Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:17]=[CH:16][CH:15]=3)=[O:12])=[C:4]2[N:3]=1.[NH3:29]>C(O)C>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([N:18]2[C:14]([NH:13][C:11]([C:10]3[CH:9]=[N:8][N:5]4[CH:6]=[CH:7][C:2]([NH2:29])=[N:3][C:4]=34)=[O:12])=[CH:15][CH:16]=[N:17]2)[CH:24]=[CH:23][CH:22]=1
Reactant: N
Reactant: O=C(Nc1ccnn1-c1cccc(C(F)(F)F)c1)c1cnn2ccc(Cl)nc12
Solvent: CCO
Product: Nc1ccn2ncc(C(=O)Nc3ccnn3-c3cccc(C(F)(F)F)c3)c2n1
Temperature: 25 °C
Yield: 4 %

Procedure:
A solution of 5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (210 mg, 0.52 mmol) in ethanol (20 mL) saturated with ammonia was heated to 100° C. overnight in a sealed tube. After cooling to room temperature, solvent was removed under reduced pressure, and the resultant residue was purified by preparative HPLC to afford 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-(3-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-amide (8 mg, yield: 4%). 1H NMR (DMSO, 400 MHz): δ 9.94 (s, 1H), 8.62 (d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.49-7.69 (m, 8H), 6.53 (s, 1H), 6.37 (d, J=7.6 Hz, 1H). MS (ESI) m/z: 388.1
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[N:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[N:20]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1nc(N)ccc1F
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2ccc(F)c(C)n2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 2-Amino-5-fluoro-6-methylpyridine instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a light yellow solid, MS (ISP): m/e=341 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][CH2:42][NH2:43])[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:36]=[C:37]([CH2:41][CH2:42][NH:43][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:15]([CH3:18])(=[O:17])=[O:16])[C:31]([F:32])=[CH:30][N:29]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Reactant: NCCc1cccc(Cl)c1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3cccc(Cl)c3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with 2-(3-chloro-phenyl)-ethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 518. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H), 8.18 (s, 1H), 7.97 (d, 1H), 7.49 (m, 2H), 7.15 (m, 4H), 4.56 (s, 2H), 3.93 (m, 1H), 3.64 (t, 2H), 3.33 (m, 2H), 3.04 (s, 3H), 2.98 (m, 2H), 2.91 (t, 2H), 1.91 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ccc(Br)cc2n1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To an ice cold solution of 7-bromo-2,4-dichloro-quinazoline (7 g, 0.0255 mol) in DCM (150 mL), morpholine (4.43 mL, 0.0509 mol) was slowly added and the reaction was continued at 0° C. for 30 min. The solvent was evaporated to dryness to get the crude compound. The crude product was purified, using column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to get the title compound (7 g, 84%). 1H NMR (300 MHz, CDCl3): δ 8.17 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 3.72-3.74 (m, 8H): LC-MS (ESI): Calculated mass: 327.0; Observed mass: 329.8 [M+H]+ (RT: 0.45 min).
Reaction SMILES: [F:1][CH:2]([C:4]1[N:9]=[CH:8][NH:7][C:6](=[O:10])[CH:5]=1)[CH3:3].[I:11]Cl.II.ClCl>C(O)(=O)C>[F:1][CH:2]([C:4]1[N:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[I:11])[CH3:3]
Reactant: CC(F)c1cc(=O)[nH]cn1
Reactant: ClI
Agent: ClCl
Agent: II
Solvent: CC(=O)O
Product: CC(F)c1nc[nH]c(=O)c1I
Temperature: 25 °C

