Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)=[C:2]=[O:3].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CCCCCC>C1COCC1>[NH:8]1[C:9]2[C:5](=[C:4]([NH:1][C:2]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=3)=[O:3])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2[nH]ccc12
Reaction time: 3 h

Procedure:
The product of Example 80A (0.16 g, 1 mmol) in THF (3 mL) was treated with 4-(trifluoromethyl)benzylamine (0.19 g, 1.1 mmol) at ambient temperature. After stirring for 3 hours, hexane was added to the reaction mixture to precipitate the title compound as a solid. mp 178° C. 1H NMR (300 MHz, DMSO-d6) δ 4.43 (d, 2H), 6.53 (t, 1H), (6.98 m, 3H), 7.26 (t, 1H), 7.57 (d, 2H), 7.62 (d, 1H), 7.71 (d, 2H), 8.37 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 334 (M+H); Anal. Calcd. For C17H14N3F3O: C, 61.26; H, 4.23; N, 12.61. Found: C, 61.28, H, 3.83; N, 12.31.
Reaction SMILES: [F:1][C@H:2]1[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]1([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[F:20])[CH3:10]>C(O)C.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:12]([F:20])=[C:11]([C@:3]2([CH3:10])[C@@H:2]([F:1])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4]2)[CH:16]=1
Reactant: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)COC[C@@H]1F
Agent: [Pd]
Solvent: CCO
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Reaction time: 2 h

Procedure:
A suspension of (5R,6R)-6-fluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (1.0 mmol) in ethanol (9 ml) and Pd/C (10%, 100 mg) was hydrogenated at 22° C. and atmospheric pressure for 2 h. The suspension was filtered and the residue evaporated to give (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine as a yellow solid. MS (ISP): m/z=256.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:17]1=[O:32]>CS(C)=O>[NH2:15][C:16]1([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:24]2[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:17]1=[O:32]
Reactant: CCCCCN1C(=O)C(N)c2ccc(OC)cc21
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCN1C(=O)C(N)(CCC(=O)OCC)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, 0.85 ml of ethyl acrylate and 1.94 g of potassium carbonate were added to 2.00 g of 3-amino-2,3-dihydro-6-methoxy-2-oxo-1-pentyl-1H-indole hydrochloride dissolved in 40 ml of dimethyl sulfoxide, the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed and dried. Insolubles were removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography [chloroform-ethyl acetate (1:1)] to afford 1.36 g of ethyl 3-[3-amino-2,3-dihydro-6-methoxy-2-oxo-1-pentyl-1H-indol-3-yl]-propionate as a pale yellow oily product.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([C:29]5([OH:28])[CH2:31][CH2:30]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C1(O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, off-white solid (41 mg, 40%), MS (ISP) m/z=415.4 [(M+H)+], mp 174.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 1-hydroxy-cyclopropanecarboxylic acid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1O[CH2:8]1)[CH:2]1[O:4][CH2:3]1.OC1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=CC=1>>[CH3:19][C:17]([C:14]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:24][CH:25]=1)[CH3:18]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C(OCC1CO1)C1CO1
Product: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1

Procedure:
By use of The Dienoxy A copolymer described above, a 1,2-polybutadiene epoxy copolymer composition of approximately 33/67 composition was prepared and both the epoxy constituent and the polybutadiene constituent were cured. It should be noted that the blend of Dienoxy A copolymer with the additional diglycidylether of bisphenol A (DGEBA) and the anhydride curative system formed a stable dispersion while a blend of 1,2-polybutadiene with DGEBA and the anhydride curative system rapidly separated into two phases.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:33][N:34]([CH3:38])[C:35]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32])=[O:36]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Reactant: CN(C)C(=O)Cl
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and dimethylcarbamyl chloride employing methods similar to those described in Step 2 of Example 373 and was obtained as a lyophile: ES+ MS: 514 (M+H+).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][C:49]1[C:54]([NH2:55])=[CH:53][CH:52]=[CH:51][N:50]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:55][C:54]4[C:49]([CH3:48])=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1ncccc1N
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2cccnc2C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-methyl-pyridin-3-ylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H48Cl2N7O3 [(M+H)+] 756.319, observed 756.3195.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[S:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[S:38][C:39]1[CH:40]=[C:41]([NH:42][C:9]([NH:8][C:6]2[N:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)=[O:17])[CH:43]=[CH:44][CH:45]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
A stirred mixture of phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as described in Example 352A Step 3) (0.15 g, 0.50 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (0.16 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C. for 15 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford an oil which was recrystallized from diethyl ether. Further purification via preparative silica gel thin-layer chromatography (eluting with a mixture of 8% methanol in dichloromethane containing 0.5% ammonia) afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea (90 mg, 35%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 7.77 (s, 1H), 7.17-7.53 (m, 10H), 6.30 (s, 1H), 3.98 (s, 6H), 2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 527 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:25]=[O:26])[C:19]2[O:23][CH:22]=[CH:21][C:20]=2[CH:24]=1>O1CCCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:25]([C:18]2[C:19]3[O:23][CH:22]=[CH:21][C:20]=3[CH:24]=[C:16]([F:15])[CH:17]=2)[OH:26])=[CH:7][N:6]=1
Reactant: O=Cc1cc(F)cc2ccoc12
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cnc(Cl)nc1Cl)c1cc(F)cc2ccoc12
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 742.5 %

