Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([CH2:32][O:33][CH3:34])[NH:31][C:27]=2[C:26]([C:35](ON2C3C=CC=CC=3N=N2)=[O:36])=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:3]1[C:2]([C:35]([C:26]2[C:27]3[N:31]=[C:30]([CH2:32][O:33][CH3:34])[NH:29][C:28]=3[C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:36])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COCc1nc2c(OC)ccc(C(=O)On3nnc4ccccc43)c2[nH]1
Reactant: Clc1cccc(Oc2ncccc2Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1nc2c(C(=O)c3cccnc3Oc3cccc(Cl)c3)ccc(OC)c2[nH]1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 18.8 %

Procedure:
A solution of 3-bromo-2-(3-chlorophenoxy)pyridine (0.43 g, Reference Example 16) in dry tetrahydrofuran (6 ml), at −70° C., was treated with butyl lithium in hexane (0.64 ml, 2.5 M). The mixture was then stirred at −70° C. for 45 minutes then treated with a solution of 1-benzotriazolyl 7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [0.177 g, Reference Example 1(a)] in dry tetrahydrofuran (2 ml) and stirring was continued at −70° C. for 10 minutes. The reaction mixture was allowed to warm to room temperature, then stirred at this temperature for 2 hours, then treated with aqueous ammonium chloride solution, and then extracted with ethyl acetate (20 ml). The organic extract was dried and concentrated to give a brown syrup which was purified by flash chromatography on silica eluting initially with a mixture of diethyl ether and pentane (1:1, v/v), then with a mixture of diethyl ether and pentane (7:3, v/v) and then with diethyl ether to give the title compound (0.04 g) as white solid, m.p. 181-183° C. [Elemental analysis:—C, 62.17, H, 4.32, N, 10.15%. Calculated :—C, 62.35, H, 4.28, N, 9.91%]. NMR (CDCl3):- δ 3.52(s, 3H), 4.13(s, 3H), 4.85(s, 2H), 6.73(d, J=8 Hz, 1H), 7.00(m, 1H), 7.12(t, J=2 Hz, 1H), 7.16(m, 1H), 7.2(dd,J=7 Hz,J=5 Hz, 1H), 7.28(t, J=8 Hz, 1H), 7.55(d, J=8 Hz, 1H), 7.85(dd,J=8 Hz,J=2 Hz, 1H), 8.83(dd,J=4 Hz,J=1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Br:16][C:17]1[CH:18]=[C:19]([C:24](Cl)=[O:25])[C:20]([Cl:23])=[N:21][CH:22]=1.BrC1C=C(C(O)=O)C(O)=NC=1.O=S(Cl)Cl>CC#N>[Cl:23][C:20]1[C:19]([C:24]([NH:1][C:2]2[C:3]([NH:8][CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:25])=[CH:18][C:17]([Br:16])=[CH:22][N:21]=1
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Reactant: CCNc1ncccc1N
Agent: O=C(O)c1cc(Br)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCNc1ncccc1NC(=O)c1cc(Br)cnc1Cl
Reaction time: 0.08 h

Procedure:
To a cooled solution of 3-amino-2-(ethylamino)pyridine (30.6 g, 223 mmol) in MeCN (740 mL) was added solid NaHCO3 (56.3 g, 669 mmol). After 5 min, crude 5-bromo-2-chloro-3-pyridinecarbonyl chloride (prepared from 5-bromo-2-hydroxy-3-pyridinecarboxylic acid and SOCl2 [as described by T. W. Gero et al. in Synth. Commun. 1989, 19, 553-559 (incorporated herein by reference) but with omission of the aqueous work-up] was added (1 equiv., 223 mmol). After 2 h, the reaction mixture was poured over ice/H2O (1.5 L) and the resulting solid was filtered, rinsed with H2O and then hexane. After drying under reduced pressure overnight, the title compound was obtained as a black solid (54.9 g, 69% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].CI.[C:14](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:14][NH:11][C:6]1[C:7]([NH2:10])=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A 1 L round bottom flask was charged with 4-nitrobenzene-1,2-diamine (40 g, 0.26 mol), methyl iodide (13 ml, 0.21 mol) and DMF (300 ml), followed by the addition of saturated sodium carbonate (60 ml) over 2-3 minutes under rapid stirring. After stirring overnight at room temperature the reaction mixture was filtered and then concentrated in vacuo to a dark red oil. The residue was purified by flash column chromatography (15 to 30% ethyl acetate/petrol) to afford the title compound (27 g, 61% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.CN(C)C=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: C1COCCN1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1ccc2nc(N3CCOCC3)n(-c3ccc(C)cc3)c2c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
240 mg of 6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 0.2 ml of N,N-dimethylformamide and 0.7 ml of morpholine, and the mixture was stirred for 7.5 hours at 110° C. Another 0.7 ml of morpholine was added and heated for another 4 hours at 110° C. It was mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 7 mg was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2cccc(Br)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(Br)c3)CC2)cc1
Yield: 65.5 %