Procedure:
To an acetic acid (150 ml) solution of 6-(1fluoroethyl)-4-pyrimidone (56.8 g) was added dropwise under room temperature and stirring an acetic acid solution of iodine monochloride prepared by adding iodine (50.8 g) to acetic acid (500 ml) and blowing chlorine (15 g) thereinto under room temperature and stirring, and the resulting mixture was stirred for 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[Cl:22]>CO.[Ni]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[Cl:22]
Reactant: COC(=O)Cc1c(Cl)cc(Nc2ncccc2[N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: COC(=O)Cc1c(Cl)cc(Nc2ncccc2N)cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of [2,6-dichloro-4-(3-nitro-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester (5 g, 14.0 mmol) and Raney Ni (˜1 g) in MeOH (100 mL) is stirred for 20 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound as a grey solid: ES-MS: 326.0/328.0 [M+H]+; tR=3.09 min (System 1); TLC: Rf=0.42 (CH2Cl2/MeOH, 95:5).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][C@H:31]([CH2:33][N:34]5[CH:38]=[C:37]([CH3:39])[N:36]=[N:35]5)[O:30][C:29]4=[O:40])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-:41].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:41][C:23]1[CH:24]=[C:25]([N:28]2[CH2:32][C@H:31]([CH2:33][N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[N:35]3)[O:30][C:29]2=[O:40])[CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([N:12]2[CH2:11][C@H:10]([CH2:9][OH:8])[O:14][C:13]2=[O:15])=[CH:17][CH:18]=1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(N5C[C@H](CO[Si](C)(C)C(C)(C)C)OC5=O)cc4)cc3)C(=O)O2)nn1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(N5C[C@H](CO)OC5=O)cc4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(5R)-5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-(4′-{(5R)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,1′-biphenyl-4-yl)-1,3-oxazolidin-2-one (0.016 g, 0.030 mM) was suspended in tetrahydrofuran (0.5 ml) and a 1N solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.03 ml) was added. The reaction was stirred at room temperature for one hour. The cloudy suspension was concentrated as a white residue.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])(=[O:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccccc1Oc1cccc(NC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Oc2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.2 %

Procedure:
To a stirred solution of methyl 2-(3-acetamidophenoxy)benzoate (4.7 g crude mixture) in dioxane (100 mL) was added 1.0 N NaOH (24 mL). After stirring at RT for 72 hr the reaction was acidified with 1.0 N HCl (24 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried (Mg SO4), and concentrated. The residue was purified by flash chromatography on silica gel (95:4:1 CHCl3/MeOH/AcOH) to give the crude title compound (2.2 g, 34%) as a beige solid: MS (ES) m/e 272.2 (M+H)+. The title compound prepared in this way contained approximately 46% of the diacid resulting from the di-ester starting material contaminant: MS (ES) m/e 392.2 (M+H)+. The mixture was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:31][C:32]([NH2:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][O:30][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:31][C:32]([NH2:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCC(CCO)CC3)cc2)cc1NCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Reaction time: 2 h
Yield: 62.7 %

Procedure:
60 mg of 4-(benzylamino)-6-({4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 57), 18 mg of triethylamine and 2 mg of 4-dimethylaminopyridine were dissolved in 5 mL of tetrahydrofuran, to which 18 mg of methanesulfonyl chloride was added under ice cooling, and stirred at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 44 mg (62%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([C:27]([O:29]C)=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].[CH:33]1([NH2:36])[CH2:35][CH2:34]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CO>[CH:33]1([NH:36][C:27]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2OCCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2OCCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
To a solution of methyl 1-{4-[(ethylamino)carbonyl]phenyl}-5-(3-phenylpropoxy)-1H-1,2,3-triazole-4-carboxylate (106 mg, 0.26 mmol) obtained in Example 1211b) in methanol (3 ml) was added 1N sodium hydroxide (1 ml), the mixture was stirred at 60° C. for 30 min, and the solvent was evaporated. The residue was adjusted to pH 2-3 with 1N hydrochloric acid. The precipitated crystals were collected by filtration, dried and dissolved in DMF (3 ml). Cyclopropylamine (15 mg, 0.26 mmol), HOBt (44 mg, 0.26 mmol) and WSC (55 mg, 0.29 mmol) were successively added, and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a white powder (88 mg, 78%).
Reaction SMILES: O=[CH:2][C@@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:22](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.CCOC(C)=O>[CH2:5]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:4][C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:2]#[CH:22]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#C[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of (S)-di-tert-butyl (4-oxobutane-1,3-diyl)dicarbamate (1.47 g, 4.86 mmol) in MeOH (30 mL) was added potassium carbonate (1.680 g, 12.15 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.40 mL, 7.29 mmol), sequentially. After stirring for 15 h, the mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (0.943 g, 65%). LCMS: Rt=0.81 min, m/z=321.1 (M+Na) Method 2m_acidic.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH:9]=[CH:8][C@H:7]2[O:11][C:12]([NH2:14])=[N:13][C@@H:6]12)=[O:4].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH2:10][CH:9]=[CH:8][C:7]1[O:11][C:12]([NH2:14])=[N:13][CH:6]=1
Reactant: COC(=O)N1CC=C[C@H]2OC(N)=N[C@H]21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)NCC=Cc1cnc(N)o1
Temperature: 25 °C

