Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](N[C@@H](CC1C=CC(C)=CC=1)C(O)=O)=O)(C)(C)C.[C:21]([O:25][C:26]([NH:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36](OC[C@H]2COC(C)(C)O2)=[CH:35][CH:34]=1)[C:30]([OH:32])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].N1([O:57][C:58]([N:62](C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(OC(N[C@H](C1C=CC(OCC(OC)OCC)=CC=1)C(O)=O)=O)(C)(C)C.C(NC1C=CC([C@@](C(OC(C)(C)C)=O)(N)C(O)=O)=CC=1)(=O)C.COCC(Cl)=O>>[C:21]([O:25][C:26]([NH:28][C@H:29]([C:33]1[CH:34]=[CH:35][C:36]([NH:62][C:58](=[O:57])[CH2:1][O:5][CH3:6])=[CH:37][CH:38]=1)[C:30]([OH:32])=[O:31])=[O:27])([CH3:22])([CH3:23])[CH3:24]
Reactant: Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Agent: CC(=O)Nc1ccc([C@@](N)(C(=O)O)C(=O)OC(C)(C)C)cc1
Agent: CCOC(COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)OC
Agent: COCC(=O)Cl
Product: COCC(=O)Nc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) 2-fluoro-4-iodoaniline was used in place of 4-bromoaniline in step 2, (ii) O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexaflurorophosphate was used as the coupling reagent in place of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexaflurorophosphate in step 4, and (iii) (R)-tert-butoxycarbonylamino-[4-(2-methoxy-acetylamino)-phenyl]-acetic acid was used in place of (R)-tert-butyloxycarbonylamino-4-methyoxyphenyl-glycine in step 4. (R)-tert-Butoxycarbonylamino-[4-(2-methoxy-acetylamino)-phenyl]-acetic acid was prepared by the same method as described for preparation of (R)-(4-acetylamino-phenyl)-tert-butoxycarbonyl-amino-acetic acid in example 26 except that methoxy-acetyl chloride was used in place of acetic anhydride in step 5.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:17])C(=O)C1>C(#N)C>[Br:17][C:2]1[S:1][C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1NCc2ccsc21
Solvent: CC#N
Product: O=C1NCc2cc(Br)sc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,5-Dihydro-thieno[2,3-c]pyrrol-6-one (0.365 g, 2.63 mmol) is dissolved in acetonitrile (10 mL), and NBS (0.47 g, 2.63 mmol) is slowly added at −10° C. The reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue taken-up in EtOAc and washed with 1M NaOH. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The crude is purified by silica gel column chromatography eluting with a 50:50 mixture and then 50:70 petroleum ether-EtOAc. The title compound is isolated (91.1 mg, 16%). HPLC (254 nm): Rt 2.55 min (70.3%), m/z 218/220 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:27]([CH3:28])[C:18]2=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=[C:17]2[N:16]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:2]([S:5][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:27]([CH3:28])[C:18]2=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=[C:17]2[N:16]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)S
Reactant: Cn1c(-c2ccccc2F)nc2cc(C(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2SC(C)(C)C)nc2cc(C(F)(F)F)cnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a mixture of tert-butylthiol (0.67 g) and DMF (12 ml), sodium hydride (60% in oil) was added under ice-cooling. The mixture was stirred under ice-cooling for 10 minutes, and then 2-(2-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (1.09 g) was added. The mixture was stirred at room temperature for 1 hour, and then stirred with heating at 60° C. for 1.5 hours, then at 80° C. for 2 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.19 g of 2-(2-tert-butylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 15).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2].[C:32](OCC)(=O)C.CCCCCC>>[OH:3][C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])([CH3:32])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c(C(C)(C)O)c2c1C(c1ccc(C(C)C)cc1)CO2
Yield: 34 %

Procedure:
Using N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 32, the title compound was synthesized in the same manner as in Example 22. Yield: 34%. Melting point: 133-134° C. (ethyl acetate-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(OCC)(=O)C>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 34.8 %