Procedure:
A solution of 5-bromo-2,4-dichloro-pyrimidine (1.0 g, 4.4 mmol, Aldrich) was dissolved in tetrahydrofuran (50 mL), cooled to −30° C., and treated slowly with isopropylmagnesium chloride (2.2 mL, 4.4 mmol, 2M in tetrahydrofuran, Aldrich). After stirring 0.5 hour between −30° C. and −25° C., the reaction was treated with a solution of 5-fluoro-benzofuran-7-carbaldehyde (0.65 g, 0.40 mmol, Step C) in tetrahydrofuran (10 mL). The temperature was slowly raised to −10° C. and then the reaction was quenched with aqueous 20% ammonium chloride. After 0.5 hours of stirring at ambient temperature, the mixture was diluted with hexane (100 mL), washed with water and dried (Na2SO4). Removal of solvent afforded crude (2,4-dichloro-pyrimidin-5-yl)-(5-fluoro-benzofuran-7-yl)-methanol as an oil. Purification was by silica gel chromatography (50% ethyl acetate/hexane) to give 930 mg of oil (˜70%). HRMS, observed: 311.9863; Calcd for (M+H)+: 311.9869
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]#[N:9])(=[O:4])[C:2]#[CH:3].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>C(Cl)(Cl)Cl>[CH2:10]([N:12]([CH2:13][CH3:14])/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH2:7][C:8]#[N:9])=[O:4])[CH3:11]
Reactant: C#CC(=O)OCCC#N
Reactant: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(/C=C/C(=O)OCCC#N)CC

Procedure:
A solution of 48 g (0.39 moles) of 2-cyanoethyl propiolate in 100 ml of chloroform was treated with a solution of 28.5 g (0.38 moles) of diethylamine in 100 ml of chloroform. The temperature was kept at 10° to 20° C. during the addition. The chloroform was stripped off and the product used without purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[CH:25][CH:24]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(-c3ccc(F)cc3)cc2)CC1
Reaction time: 1 h
Yield: 79.4 %

Procedure:
12.5 g of acetyl-4-piperidinecarbonyl chloride were added portionwise to a mixture of 10 g of 4-fluoro-1,1′-biphenyl, 17.5 g of aluminum-(III)-chloride and 60 g of 1,2-di-chloroethane. Upon completion, stirring was continued for 1 hour at reflux temperature. The reaction mixture was poured into a mixture of crushed ice and hydrochloric acid. The product was extracted with DCM. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 15 g (80.8%) of 1-acetyl-4-[(4′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl]piperidine (interm. 3).
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[C:3]#[N:4].[C:6]([N:10]=[C:11]=[O:12])([CH3:9])([CH3:8])[CH3:7]>O1CCCC1>[C:3]([CH:2]([NH:1][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH3:5])#[N:4]
Reactant: CC(N)C#N
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Product: CC(C#N)NC(=O)NC(C)(C)C

