Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[K])(C)(C)C.[CH:7]12[S:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9](=O)[CH2:8]2.S([CH2:26][N+:27]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CCOCC>CC(O)(C)C.COCCOC.COCCOC>[CH:7]12[S:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]([C:26]#[N:27])[CH2:8]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CC2CCC(C1)S2
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: COCCOC
Product: N#CC1CC2CCC(C1)S2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-BuOK (2.41 g, 21.52 mmol) in t-BuOH/DME 1:2 (24 ml) was added at 0° C. to a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.53 g, 10.75 mmol) and tosylmethyl isocyanide (2.3 g, 11.83 mmol) in DME (20 ml). The solution was stirred for 3 hours at room temperature. After addition of ether, the mixture was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated. After purification by chromatography on silica gel (hexane/AcOEt 85/15), 8-thiabicyclo[3.2.1]octane-3-carbonitrile was obtained as a colorless oil (1.03 g, 63%).
Reaction SMILES: C(O[C:4](=[C:9]=[O:10])[CH2:5][C:6]([OH:8])=[O:7])C.[CH2:11]([Li])[CH2:12]CC.[Cl:16][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1C(Cl)=O>O1CCCC1>[CH2:11]([O:8][C:6](=[O:7])[CH2:5][C:4]([C:18]1[C:17]([Cl:16])=[N:25][CH:24]=[CH:23][CH:22]=1)=[C:9]=[O:10])[CH3:12]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCOC(=C=O)CC(=O)O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=C=O)c1cccnc1Cl
Yield: 57.9 %

Procedure:
3-ethoxy-3-carbonylpropionic acid (13.2 g, 100 mmol) was dissolved in tetrahydrofuran (100 mL), n-butyl lithium (25.6 g, 400 mmol) was added dropwise at −78° C., reacted at low temperature for 1 h, 2-chloronicotinoyl chloride (17.5 g, 99.4 mmol) in tetrahydrofuran (20 mL) solution was added, and continuously reacted at low temperature for 3 h. After reaction was complete, extraction was performed with water/dichloromethane, organic phase was rotated for dryness, and separated by column chromatography to obtain product 13.8 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][C@H:14]([OH:18])[CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd].O=[Pt]=O>[C:6]([OH:34])(=[O:5])[CH3:7].[C:6]([OH:34])(=[O:5])[CH3:7].[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C@H:14]([OH:18])[CH2:15][CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(Cc1ccccc1)C[C@H](O)CC#N)C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCN)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 280.6 %

Procedure:
The Nεbenzyl nitrile (26) (4.80 g, 10.7 mmol) was dissolved in glacial acetic acid (100 ml); 10% Pd—C (0.50 g) and PtO2 (1.00 g) were added; and hydrogen gas was introduced. The reaction was complete after 6 hours, and the catalyst was filtered through a bed of Celite and washed with acetic acid. The filtrate was concentrated in vacuo. Azeotropic removal of the acetic acid with toluene gave (27) as a colorless oil (5.10 g, 99%) 1H NMR (500 MHz) (CD3OD) d 4.02-3.94 (m, 2H), 3.14-2.86 (m, 6H), 1.94 (s, 6H), 1.87-1.58 (m, 8H), 1.46 (s, 9H), 1.44 (s, 9H). 13C NMR (CD3OD) δ169.6, 156.54, 85.3, 70.2, 62.6, 56.6, 54.2, 53.9, 34.0, 31.1, 28.2, 26.3, 23.2. HRMS m/z calcd. for C19H40N3O5 390.2968, found 390.2977. [α]25D+0.6° (c=1.00, CH3OH).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(Cl)Cl.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>C(N(CC)CC)C>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Yield: 91.2 %