Procedure:
0.38 g (0.001.41 mol) of 1-(3-bromo-benzyl)-piperidin-4-ol and 0.49 ml (0.0035 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.23 ml (0.00176 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.358 g (65%) of 1-(3-bromo-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:6](O)=[O:7].[N:29]1[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[S:31][C:30]=1[NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)(=[O:16])=[O:17])=[CH:11][CH:10]=1)[C:6]([NH:38][C:30]1[S:31][C:32]2[C:37]([N:29]=1)=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:7]
Reactant: Nc1nc2cccnc2s1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1nc2cccnc2s1)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 119 %

Procedure:
The compound of example A78 was obtained by similar method described in example A75 using (2,4-Difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid (Preparation 2) (0.1 g, 0.27 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.042 g, 0.33 mmol), HOBt (0.044 g, 0.33 mmol), and EDCI (0.062 g, 0.33 mmol), N-methyl morpholine (0.034 g, 0.33 mmom) in DMF (10 mL) to provide the title compound (0.175 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([CH2:28][C:29](O)=[O:30])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH2:28][C:29]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:30])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN(c1cccc(Cl)c1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN(c1cccc(Cl)c1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
The mixture of [[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-acetic acid 100 mg, 0.211 mmol), Cyclohexylamine (25 mg, 0.253 mmol), EDC.HCl (48 mmg, 0.253 mmol), HOBt (34 mmg, 0.253 mmol) and DIPEA (82 mmg, 0.633 mmol) in acetonitrile (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 48 mg of rac-2-[[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(3-chloro-phenyl)-amino]-N-cyclohexyl-acetamide as a yellow solid. MS: [M+H]+=556.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[N:54]1([S:58]([NH:61][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]3)=[CH:31][C:32]=2[F:38])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC1(C)CCCC(COc2cc(F)c(C(=O)O)cc2C2CC2)C1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(C)CCCC(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 158 step 5 and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained (0.12 g, 41%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.72-8.59 (m, 1H), 7.63-7.55 (m, 1H), 6.61-6.51 (m, 1H), 4.34-4.16 (m, 4H), 3.86-3.70 (m, 2H), 2.34-2.20 (m, 2H), 2.13-2.00 (m, 2H), 1.97-1.86 (m, 1H), 1.70-1.38 (m, 4H), 1.20-0.90 (m, 11H), 0.72-0.63 (m, 2H); MS (ES+) m/z 439.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([NH:26][C:27]2[N:32]=[C:31]([C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH3:42])[CH:34]=3)[CH:30]=[CH:29][N:28]=2)=[CH:20][C:19]=1[NH2:43].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)[C:19]([NH2:43])=[CH:20][C:21]=1[NH:26][C:27]1[N:32]=[C:31]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH3:42])[CH:34]=2)[CH:30]=[CH:29][N:28]=1
Reactant: COc1cc(Br)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 83.4 %

Procedure:
1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.74 mg, 0.03 mmol) was added to a solution containing 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 144, 220 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was heated at 100° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc. This solution was washed with water (×3), brine, and was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (191 mg, 84%) as a tan solid after trituration with diethyl ether; 1H NMR: 2.31 (3H, s), 2.37-2.43 (2H, m), 2.61 (2H, t), 3.01-3.04 (2H, m), 3.76 (3H, s), 3.89 (3H, s), 4.37 (2H, br s), 5.70-5.73 (1H, m), 6.63 (1H, s), 7.18-7.22 (2H, m), 7.25-7.29 (1H, m), 7.54 (1H, d), 7.63 (1H, s), 7.81 (1H, s), 8.31 (1H, d), 8.34 (1H, s), 8.46 (1H, d); m/z: ES+ MH+ 441.57.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:17])OCC(Cl)(Cl)Cl.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:29]=[C:28]([NH2:30])[NH:27][N:26]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:30][C:28]1[NH:27][N:26]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[F:18])[CH:29]=1)=[O:17]
Reactant: O=C(Nc1cccc(Cl)c1Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc(-c2ccccc2F)n[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(-c2ccccc2F)n[nH]1)Nc1cccc(Cl)c1Cl
Yield: 92.1 %

