C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1Cc2cc(C(=O)N3CCC(C4CCNCC4)CC3)ccc2N[C@H](CC(=O)O)C1=O

Procedure:
Using the procedure of Preparation 8(j), except substituting the compounds of Example 26(b) and 27(b) for the compound of Preparation 8(i) gave the following compounds: 26(c). (R)-7-[(4,4'-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate: [α]D +92.4 (c 0.5,CH3OH); MS(ES) m/e 429 [M+H]+ ; 427 [M-H]- ; HPLC tR 12.7 min (Ultrasphere C18, 4.6×250 mm, 1.5 mL/min, gradient, A:acetonitrile B: water-0.1% TFA, 5-60% acetonitrile over 20 min, UV detection at 220 nm); Anal. (C23H32N4O4.4.5 CF3CO2H.3.33 H2O) calcd: C, 37.44; H, 4.16; N, 5.29. found: C, 37.43; H, 3.81; N, 5.20. 27(c). (S)-7-[(4,4'-bipiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate: [α]D -105.9 (c 0.6,CH3OH); MS(ES) m/e 429 [M+H]+ ; 427 [M-H]- ; HPLC tR 12.6 min (Ultrasphere C18, 4.6×250 mm, 1.5 mL/min, gradient, A:acetonitrile B: water-0.1% TFA, 5-60% acetonitrile over 20 min, UV detection at 220 nm); Anal. (C23H32N4O4.3 CF3CO2H.1.25 H2O) calcd: C, 43.92; H, 4.77; N, 7.06. found: C, 44.09; H, 5.00; N, 7.29.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[Br:23]N1C(=O)CCC1=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2cc(Cc3ccccc3)ccc2c1O

Procedure:
A mixture of 7-Benzyl-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (302 mg, 1.03 mmole, prepared according to procedures in U.S. Pat. No. 7,928,120 B2 for example 22c) and N-bromosuccinimide (202 mg, 1.13 mmole) in anhydrous dichloromethane (5 ml) was stirred at room temperature for twenty hours before it was quenched with water, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (259 mg). LC-MS ESI+: 372, 374 (79Br/81Br) (M+1)+; ESI−: 370, 372 (79Br/81Br) (M-b) 7-Benzyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:3]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1C
Yield: 32 %

Procedure:
Using ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (500 mg), sodium hydride (60% in oil, 175 mg) and 4-fluorobenzenesulfonyl chloride (848 mg), a procedure as in Reference Example 4 was performed to give the title compound as a brown oil (yield 270 mg, 32%).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][N:7]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:6]1)=[O:4].ClOC(C)(C)C.O>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][N:7]([C:19](=[O:27])[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:6]=1)=[O:4]
Reactant: CNC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Agent: CC(C)(C)OCl
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-methyl 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carbamide and TEA in DCM at 0° C. was added a cooled (0° C.) solution of tert-butyl hypochloride (57 mL, 0.5 mmol) in DCM. The reaction mixture was stirred for 1.5 hours at 0° C. Cold water was added to wash the solution. Organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed by water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by chromatography on silica gel eluting with MeOH-DCM to give the title compound (14 mg); 1H-NMR (CDCl3): δ 10.04 (1H, br s), 7.57 (2H, m), 7.52 (1H, d), 7.37 (1H, d), 7.24 (1H, m), 7.12 (4H, m) 5.9 (1H, br s), 4.15 (2H, t), 3.27 (2H, t), 2.92 (3H, d); MS (ES): 378 (MH+).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[C:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][N:9]2[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.O>CN(C)C=O>[CH3:1][S:2][C:5]1[C:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][N:9]2[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: Brc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Temperature: 70 °C
Reaction time: 11 h
Yield: 81.3 %

Procedure:
Sodium thiomethoxide (0.0265 g, 0.38 mmol) was added to a solution of 4-bromo-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (0.100 g, 0.26 mmol) in N,N-dimethylformamide (1 ml), and the resulting mixture was heated at 70° C. and stirred for 11 hours. The reaction solution was added to water and extracted three times with toluene/ethyl acetate=1/1, and the extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=10/1) to obtain 4-(methylthio)-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (0.0737 g, 80%).
Reaction SMILES: C[O-].[K+].C([S:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16]Br)[C:9]([O:11][CH3:12])=[O:10])(=O)C>C1COCC1>[S:7]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:8]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(CCCCBr)SC(C)=O
Agent: C[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCCS1