Procedure:
Diethyl aminomalonate hydrochloride (20.5 g) was suspended into 180 ml of methylene chloride, and 29.4 g of triethylamine was added while cooling with ice-cold water. After 30-minute-stirring, 15 g of p-toluoyl chloride was added dropwise, and the mixture was stirred for 24 hours at room temperature. The reaction solution was washed with water, dilute hydrochloric acid, and water, dried over anhydrous magnesium sulfate and concentrated. To the residue was added isopropyl ether, and the resultant crystals were collected by filtration and dried to provide 25.9 g of the objective compound as white crystal. M.p. 101–102° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[F:21][C:22]([F:39])([F:38])[O:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][C:32]([CH3:37])=[C:33]([CH2:35]I)[N:34]=2)[CH:27]=[CH:28][CH:29]=1>>[F:39][C:22]([F:21])([F:38])[O:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][C:32]([CH3:37])=[C:33]([CH2:35][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:34]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2cccc(OC(F)(F)F)c2)nc1CI
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(OC(F)(F)F)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-trifluoromethoxyphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 64 of molecular weight 519.52 (C27H28F3NO6), MS(ESI): 520.20 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[CH:12][N:11]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Brc1cnc(-c2cccnc2)nc1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2cnc(-c3cccnc3)nc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A mixture of 110 mg of 4-benzyl-5-bromo-2-(3-pyridyl)pyrimidine, 59 mg of 3-ethynyl-3-quinuclidinol, 19 mg of tetrakis(triphenylphosphine)palladium(0), 10 mg of cuprous iodide, 0.14 ml of triethylamine and 1.5 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 100° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 2.5% methanol/ethyl acetate, to give 62 mg of the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1I>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[Cl:37])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccccc1I
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2Cl)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 1-chloro-2-iodobenzene according to the general procedure C. Obtained as a yellow oil (886 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([O:4][C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:25]([OH:27])=O)[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH3:3].CN1CCCCC1.[C:36]1([CH2:42][CH2:43][CH2:44][NH2:45])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:3][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:17]([NH:19][C@@H:20]([C:25]([NH:45][CH2:44][CH2:43][CH2:42][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:27])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:6])[CH3:28]
Reactant: NCCCc1ccccc1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Temperature: 0 °C

Procedure:
The title product of Example 2 (7.4 g, 17.9 mmol) dissolved in 75 ml of CH2Cl2 was flushed with Ar and cooled to 0° C. N-methylpiperidine (NMP, 2.2 ml, 17.9 mmol) was added to the reaction before it was cooled to -78° C. and charged with 2.5 ml (17.9 mmol) of IBCF. The reaction was allowed to warm to -15°, maintained at this temperature for 15 min., cooled to -78°, and charged with 2.4 g (17.9 mmol) of 3 phenylpropyl amine (PPA). The crude product, obtained after a reaction work up by the method of Example 1, was chromatographed on a Waters prep 500 using a Porasil cartridge eluting with 2% to 3% ethanol (EtOH)/CH2Cl2. The title product was obtained as a white solid (4.54 g).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[CH3:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:26])[NH:20]2>>[Cl:25][C:24]1[C:16]([CH3:15])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:26])[C:18]2=[CH:9][C:8]1[CH:11]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Product: COc1cc(C)c(C=C2C(=O)Nc3ccc(Cl)c(C)c32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 4-methyl-5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][N:67]4[CH2:70][CH2:69][CH2:68]4)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][N:67]4[CH2:70][CH2:69][CH2:68]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=533, obsd.=533).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([F:18])[CH:14]=[CH:13][C:3]=1[C:4](C1C=CC(F)=CC=1)=[O:5].[OH:19]O>>[F:18][C:15]1[CH:14]=[CH:13][C:3]([OH:19])=[CH:2][CH:16]=1.[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([F:18])[CH:14]=[CH:13][C:3]=1[C:4]([OH:5])=[O:19]
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)c(Cl)c1Cl
Reactant: OO
Product: O=C(O)c1ccc(F)c(Cl)c1Cl
Product: Oc1ccc(F)cc1
Yield: 78 %
Yield: 60 %