Procedure:
A solution of 3-nitrobenzoyl chloride (4.76 g) in dichloromethane (20 ml) was added to a suspension of aluminum chloride (3.42 g) in dichloromethane (50 ml) at 25° C., and the mixture was stirred at the same temperature for an hour. A solution of indole (3.0 g) in dichloromethane (20 ml) was added to the mixture at 25° C. After stirring for an hour at 25° C., the reaction mixture was poured into a mixture of ethyl acetate and ice water. The organic layer was separated, washed with water, and dried over magnesium sulfate. After evaporation of solvent, the crystalline residue was recrystallized from ethyl acetate to give 3-(3-nitrobenzoyl)indole (2.37 g) as pale red crystals. The mother liquid was purified by column chromatography on silica gel (20 g) with chloroform as eluent to give another crystals of 3-(3-nitrobenzoyl)indole (0.277 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[N:11]=[C:10]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:9]([N+:18]([O-:20])=[O:19])=[C:8]([CH:21]([CH3:23])[CH3:22])[N:7]=1>CO>[CH3:1][O:2][C:6]1[N:11]=[C:10]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:9]([N+:18]([O-:20])=[O:19])=[C:8]([CH:21]([CH3:23])[CH3:22])[N:7]=1
Reactant: C[O-]
Reactant: CCC(CC)Nc1nc(Cl)nc(C(C)C)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCC(CC)Nc1nc(OC)nc(C(C)C)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of sodium methylate in methanol (prepared from 1.2 g (50 m-moles) of sodium in 50 ml of methanol) is added to 14.4 g (50 m-moles) of 2-chloro-4-(3-pentylamino)-5-nitro-6-isopropyl-pyrimidine in 100 ml of methanol and the mixture is stirred for 1 hour. The solvent is distilled off and the residue is suspended in water and extracted with ether. The ethereal extracts are dried over MgSO4 and evaporated to yield 14 g of 2-methoxy-4-(3-pentylamino)-5-nitro-6-isopropyl-pyrimidine as an oil (nD20 : 1.5412).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]([NH:33][C:34]1[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:44])[CH:40]=3)[N:35]=1)[CH2:28][CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH:29]([NH:33][C:34]1[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:44][C:1]([NH:22][CH:19]4[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]4)=[O:12])[CH:40]=3)[N:35]=1)[CH2:28][CH2:27]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)N1CCC(N)CC1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Product: CC(C)N1CCC(NC(=O)Nc2ccc3nc(NC4CCc5cc(F)ccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no: 127285-08-9) and rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine; MS: m/e=460.6 (M−H+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C1(C)C=CC=CC=1>C(OCC)(=O)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>[F:19][C:20]1[CH:25]=[C:24]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCCc2ccc(-c3cccc(F)c3)cc21
Temperature: 80 °C
Yield: 54.4 %

Procedure:
Cesium carbonate (869 mg, 2.67 mmol) was added to a solution of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (300 mg, 1.33 mmol), (3-fluorophenyl) boronic acid (372 mg, 2.67 mmol) and toluene (20 mL) in a 50 mL Schlenk tube. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then tetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient), to afford 174 mg (54%) of 7-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:20]=[O:21])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([F:30])([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>[Zn]>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH:20]([OH:21])[C:23]([F:30])([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=C[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: [Zn]
Product: CCOC(=O)C(F)(F)C(O)C(CC1CCCCC1)NC(=O)OCc1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared in 37% yield from N-benzyloxycarbonyl-3-cyclohexylalaninal, ethyl bromodifluoroacetate and zinc by the procedure described in Example 1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=1[CH2:22][C:23](O)=[O:24])([CH3:9])[CH3:8].[CH:26]([C:29]1[CH:34]=[C:33]([S:35][C:36]#[N:37])[CH:32]=[C:31]([CH:38]([CH3:40])[CH3:39])[C:30]=1[O:41][S:42](=[O:45])(=[O:44])[NH2:43])([CH3:28])[CH3:27].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O>[CH:26]([C:29]1[CH:34]=[C:33]([S:35][C:36]#[N:37])[CH:32]=[C:31]([CH:38]([CH3:40])[CH3:39])[C:30]=1[O:41][S:42](=[O:44])(=[O:45])[NH:43][C:23](=[O:24])[CH2:22][C:11]1[C:10]([CH:7]([CH3:8])[CH3:9])=[CH:15][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:13][C:12]=1[CH:19]([CH3:21])[CH3:20])([CH3:27])[CH3:28]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Reactant: CC(C)c1cc(SC#N)cc(C(C)C)c1OS(N)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(SC#N)cc2C(C)C)c(C(C)C)c1
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Oxalyl chloride (0.6 mL, 6.9 mmol) was added dropwise to a solution of 2,4,6-triisopropylphenyl acetic acid (1.52 g, 5.8 mmol) in 150 mL toluene with 4 drops of N,N-dimethylformamide as a catalyst. The resulting solution was stirred overnight and then concentrated in vacuo. The residue was redissolved in 150 mL dichloromethane. Sulfamic acid 2,6-diisopropyl-4-thiocyanato-phenyl ester (1.70 g, 5.8 mmol) and triethylamine (2.0 mL) were added, and the resulting mixture was stirred for 2 hours. Washed with 1M HCl, dried the organic layer over magnesium sulfate, filtered, and concentrated to give 2.24 g of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 2,6-diisopropyl-4-thiocyanato-phenyl ester as a white solid; mp 164-165° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH3:19])=[CH:12][CH:11]=2)[C:5]([C:28]#[N:29])=[C:4]([SH:30])[N:3]=1.Cl[CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38].C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])[CH3:19])=[CH:14][CH:15]=2)[C:5]([C:28]#[N:29])=[C:4]([S:30][CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])[N:3]=1
Reactant: C[C@@H](COc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1)O[Si](C)(C)C(C)(C)C
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(F)cc2)nc1CSc1nc(N)c(C#N)c(-c2ccc(OC[C@H](C)O[Si](C)(C)C(C)(C)C)cc2)c1C#N