Procedure:
A solution of 2,2,2-trichloroethyl 2,3-dichlorophenylcarbamate (0.286 g, 0.847 mmol; general method D), 3-(2-fluorophenyl)-1H-pyrazol-5-amine (0.150 g, 0.847 mmol) and I-PR2NET (0.219 g, 1.69 mmol) in DMF (1 mL) was stirred at 90° C. overnight. Water was added (30 mL) and the mixture was extracted with EtOAc (3×30 mL), dried (MgSO4), filtered and concentrated to yield crude 1-(2,3-dichlorophenyl)-3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)urea as an off-white solid (285 mg, 92% yield). 1H-NMR (DMSO-d6): δ 9.86 (s, 1H), 8.25 (d, 1H, J=7.2 Hz), 7.81 (t, 1H, J=7.2 Hz), 7.45-7.27 (m, 5H), 6.65 (s, br, 1H). 5.67 (s, 1H), one urea proton not visible. LC-MS (EI) m/z: 365.0 367.0 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[CH3:41])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:18]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:39]2[CH:38]=[C:16]([CH:15]=[CH:14][C:40]=2[CH3:41])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=2)=[O:18])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(NC(C)C)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 67-68° C.; 1H NMR (300 MHz, CDCl3) δ: 8.97 (1H, s), 8.06 (1H, s), 7.98-8.01 (1H, d, J=9.0 Hz), 7.97 (1H, s), 7.83-7.85 (1H, d, J=6.0 Hz), 7.58-7.60 (1H, d, J=6.0 Hz), 7.30-7.32 (2H, m), 6.61-6.64 (1H, d, J=9.0 Hz), 5.05 (1H, s), 4.02-4.05 (1H, m), 3.70 (2H, s), 2.79-2.99 (8H, brs), 2.66 (3H, s), 2.52 (3H, s), 1.29 (6H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H34F3N6O: 551.2741. found: 551.2734.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[S:11]([Cl:15])(=O)(=[O:13])[OH:12]>O>[Cl:15][S:11]([C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2](=[O:10])[N:1]=2)[CH:5]=1)(=[O:13])=[O:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: O=C1C=c2cc(S(=O)(=O)Cl)ccc2=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
1,3-Dihydro-indol-2-one 64a (13.3 g, 100 mmol) was added slowly with chlorosulfuric acid (26.6 ml, 400 mmol) in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred for 1 hour in an ice-water bath, for another 1 hour at room temperature, and heated to 68° C. for 1 hour. The reaction mixture was cooled down to room temperature, added slowly with water (400 ml), stirred and yellow precipitates were formed. After standing for 1 hour at room temperature, the filter cake was washed with water (20 ml×4) and dried to obtain the title compound 5-chlorosulfonyl-indol-2-one 64b (15.0 g, yield 65%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([CH:28]=[CH2:29])[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([CH:28]2[CH2:29][O:39]2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1
Reactant: C=Cc1c(C)c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CO1
Reaction time: 8 h

Procedure:
N-[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (740 mg, 1.7 mmol) was stirred in methylene chloride (5.7 mL) and m-chloroperbenzoic acid (2.1 g, 8.7 mmol) was added. The mixture was stirred overnight. The suspension was filtered and the solids were washed with dichloromethane. Evaporation of the filtrates gave the desired compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]1[CH:9]=[C:8]2[O:10][S:11]([C:14]3=[CH:15][CH:16]=[CH:17][C:6](=[C:7]23)[CH:5]=1)(=[O:13])=[O:12]>>[OH:10][C:8]1[CH:9]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:14]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:15][CH:16]=[CH:17]2
Reactant: CNC
Reactant: O=S1(=O)Oc2cccc3cccc1c23
Product: CN(C)S(=O)(=O)c1cccc2cccc(O)c12
Reaction time: 20 h