Procedure:
If the procedure is as described in Example 13, except that 50.1 g (0.175 mol) of 2,3-dichloro-4,4'-difluorobenzophenone and 10 g of 90 percent hydrogen peroxide, solution are used, 11.8 g (0.105 mol, 60%) of 4-fluorophenol and 28.3 g (0.136 mol, 78%) of 2,3-dichloro-4-fluorobenzoic acid are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.CN1CCCC1=O.[C:25](Cl)(=O)[C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C)C1C=CN=CC=1.O>[C:26]([C:29]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[N:1]=1)([CH3:28])([CH3:27])[CH3:25]
Reactant: Nc1ncccc1C(=O)O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1nc2ncccc2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a mixture of 2-aminonicotinic acid (13.8 g, 100 mmol), 4-dimethylaminopyridine (1.2 g, 10 mmol), triethylamine (55.8 mL, 400 mmol) and N-methylpyrrolidone (140 mL, 42 mmol) was added pivaloyl chloride (24.1 g, 200 mmol) dropwise at 0° C., and after the drop wise addition was finished, which was stirred overnight at room temperature. To the reaction mixture was added water, extracted with toluene, and the organic layer was washed with water and saturated sodium chloride water. After the solution was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under a reduced pressure. To the residue was added n-heptane, which was suspended and stirred at 0° C., which was filtered, so as to obtain the title compound (16.6 g).
Reaction SMILES: [CH2:1]([N:7]([C:14]1[C:15](OCC)=[N:16][S:17](=[O:20])(=[O:19])[N:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:24]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH2:31])([CH3:27])([CH3:26])[CH3:25]>CCO>[C:24]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:31][C:15]1[C:14]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:18][S:17](=[O:19])(=[O:20])[N:16]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1OCC
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CCO
Product: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of 4-(N,N-di-n-hexylamino)-3-ethoxy-1,1-dioxo-1,2,5-thiadiazole (400 mg, 1.02 mmol) and L-tyrosine t-butyl ester (261 mg, 1.1 mmol) in EtOH (10 mL) was stirred at room temperature for 36 hrs. The solvent was removed under reduced pressure residue purified by flash column chromatography (silica, hexane:EtOAc 3:1 then 1:1) to give N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine tert-butyl ester as a white waxy solid (400 mg, 73%). Anal. Calc'd for C27H44N4O5 S.0.55EtOAc: C, 59.93; H, 8.34; N, 9.57. Found: C, 59.84; H, 8.44; N, 9.62.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[NH:25]([C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[O:43][CH3:44])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[C:26]1([NH:25][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][C:37]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([C@H:12]4[CH2:17][CH2:16][C@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[N:3]=3)=[CH:36][C:35]=2[O:43][CH3:44])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B(O)O)ccc1C(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)Nc1ccccc1