Procedure:
A solution of product 5 (1.2 g, 6.1 mmol, 0.08M) in DMSO (75.5 ml) is heated at 175° C. for 1 h 30. After cooling at ambient temperature, the reaction mixture is poured onto water (200 ml), basified (5% Na2CO3) to a pH of greater than 10 and then extracted with DCM (4×150 ml). The aqueous phase is then saturated with NaCl and then extracted with DCM (4×150 ml). The organic phases are combined, dried (MgSO4) and then evaporated. The crude product obtained (6.6 g) is then purified by chromatography on silica gel (DCM (sat. NH3) and then DCM (sat. NH3)/MeOH, 98/2). Product 18 (Rf=0.36, DCM/MeOH(NH3): 98/2) is obtained in the form of a brown semisolid (265 mg, 22%), an inseparable mixture of Z/E (14:86) isomers.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[H-].[Na+].[N:28]([CH:31]([CH3:33])[CH3:32])=[C:29]=[O:30]>CN(C=O)C>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:4]2[N:5]=[C:6]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:7]=[C:2]([NH:1][C:29]([NH:28][CH:31]([CH3:33])[CH3:32])=[O:30])[N:3]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: CC(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of compound (1) (1.0 g) and sodium hydride (0.11 g), in DMF (20 ml) was stirred for 20 minutes at RT under argon flow. Then, 2-isocyanato-propane (0.27 ml) was added dropwise over 30 minutes and the reaction mixture was allowed to stir at RT overnight. The solvent was evaporated and water added. The residue was filtered, washed with water and diethyl ether, and recrystallized from 1,4-dioxane. The precipitate was filtered off and dried, yielding 0.95 g (85.1%) of N-[4-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-N′-(1-methylethyl)-urea (compound 6, mp. 267-268° C.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18][O:19][CH2:20]Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:18][O:19][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCl
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2,4-di-tert-butylphenol (20.6 g, 0.1 mol) in dry THF (50 mL) is added with stirring to a suspension of NaH (2.4 g, 0.1 mol) in dry THF (150 mL). After 1 h of stirring, the mixture is cooled to 0° C., and chloromethyl methyl ether (7.6 mL, 0.1 mol) is added. The reaction mixture is stirred at room temperature for 2 h, quenched with water (500 mL) and extracted with Et2O (2×100 mL). The combined organic phase is dried over MgSO4 and evaporated under reduced pressure. The residue is used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:22])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.N1C=CC=CC=1.O>[Br:22][C:3]1[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:10][C:9]2[C:5](=[C:6]([C:18]([NH:20][CH3:21])=[O:19])[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:8]=2)[CH:4]=1
Reactant: CNC(=O)c1c2cc(Br)c(N)cc2nn1-c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(Br)c(NS(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-(4-fluorophenyl)-N-methyl-2H-indazole-3-carboxamide (0.75 g, 2.1 mmol) in DCM/Pyridine (10 mL/3 mL) was added MsCl (1.2 g, 10.5 mmol) under N2 at 0° C. for 30 min. The reaction was stirred at 25° C. for 8 hours. The reaction mixture was diluted with water, extracted with EtOAc and washed with brine, and then dried over Na2SO4. After concentration, the residue was purified by column chromatography (PE:EA=2:1) to give crude 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)-2H-indazole-3-carboxamide (0.65 g, yield: 78%). 1H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 8.03 (s, 1H), 7.56˜7.60 (m, 2H), 7.20˜7.25 (m, 2H), 6.97 (s, 1H), 5.73 (s, 1H), 3.08 (s, 3H), 2.99 (d, J=4.8 Hz, 3H). MS (M+H)+: 441/443.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]#[N:10])([CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH:16]([CH3:21])[O:17][CH:18]([CH3:20])[CH2:19]2)[CH2:23][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)=[CH:4][CH:3]=1
Reactant: CC1CN(CCCC(C#N)c2ccc(Cl)cc2)CC(C)O1
Reactant: ClCn1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCC(C#N)(Cn2cncn2)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This compound (1.2 g.) was prepared using the procedure described in Example 2b except using 1.0 g. (3.3 mmoles) of 2-(4-chlorophenyl)-5-(2,6-dimethyl-4-morpholinyl)valeronitrile, 0.38 g. (3.3 mmoles) of 1-(chloromethyl)-1,2,4-triazole, and 0.16 g. (3.6 mmoles) of sodium hydride in 35 ml. of DMF and was isolated as a yellow oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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[O:6][CH2:5]1.[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)#[N:29]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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:34](=[O:35])[C:33]5[CH:37]=[CH:38][C:30]([C:28]#[N:29])=[CH:31][CH:32]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (22.6 mg, 60.2%), MS (ISP) m/z=461.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 4-cyanobenzoic acid.
Reaction SMILES: CN(C=O)C.F[C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:10]2[NH:11][C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[CH:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([SH:30])[C:24]=2[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:20]1[C:29]2[C:24](=[C:25]([S:30][C:7]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:10]4[NH:11][C:12](=[O:14])[NH:13][C:9]=4[CH:8]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Sc1cccc2cnccc12
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc2[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a DMF solution 15 ml of 5-fluoro-6-nitrobenzoimidazolinone 500 mg (2.5 mmol) and 5-isoquinolinethiol 450 mg (2.8 mmol), potassium carbonate 550 mg (4.0 mmol) was added, and the mixture was heated with stirring for 2 hours at 100° C. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated water solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol, and 5-(5-isoquinolylsulfanyl)-6-nitro-2,3-dihydro-1H-benzo[d]imidazol-2-one 346 mg (40.3%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.[OH-].[Ca+2].[OH-].[C:17](CC(Cl)=O)([CH3:20])([CH3:19])[CH3:18]>Cl>[C:17]([C:6]1[C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:3][C:2]=1[CH3:1])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Product: Cc1[nH]n(-c2ccccc2)c(=O)c1C(C)(C)C
Reaction time: 8 h