Procedure:
Neat potassium methoxide (133 mg, 1.893 mmol) was added to a solution of methyl 2-(acetylthio)-6-bromohexanoate (536 mg, 1.893 mmol) in an. THF (18 mL) and the mixture was stirred at rt for 2 days under nitrogen. The crude isolate was purified by silica gel FCC (DCM) to afford methyl tetrahydro-2H-thiopyran-2-carboxylate as a clear oil which was saponified (1N NaOH, MeOH-THF) to afford Cap P-38.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[NH:5][CH2:4][C:3]3[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:13][CH:12]=1
Reactant: NCc1ccccc1N
Reactant: S=C=Nc1ccc(Cl)cc1
Product: Clc1ccc(NC2=Nc3ccccc3CN2)cc1

Procedure:
The title compound (MS: m/e=257.9 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 4-chlorophenylisothiocyanate.
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]([NH:27][CH2:28][C:29]#[N:30])[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].Cl.C(N(CC)CC)C.[N-:40]=[N+:41]=[N-:42].[Na+]>>[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]([NH:27][CH2:28][C:29]3[NH:42][N:41]=[N:40][N:30]=3)[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: Cc1cc(F)ccc1-c1nc(NCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NCc2nnn[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 9.9 %

Procedure:
Following the procedure outlined in Example 210, the crude product of Example 212(a), [8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-acetonitrile (460 mg), triethylaminehydrochloride (1.54 g, 11.2 mmol) and NaN3 (728 mg, 11.2 mmol) were reacted to give the desired product 50 mg (9.6%). LC-MS: 465.2 (MH+, m/z), 1.79 (Rt, min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[NH2:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=1>>[NH2:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][C:31]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]3([CH3:20])[CH3:21])=[O:32])[CH:26]=[CH:27][CH:28]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: Nc1cccc(CCC(=O)Cl)c1
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3cccc(N)c3)c([N+](=O)[O-])cc21

Procedure:
The compound is synthesized from A8 (213 mg) and freshly prepared 3-(3-amino-phenyl)-propionyl chloride (223 mg; 1.21 mmol) as described in Example 1a.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1C(F)(F)F
Yield: 85 %

Procedure:
Prepared in analogy to example 8 from 4-nitro-3-(trifluoromethyl)-phenol and 3-Fluoro-benzylbromide. Yield=85%. Yellowish solid. MS (ISP): m/e=333.2 (M++NH4).
Reaction SMILES: [C:1]([C:5]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[CH:24]=[C:25]([CH3:35])[C:26]4[O:30][C:29]([C:31](O)=[O:32])=[CH:28][C:27]=4[CH:34]=3)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=2[CH3:36])[O:9][CH2:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.Cl.C[O:43][C:44](=[O:47])[CH2:45][NH2:46]>CN(C1C=CN=CC=1)C>[C:1]([C:5]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[CH:24]=[C:25]([CH3:35])[C:26]4[O:30][C:29]([C:31]([NH:46][CH2:45][C:44]([OH:47])=[O:43])=[O:32])=[CH:28][C:27]=4[CH:34]=3)([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:14][C:13]=2[CH3:36])[O:6][CH2:7][CH2:8][O:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc(C)c2oc(C(=O)NCC(=O)O)cc2c1
Yield: 97.1 %

Procedure:
5-{1-[4-(2-tert-Butyl-[1,3]dioxolan-2-ylmethoxy)-3-methyl-phenyl]-1-ethylpropyl}-7-methyl-benzofuran-2-carboxylic acid (180 mg, 0.364 mmol), EDC (105 mg, 0.546 mmol), DMAP (133 mg, 1.09 mmol, and glycine methyl ester hydrochloride (68 mg, 0.55 mmol) are reacted to produce the intermediate followed by hydrolysis analogous to Example 7 to give title compound (195 mg, 97%).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12](=O)[CH3:13])[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[NH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClC(Cl)C>[CH3:9][C:8]1[N:23]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]([CH3:13])=[CH:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(C(C)=O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 3-phenylhexane-2,5-dione (0.330 g, 1.735 mmol) in dichloroethane (5 ml) was added triethylamine (0.725 ml, 5.20 mmol), followed by ethyl 2-aminoacetate hydrochloride (0.291 g, 2.082 mmol). The reaction was stirred overnight at room temperature, after which LCMS showed formation of the desired product. The reaction mixture was purified directly on an ISCO automated chromatography system (silica gel) using an EtOAc/hexane gradient. The desired fractions were collected and concentrated in vacuum and the crude mixture was taken directly to the next step without further purification.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:16][C@@H:15]3[C@@H:11]([CH2:12][O:13][C:14]3=[O:17])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C(O)C>[CH:18]1([NH:21][C:14]([C@@H:15]2[C@H:11]([CH2:12][OH:13])[CH2:10][N:9]([C@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH2:16]2)=[O:17])[CH2:20][CH2:19]1
Reactant: C[C@H](c1ccccc1)N1C[C@@H]2COC(=O)[C@@H]2C1
Reactant: NC1CC1
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1C[C@@H](CO)[C@@H](C(=O)NC2CC2)C1
Temperature: 80 °C
Reaction time: 44 h