Procedure:
100 mg (0.18 mmol) of the compound from Example 7A, 45 mg (0.20 mmol) of 4-(chloromethyl)-2-(4-fluorophenyl)-5-methyl-1,3-oxazole and 46 mg (0.55 mmol) of sodium bicarbonate in 2 ml of dry DMF are stirred at RT for 20 h. The mixture is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). Removal of the solvent on a rotary evaporator gives the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[NH:17][C:16]2=[O:27])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:32])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:24])([F:25])[F:26])[N:17]([CH3:32])[C:16]2=[O:27])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c(F)c(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-fluoro-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-fluoro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 66°-68° C.,
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:28]4[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:27]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5cccc(N(C)S(C)(=O)=O)c5)cccn4n3)c2)CC1

Procedure:
A mixture of 4-(3-bromo-phenyl)-piperidine; hydrochloride (1.0 g, 3.6 mmol), 37% formaldehyde in water (3.7 mL, 120 mmol), Acetic acid (0.25 mL, 4.4 mmol) and methanol (20 mL) was stirred for 15 minutes at room temperature. The mixture was cooled to 10° C. in an ice/water bath. Sodium cyanoborohydride (3.0 g, 48 mmol) was added portionwise. A mild exotherm was noted. The mixture was stirred and warmed to room temperature over 18 hours. The mixture was poured into saturated aqueous ammonium chloride (200 mL) and stirred for 1 hour at room temperature. The mixture was extracted with dichloromethane (3×75 ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to an oil. The residue was triturated in ether (200 mL) and filtered. The filtrate was evaporated to an oil (0.585 g). The oil was dissolved in ether and stirred. Hydrogen chloride (2.0M in ether, 2.0 mL) was added dropwise and stirred for 30 minutes. The precipitate was filtered and rinsed with ether. 4-(3-Bromo-phenyl)-1-methyl-piperidine hydrochloride was isolated as a crude white solid (0.432 g, 41%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.52 (s, 1H), 7.47-7.41 (m, 2H), 7.37-7.21 (m, 2H), 3.52-3.41 (m, 2H), 3.10-2.95 (m, 2H), 2.85-2.78 (m, 1H), 2.75 (s, 3H), 2.15-2.78 (m, 4H). MS=254, 256 (MH)+. 129b) N-Methyl-N-(3-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.093 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.6 Hz, 1H), 8.10-8.07 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.27 (t, J=7.9 Hz, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.88 (d, J=7.7 Hz, 1H), 6.83 (s, 1H), 3.42 (s, 3H), 3.03-2.96 (m, 2H), 2.90 (s, 3H), 2.55-2.45 (m, 1H), 2.34 (s, 3H), 2.12-2.00 (m, 2H), 1.90-1.80 (m, 4H). MS=491 (MH)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([NH:13][C:14]3[CH:15]=[CH:16][C:17]4[S:21][C:20]([CH3:22])=[N:19][C:18]=4[CH:23]=3)=[N:8][CH:7]=[CH:6][C:5]=2[C:4]=1[NH2:24].F[C:26]1[C:31]([C:32]2[N:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[CH:33]=2)=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH3:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([NH:13][C:14]3[CH:15]=[CH:16][C:17]4[S:21][C:20]([CH3:22])=[N:19][C:18]=4[CH:23]=3)=[N:8][CH:7]=[CH:6][C:5]=2[C:4]=1[NH:24][C:26]1[C:31]([C:32]2[CH:33]=[C:34]([NH:38][CH3:39])[N:35]=[CH:36][N:37]=2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Cc1nc2cc(Nc3nccc4c(N)c(C)ccc34)ccc2s1
Reactant: CNc1cc(-c2cccnc2F)ncn1
Agent: Cl
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(Nc4ccc5sc(C)nc5c4)nccc23)ncn1
Temperature: 87 °C