Procedure:
3-Methyl-1-phenylpyrazol-5-one (5 g; 0.029 mole) was placed in a flask equipped with a stirrer and reflux condenser. Dry and distilled dioxane (40 ml) was added by warming and to the clear solution calcium hydroxide (6.4 g; 0.086 mole) was added followed by drop wise addition of tert-butylacetyl chloride (4.8 ml; 0.034 mole). The mixture was heated to reflux for 4 hours and then poured into 2M HCl (200 ml) to decompose the calcium complex. A light brown precipitate formed immediately, which was filtered off under suction after refrigerating overnight. The product washed with water and dried under vacuum at 50° C. The product was recrystallised from methanol to give an off-white crystalline solid, m.p 85-86° C.; 6.8 g (82%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:32])[C:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][CH2:8][C:7](=[CH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:12])[CH2:6][CH2:5]1>[Pd].CO>[CH3:32][N:3]([CH3:2])[C:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:12])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCc2c[nH]c3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCc2c[nH]c3ccccc23)CC1
Reaction time: 6 h
Yield: 29 %

Procedure:
Palladium-on-charcoal (5%, 20 mg) was added to a solution of 2-(4-dimethylamino-4-phenyl-cyclohexylidene)-N-[3-(1H-indol-3-yl)propyl]-acetamide (base of Example 16; 305 mg, 0.734 mmol) in abs. methanol (30 ml). The reaction mixture was hydrogenated at RT under a pressure of 3 bar for 6 h. The catalyst was separated off over Celite and the filtrate was concentrated. After separation of the residue (289 mg) by chromatography on silica gel (20 g) with EA/methanol (2:1), the product was isolated as a beige-coloured oil in a yield of 29% (95 mg).