Procedure:
(1S,5R)-7-[(1R)-1-Phenylethyl]-3-oxa-7-azabicyclo[3.3.0]octane-2-one (7.73 g, 33.4 mmol) was dissolved in ethanol (92 mL). To this solution, cyclopropylamine (46.3 ml) was added and the mixture was stirred at 80° C. for 44 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diisopropylether (300 mL) was added to the residue and the solution was heated to form crystals. The solution was concentrated to approximately half the original volume and the crystals formed were filtered. The collected crystals were washed with diisopropyl ether and were dried under reduced pressure to give (3R,4S)—N-cyclopropyl-4-hydroxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide as white crystals (4.41 g). The filtrate and the washings were then combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=1:1->ethyl acetate) to give additional (3R,4S)—N-cyclopropyl-4-hydroxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide (1.50 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:15].C([O-])(=O)C.[Na+].[Br:21]Br>C(O)(=O)C>[Br:21][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:15])[C:3]12[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1Nc2ccccc2C12CCCCC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C12CCCCC2
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (17.6 g, 0.09 mol) in acetic acid (300 cm3) was added sodium acetate (8.0 g, 0.1 mol) and bromine (14.6 g, 0.091 mol) with stirring. After 30 min. at room temperature, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with water, dried (MgSO4) and evaporated and the residue was triturated with hexane. The precipitate was collected, and dried in vacuo to obtain the subtitled compound (16.5 g, 67%) as off-white crystals: mp 196–199° C.; 1H NMR (DMSO-d6) δ 1.62 (m, 10H), 6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58 (dd, 1H, J=8.2, 1.8 Hz), 10.44 (s, 1H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH2:45]([NH2:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1.CO>[CH2:45]([NH:52][CH:18]1[CH2:17][CH2:16][N:15]([C:13]2[N:14]=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=2)[CH2:20][CH2:19]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(NCc4ccccc4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (85 mg) in dichloromethane (3 mL) and tetrahydrofuran (3 mL) was treated with benzylamine (0.030 mL), followed by glacial acetic acid (0.016 mL) and sodium triacetoxyborohydride (89 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH3:11])=[C:7]([CH:9]=[O:10])[O:8][C:4]=2[CH:3]=1.[CH:14]1([Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[CH:14]1([CH:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([F:1])[CH:13]=[CH:12][C:5]=3[C:6]=2[CH3:11])[OH:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1c(C=O)oc2cc(F)ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2cc(F)ccc12
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution (20 mL) of 6-fluoro-3-methyl-1-benzofuran-2-carbaldehyde (940 mg) synthesized above in tetrahydrofuran was added a 1.0M solution (7.92 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give the title object compound (931 mg, 67%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:33])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[O:34]([C:41]([NH:43][OH:44])=O)C1C=CC=CC=1>C1COCC1>[OH:44][NH:43][C:41]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:33])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12]1)=[O:34]
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCN(C(=O)NO)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
(5-Chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-piperidin-4-yl-amine (0.160 g, 0.34 mmol) and N-(phenoxycarbonyl)-hydroxylamine (0.068 g, 0.44 mmol) were combined in THF (4 mL) and the mixture was stirred at 70° C. for 2 hours and then 45° C. for 48 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 85:10:5, v/v/v) to give 4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-piperidine-1-carboxylic acid hydroxyamide (0.082 g, 45%) as a white solid. 1H NMR (CDCl3) δ 1.25-1.37 (m, 2H), 1.61 (s+m, 8H), 2.26 (s, 3H), 2.55 (t, 2H. J=12.0 Hz), 2.64 (m, 1H), 3.45 (s, 2H), 3.73 (s, 2H), 3.92 (d, 2H, J=12.0 Hz), 6.89-6.95 (m, 4H), 7.21 (m, 1H), 7.39 (s, 1H), 7.87 (d, 1H, J=9.0 Hz), 8.21 (d, 1H, J=3.0 Hz), 8.50 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 18.7, 27.9, 31.3, 42.5, 43.7, 54.4, 58.7, 115.5, 115.7, 121.8, 122.3, 127.6, 127.7, 129.7, 130.8, 134.6, 135.0, 138.0, 143.5, 145.0, 146.9, 161.0, 163.0. HPLC: 90%. ES-MS m/z 527 [M+H]+. Anal. Calcd. for C28H33N5O2ClF.0.6H2O.0.1 CH2Cl2: C, 61.89; H, 6.36; N, 12.84; Cl, 7.80. Found: C, 61.83; H, 6.19; N, 12.62; Cl, 8.06.