Procedure:
To a stirring solution of 21.1 g (0.3 mole) 2-aminopropionitrile in 300 ml. dry tetrahydrofuran under a nitrogen atmosphere, there is added 30.7 g (0.3 mole) t-butyl isocyanate (97%). The resulting mixture is heated at reflux for five hours. At the end of this period, the tetrahydrofuran is removed at reduced pressure. The solid is recrystallized from methanol:water, 60:40, to give N-(1-cyanoethyl)-N'-(1,1-dimethylethyl)urea, m.p. 161°-3°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH3:36])[C:34]=1[NH2:35])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:7]=1.[F:37][C:38]([F:44])([F:43])[CH2:39][C:40](O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:21]2[NH:20][C:19](=[O:31])[N:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[C:6]([O:5][C:4]5[CH:32]=[C:33]([CH3:36])[C:34]6[N:35]=[C:40]([CH2:39][C:38]([F:44])([F:43])[F:37])[NH:1][C:2]=6[CH:3]=5)[N:11]=[CH:10][N:9]=4)[CH2:17][CH2:16]3)[CH2:24][CH2:23][C:22]=2[CH:25]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(CC(F)(F)F)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g (0.42 mmol) 3-{1-[6-(3,4-diamino-5-methyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 60 mg (0.46 mmol) 3,3,3-tri-fluoropropionic acid, 0.15 g (0.47 mmol) TBTU and 0.14 mL (1.0 mmol) TEA in 2.0 mL DMF were stirred for 4 h at RT. Then 2.0 mL glacial acetic acid was added and the mixture was stirred overnight at RT. In addition the reaction mixture was stirred for 1 h at 100° C., then cooled and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:22])[C@@H:11]([OH:21])[C@@H:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C([N+]([O-])=O)=CC=C([O:32][C:33]([O:35][CH2:36][C:37]2[S:41][CH:40]=[N:39][CH:38]=2)=O)C=1>O1CCCC1.C(Cl)(Cl)Cl>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@H:10]([OH:22])[C@H:11]([OH:21])[C@@H:12]([NH:20][C:33]([O:35][CH2:36][C:37]1[S:41][CH:40]=[N:39][CH:38]=1)=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@@H](N)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1

Procedure:
A solution of 0.133 mmol of (2S,3R,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane and 0.147 mmol of ((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate in 10 ml of tetrahydrofuran was stirred at ambient temperature for 16 h. The resulting solution was diluted with 50 ml of chloroform, washed with several portions of 3N aqueous NaOH, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography of the residue provided the desired compound.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([NH:15][C:16]([CH:18]1[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][NH2+:19]1)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:9]1([CH2:8][NH:15][CH2:16][CH:18]2[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCc1ccccc1)C1[NH2+]CCCC1c1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc(CNCC2NCCCC2c2ccccc2)cc1
Reaction time: 18 h
Yield: 20 %

Procedure:
To a solution of 2-[(benzylamino)carbonyl]-3-phenylpiperidinium trifluoroacetate (604 mg, 1.48 mmol) in THF (2 ml) at 0° C. was added 2M borane-THF complex in THF (7.5 ml, 14.8 mmol). The reaction was allowed to stir for 18 h. Additional 2M borane-THF complex in THF (1.5 ml, 2.96 mmol) was added to the reaction mixture and allowed to stir for an additional 24 h. The reaction was quenched with methanol, concentrated in vacuo, and concentrated again from 4M HCl in dioxane. The crude product was purified via reverse phase preparative HPLC to yield 1-phenyl-N-[(3-phenylpiperidin-2-yl)methyl]methanamine (20%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.28 (m, 10H), 4.05 (m, 2H), 3.82 (m, 1H), 3.58 (d, J=10.9 Hz, 0.4H), 3.38 (m, 2H), 3.21 (m, 0.6H), 2.96 (m, 1H), 2.20 (m, 1H), 1.97 (m, 3H).
Reaction SMILES: [CH:1]([NH:4][N:5]=[C:6]([CH2:8][CH3:9])[CH3:7])([CH3:3])[CH3:2].Cl[O-:11].[Na+]>>[CH:1]([N:4]=[N:5][C:6]([OH:11])([CH2:8][CH3:9])[CH3:7])([CH3:3])[CH3:2]
Reactant: [O-]Cl
Reactant: CCC(C)=NNC(C)C
Agent: [Na+]
Product: CCC(C)(O)N=NC(C)C
Reaction time: 3 h