Procedure:
trans-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (266 mg, 0.604 mmol), 4-(anilinocarbonyl)-3-methoxyphenylboronic acid (180 mg, 0.664 mmol), palladium tetrakistriphenyphosphine (42 mg, 0.036 mmol) and sodium carbonate (154 mg, 1.449 mmol) were mixed with ethylene glycol dimethyl ether (8 mL) and water (4 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give trans-N1-phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (226 mg, 69%). 1H NMR (CDCl3) δ 1.58 (m, 4H), 2.17 (m, 7H), 2.32 (s, 3H), 2.52 (m, 2H), 2.69 (2.69, 3H), 4.16 (s, 3H), 4.78 (m, 1H), 5.49 (bs, 2H), 7.14 (m, 1H), 7.43 (m, 4H), 7.69 (m, 2H), 8.44 (m, 2H), 9.77 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =541.2, Rt=2.61 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.N[CH:31](C1C=CC(C(OC)=O)=CC=1)[CH2:32]C>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH:19]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[CH2:31][CH3:32])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reactant: CCC(N)c1ccc(C(=O)OC)cc1
Product: CCC(NC(=O)c1cc(F)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(1-aminopropyl)benzoate: 1H-NMR (CDCl3) δ 8.33–8.26 (2H, m), 8.05–7.99 (3H, m), 7.39 (2H, d, J=8.4 Hz), 7.20–7.15 (4H, m), 5.15 (1H, q, J=7.3 Hz), 3.90 (3H, s), 1.92 (2H, dq, J=7.3, 7.3 Hz), 0.95 (3H, t, J=7.3 Hz); MS (ESI) m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([N+:26]([O-])=O)[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:26][C:18]1[CH:17]=[C:16]([CH:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH:21]=[CH:20][C:19]=1[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1N
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 67, 100 mg, 0.236 mmol) in methanol (2 mL) was treated with a solution of ammonium chloride (27 mg, 0.500 mmol) in water (200 μL). The reaction mixture was then treated with zinc dust (151 mg, 2.31 mmol). The reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The celite pad was washed well with methanol. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (40 mg, 43%) as a white solid: mp 207-209° C.; EI-HRMS m/e calcd for C18H23N3O3S2 (M+) 393.1181, found 393.1180.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>ClCCl>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.7 %

Procedure:
Amine preparation: to N-BOC-piperazine (500 mg) in dichloromethane (5 mL) and triethylaamine (0.41 ml) was added 4-nitrophenyl chloroformate (541 mg). After 1 hour the reaction mixture was diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvent was removed in vacuo to yield piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (940 mg).
Reaction SMILES: [NH:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].I[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O>C(OC)(C)(C)C.O.O1CCCC1>[CH2:17]([N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[CH2:18][CH3:19]
Reactant: CCCI
Reactant: N#CCCCCCNCCCCCC#N
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCCN(CCCCCC#N)CCCCCC#N
Temperature: 60 °C
Yield: 81 %

Procedure:
A mixture of 6,6′-imino-bis-capronitrile (20.7 g, 100 mmol), 1-iodopropane (18.7 g 110 mmol), potassium carbonate (16.6 g, 120 mmol), and 100 mL of tetrahydrofuran was stirred and heated at 60° C. under nitrogen for three days. The product mixture was cooled to room temperature, and 25 mL of water was added to dissolve most of the solids. The aqueous layer was drawn off in a separatory funnel, a 125-mL portion of methyl t-butyl ether was added, and another small aqueous layer thus formed was drawn off. Gas chromatographic analysis of the product solution showed it to contain a small amount of unreacted secondary amine. Therefore, 10 g of anhydrous potassium carbonate and 2.5 g of 4-nitrobenzoyl chloride were added, and the mixture was stirred at room temperature for 30 minutes. Subsequent analysis by gas chromatography showed this treatment to have completely eliminated the unreacted starting material. The mixture was filtered, and solvent was removed by rotary evaporation at reduced pressure. Molecular distillation of the residue under high vacuum afforded 20.2 g (81 mmol, 81% of theory) of 6,6′-propylimino-bis-capronitrile.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[OH:19][N:18]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)[C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1
Reactant: NO
Reactant: CSc1cccc(C(=O)c2nnnn2C)c1
Agent: Cl
Solvent: c1ccncc1
Product: CSc1cccc(C(=NO)c2nnnn2C)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
To a stirred solution of [3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methanone (5.62 g, 24 mmol) in dry pyridine (30 mL) was added hydroxylamine hydrochloride (4.17 g, 60 mmol). The reaction mixture was stirred at 70° C. for 5 h, then concentrated in vacuo and diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and dried over MgSO4. Evaporation of the solvent in vacuo afforded N-hydroxy-1-[3-(methylsulfanyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine as a yellow solid [6.91 g, yield 99.3%; HPLC/MS: m/z=250 (M+H); logP(HCOOH)=1.98].