Procedure:
Dry dimethylamine gas was passed through a solution of 1,8-naphthasultone [5.0 g, 24 mmoles, described by I. Hideo, Japanese Patent 4927, Aug. 31, 1951; Chem. Abstr., 47, 9364b (1953)] for 1.5 hr at 20°-22° C. The mixture was stirred for 20 hr. The resulting yellow crystals were collected by filtration. The filtrate was concentrated to give more crystals. The two batches of crystals were combined giving 5 g of 8-hydroxy-N,N-dimethyl-1-naphthalenesulfonamide; mp 95° C.; NMR (CDCl3) δ 2.88 (s, 6H), 7.1-8.3 (m, 6H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([F:39])[CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:35]3[CH:34]=[C:33]([F:32])[CH:38]=[C:37]([F:39])[CH:36]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cc(F)cc(F)c1)N1CCN(C2CCC2)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3,5-difluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (69%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14]C(O)=O)[CH3:11].N1CCCCC1>N1C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:18])[CH:14]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[CH3:11]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(C)cc1
Yield: 79 %

Procedure:
Application of the previously unused Knoevenagel condensation (Silva, N. M. et al., Eur. J. Med. Chem. 2002, 37, 163-170; Diaz, J. L. et al., Chem. Mater. 2002, 14, 2240-2251; Ren, X. et al., Tetrahedron: Asymmetry 2002, 13, 1799-1804) of p-tolualdehyde with malonic acid monoethyl ester (Breslow, D. S. et al., J. Am. Chem. Soc. 1944, 66, 1286-1288) in pyridine containing a catalytic amount of piperidine gave the known α,β-unsaturated ethyl cinnamate 5 (Tsuge, O. et al., J. Org. Chem. 1982, 47, 5171-5177; Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1999, 1357-1366; Chuzel, O.; Piva, O. Synth. Commun. 2003, 33, 393-402) in 79% yield. Reaction of 5 with (p-tolylsulfonyl)methyl isocyanide (TosMIC) afforded β-substituted pyrrole 6 (a known compound with incomplete data (Di Santo, R. et al., Med. Chem. Res. 1997, 7, 98-108)) in 74% yield. Removal of the ethoxycarbonyl group of pyrrole 6 by treatment with NaOH in ethylene glycol at 160° C. gave the known β-substituted pyrrole 7 (Sakai, K. et al., Chem. Pharm. Bull. 1980, 28, 2384-2393; Campi, E. M. et al., Aust. J. Chem. 1992, 45, 1167-1178; Pavri, N, P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649-2651) in 71% yield. Vilsmeier-Haack formylation of 7 yielded a mixture of regioisomers owing to substitution at the 2- or 5-position. After column chromatography, the two regioisomers were determined to be present in ˜13:1 ratio by 1H NMR integration of the methyl unit of the p-tolyl group. Selective precipitation readily afforded the major regioisomer 8 in 64% yield (Scheme 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:36]=[CH:35][C:27]([C:28]([N:30]=[CH:31][N:32](C)C)=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:38]N>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:36]=[CH:35][C:27]([C:28]3[NH:38][N:32]=[CH:31][N:30]=3)=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CN(C)C=NC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3ncn[nH]3)cc2)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A mixture of 4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N-dimethylaminomethylene-benzamide (7.0 mg, 0.014 mmol) and hydrazine hydrate (5 mg, 0.1 mmol) in acetic acid (200 μL) is stirred at 90° C. for 1 h and cooled down to room temperature. The solvent is removed under vacuum and residue is treated with saturated aqueous NaHCO3 solution (1 mL) and extracted with EtOAc (3×2 mL). The organic layers are combined and concentrated. The residue is purified by preparative thin layer chromatography (silica gel, 2% MeOH/CH2Cl2) to provide the titled compound 5-(4-chloro-phenyl)-1-phenyl-6-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid (4.8 mg, 73%). 1H NMR (CDCl3) δ(ppm) 8.40(s, 1H), 8.34(s, 1H), 8.15(d, 2H), 8.03(d, 2H), 7.51(t, 2H), −7.45 (d, 2H), 7.34 (t, 1H), 7.31(d, 2H), 7.11(d, 2H); HPLC-MS calculated for C25H16ClN7O (M+H+): 466.1. Found: 466.1.