Procedure:
Into a 250 ml 4-neck round bottom flask equipped with a reflux condenser, thermometer, graduated addition funnel and a magnetic stirrer was added 18.1 grams (0.14 moles) of methyl ethyl ketone isopropyl-hydrazone. With efficient stirring 170 mls of 12.4% by wt. aqueous sodium hypochlorite was added dropwise while holding the reaction temperature at 25°-30° C. with a water bath. The oxidation was monitored by gas chromatography and after 3 hours stirring the hydrazone was completely oxidized. The reaction mixture was transferred to a separatory funnel and the spent aqueous hypochlorite solution separated. The organic layer was washed with 40 ml of cold 15% sodium bisulfite solution and then 25 ml of sodium bicarbonate solution. The organic layer was taken up in 50 ml of pentane, dried over anhydrous sodium sulfate, filtered and the pentane evaporated on a rotating evaporator under reduced pressure at 10°-20° C. The residue was an orange-yellow liquid weighing 9.4 grams (46.5% crude yield). The infrared spectrum of the product was similar to the infrared spectrum of 2-isopropylazo-2-hydroxybutane prepared by the α-chloro route (Example 5-a- 2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:24]1([N:30]2[CH:34]=[N:33][C:32]([C:35](Cl)=[O:36])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:35]([C:32]2[N:33]=[CH:34][N:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:31]=2)=[O:36])[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)c1ncn(-c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 2.19 g (10.5 mmol) 3-methyl-piperazine-1-carboxylic acid tert-butyl ester and 2.50 mL (14.6 mmol) DIPEA in 15 mL DCM was added a solution of 2.18 g (10.5 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carbonyl chloride in 15 mL DCM. The reaction mixture was stirred at RT for 3 days, then washed with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl.C1COCC1>[ClH:1].[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:10]1([CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:24])[CH3:35]
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCCC1(Cc2ccncc2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,3-dihydro-1-phenyl-3-(4-pyridinylmethyl)-2H-indol-2-one hydrochloride (33.7 g, 0.1 mol) in 200 ml CH2Cl2 was treated with 150 ml 1N NaOH. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to an oil which solidified on cooling. The "free base" was dissolved in 150 ml dry THF, cooled in an ice bath, treated with Nail (2.88 g, 0.12 mol), and stirred under dry nitrogen for 30 min. The mixture was treated with ethyl 4-bromobutyrate (19.5 g, 0.1 mol) in 25 ml dry THF. The mixture was stirred in the ice for 1 h and 16 h at room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between 300 ml Et2O and 200 ml water. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, treated with 150 ml 1N HCl-Et2O, and concentrated in vacuo. The residue was dissolved in 100 ml anhydrous EtOH with warming and stirred at room temperature for 24 h. The resulting crystals were collected by filtration, washed with a small portion of cold EtOH and Et2O, and dried in vacuo at 80° C. to give the desired product in 86% (38.6 g) yield; mp 182.5°-183.0° C.; IR(nujol): C=O @1722 and 1703 cm-1 ; NMR(DMSOd6TMS: δ1.15 (t, 3H, CH3), 1.2, 1.3 (2m, 2H, CH2CCCO), 2.1 (m, 2H, CH2CCO), 2.26 (t, 2H, CH2CO), [3.43 (d, 1H, J12), 3.64 (d, 1H, J12) CH2 -Pyr], 4.02 (q 2H, OCH2), [6.54 (m, 1H), 7.2 (m, 2 H), 7.5 (m, 5H), 7.68 (m, 1H) Ar--N-Phe], [7.10 (d, 2H), 8.70 (d, 2H) 4-Pyr]; Anal calcd for C26H26N2O3HCl, MW 450.97: C, 69.25; H, 6.04; N, 6.21. Found: C, 69.02; H, 5.98; N, 6.52. Mass spec m/e 415(M+1-HCl).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1.Cl>O1CCCC1>[NH2:4][C:3]1[O:13][C:9]([CH3:8])=[CH:10][C:11](=[O:12])[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: C=C1CC(=O)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(=O)c(C#N)c(N)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of malononitrile (3.3 g, 50 mmol) in anhydrous tetrahydrofuran (100 mL) was added sodium hydride (60%, 2.2 g, 55 mmol) at −10° C. The resulting reaction mixture was stirred for 2 hours. Then diketene (4.2 g, 50 mmol) was added dropwise to the solution. The reaction mixture was allowed to warmed to room temperature and continued to stir for 30 minutes. The mixture was neutralized with hydrochloric acid, and then concentrated in vacuo to give crude product as red solid, which was used in the next step without further purification.