Procedure:
6-methyl-N1-(2-methylbenzo[d]thiazol-5-yl)isoquinoline-1,5-diamine hydrochloride (5.94 g, 16.6 mmol) and 6-(2-fluoropyridin-3-yl)-N-methylpyrimidin-4-amine (4.74 g, 23.2 mmol, 1.40 equiv.) were combined in a 350 mL screw-cap pressure tube and flushed with nitrogen. 1M LiHMDS in THF (102 mL) were added in two portions (2×51 mL) at room temperature. The pressure tube was sealed and placed immediately in a pre-heated (87° C.) sonicator bath. The reaction mixture was sonicated at 85° C. for 30 min., cooled to room temperature. The resulting thick suspension was diluted with THF (0.2 L) and quenched into a mixture of sat. aq. NH4Cl (50 mL) and brine (100 mL). The organic layer was separated and concentrated in vacuo with silica (26 g). Column chromatography (CH2Cl2:THF 3:1)—two fractions were collected, the first contained starting material (0.5 L), fraction contained the title compound (2 L). The second fraction was concentrated in vacuo to dryness. The resulting foam was suspended in Et2O (0.12 L) and sonicated until all the material was converted into a homogenous suspension of fine yellow precipitate. 6-Methyl-N5-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl)-N1-(2-methylbenzo[d]thiazol-5-yl)isoquinoline-1,5-diamine was isolated by filtration as a light yellow powder (2.35 g, 28% yield). MS (M+H)+ 505.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:43]([C:47]1[S:48][CH:49]=[C:50]([CH2:52][S:53][CH2:54][CH2:55][NH2:56])[N:51]=1)[C:44]([NH2:46])=[NH:45].[C:57](=S)=[S:58]>CCOCC.C(O)C>[NH:43]([C:47]1[S:48][CH:49]=[C:50]([CH2:52][S:53][CH2:54][CH2:55][NH:56][C:57]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]2[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH3:25])=[S:58])[N:51]=1)[C:44]([NH2:46])=[NH:45]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COc1ccc(CN(CCN(C)CCCCCCN)c2ccccn2)cc1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(CN(CCN(C)CCCCCCNC(=S)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1
Reaction time: 12 h

Procedure:
0.48 g (1.3 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and 0.27 g (1.3 mmol) of dicyclohexylcarbodiimide are dissolved at -10° C. in absolute ether with 0.5 ml of carbon disulfide, the temperature is increased in the course of 3 hours to 20° C. and the batch is stirred for a further 12 hours. The solid that precipitates is filtered off and the filtrate is concentrated in vacuo. 0.30 g (1.3 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine dissolved in a small amount of absolute ethanol is added to the concentrated residue and the reaction batch is heated under reflux for 2 hours. It is then concentrated in vacuo and the residue is purified by rotation chromatography to yield the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=644 ([M+H]+, 1), 121 (100). For further analysis, a portion of the compound is converted into the tartaric acid salt and recrystallised from acetonitrile/isopropanol/petroleum ether; m.p.: 78° C. (acetonitrile/isopropanol/petroleum ether).
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[F:11][C:12]([F:22])([F:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:14]>C(O)(C)C>[F:11][C:12]([F:21])([F:22])[C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:14]
Reactant: NC(c1ccccc1)C(F)(F)F
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(C)O
Product: N[C@H](c1ccccc1)C(F)(F)F
Yield: 31.2 %

Procedure:
L-Tartaric acid (36 g, 240.0 mmol) was added to a solution of 2,2,2-trifluoro-1-phenylethanamine (40 g, 228.57 mmol) in isopropanol (400 mL). The solution was heated to reflux for 30 min. The mixture was cooled and the solid was collected by filtration. The material was diluted with Na2CO3/H2O and the aqueous mixture was extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over K2CO3 and concentrated under reduced pressure to afford (1R)-2,2,2-trifluoro-1-phenylethanamine (12.5 g, 31% yield) as a white solid.