Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[C:30](O)=[O:31])=[CH:25][CH:24]=1.C(Cl)CCl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[C:30](=[O:31])[C:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)=[O:33])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccc(F)cc2)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a solution of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (500 mg, 1.70 mmol, as described in example 1, step 3) in CH2Cl2 (15 mL) was added under a nitrogen atmosphere at 0° C. (4-fluoro-phenyl)-oxo-acetic acid (300 mg, 1.78 mmol, commercially available) and EDC (342 mg, 1.78 mmol). After stirring for 12 h a ambient temperature, the mixture was washed with aqueous Na2CO3 (saturated, 15 mL) and water (15 mL), the combined aqueous layers were extracted with CH2Cl2 (3×15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (527 mg, 70%) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][CH3:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:24]([CH3:25])[C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[S:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: CNc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CN(C(=S)NC(=O)Cc1ccccc1)c1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a suspension of the 222 (102 mg, 2.88 mmol) in THF (3 ml) was added 2-phenylacetyl isothiocyanate (51 mg, 0.288 mmol). The reaction mixture was stirred for 1 hr, transferred onto a chromatography column and eluted with a mixture EtOAc/MeOH (19:1) to afford title compound 223 (30 mg, 20% yield) as a white solid. 1HNMR: (DMSO-d6) δ (ppm): 10.88 (s, 1H), 8.51 (d, J=5.3 Hz, 1H), 7.91 (s, 1H), 7.41-7.18 (m, 6H), 7.04 (m, 4H), 6.5 (d, J=5.3 Hz, 1H), 4.0 (s, 3H), 3.6 (s, 2H), 3.43 (s, 3H). MS (m/z): 532.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:7][C:6]([C:5]2[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:8][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COc1cc(OC)cc(C(=N)N)c1
Product: COc1cc(OC)cc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
The title compound, MS: m/e=405.4 (M+H+), was prepared from 3,5-dimethoxy-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:8]=[C:9]([Mg]Br)[CH:10]=[CH:11][CH:12]=1.[CH2:15]([N:22]1[CH2:27][CH:26]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH:24]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C1=CCN(Cc2ccccc2)CC1
Reactant: Br[Mg]c1cccc(Br)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(Cc2ccccc2)CC1c1cccc(Br)c1
Temperature: 20 °C
Yield: 60.5 %

Procedure:
A 0.5 M THF solution of (3-bromophenyl)magnesium bromide (20 mL, 10 mmol) was cooled to −15° C., and methyl 1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (1.05 g, 4.3 mmol) in toluene (3.0 mL) was slowly added for 3 h at −15° C. The reaction mixture was warmed to 20° C. and quenched by addition of saturated NH4Cl aqueous solution followed by extraction with EtOAc. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give methyl 1-benzyl-3-(3-bromophenyl)piperidine-4-carboxylate (1.0 g, 2.6 mmol).
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]([C:9]2[NH:10][N:11]=[CH:12][CH:13]=2)=[N:2]1.[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:6]([C:5]3[NH:1][N:2]=[C:3]([C:9]4[NH:10][N:11]=[CH:12][CH:13]=4)[CH:4]=3)=[O:8])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(-c2ccn[nH]2)n[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2ccn[nH]2)n[nH]1
Yield: 15.6 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1H,2′H-3,3′-bipyrazole-5-carboxylic acid (2.245 mmol, 0.4 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.871 mmol, 0.521 g) and using DMF (10 ml) as the solvent. Water was added to the reaction mixture and the mixture was extracted with EtOAc. The organic phase was washed with 2M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.1277 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.19 (d, 3H), 4.27-4.56 (m, 3H), 6.64 (bs, 1H), 6.84 (bs, 1H), 6.98 (d, 1H), 7.77 (bs, 1H), 7.81-7.87 (m, 2H), 7.93-7.6 (m, 1H), 8.07 (br. s, 1H), 12.57-13.78 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([NH:22][CH3:23])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:22]([C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(Cl)c2c1
Product: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloro-6-nitro-quinazoline and 4-methoxy-N-methylaniline by a procedure similar to example 10. 1H NMR (CDCl3): 8.31 (dd, J=9.6, 3.6, 1H), 7.78 (d, J=9.3, 1H), 7.73 (d, J=2.4, 1H), 7.21 (m, 2H), 7.06 (m, 2H), 3.90 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([SH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[OH:28][CH2:27][C:24]1[CH:25]=[CH:26][C:14]2[C:13]([S:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:16][C:15]=2[CH:23]=1
Reactant: CCOC(=O)c1sc2cc(CO)ccc2c1Cl
Reactant: COc1cccc(S)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(CO)ccc2c1Sc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--1.1 ml, 7.23 mmol) was added to a mixture of ethyl 3-(chloro)-6-(hydroxymethyl)benzo[b]thiophene-2-carboxylate (Preparation 15--1.63 g, 6.02 mmol) and 3-methoxybenzenethiol (1.1 ml, 9.03 mmol) in anhydrous dimethylformamide (8 ml) under a nitrogen atmosphere. The solution was stirred at ambient temperature for 18 hours, and then heated to 60° C. for 3 hours. The solution was partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was crystallised from diethyl ether and hexane to give the title compound as a colourless solid (1.77 g).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][N:21]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.Cl.[CH2:44]([O:51][NH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:13]([O:20][N:21]([C:22](=[O:28])[CH2:23][CH2:24][C:25](=[O:27])[NH:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][NH:52][O:51][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Reactant: NCCCCCNOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Carbonyldiimidazole (CDI, 0.592 g, 3.65 mmol) was added to (8) (1.42 g, 3.48 mmol) in dry CH2Cl2 (90 mL) . After stirring for 1 hour, the solution was cooled to 0° C. and (6) (free amine, 0.74 g, 3.55 mmol) in CH2Cl2 (65 mL) was added by cannula over 5 minutes. After stirring for 12 hours (0° C. to room temperature), solvent was removed by rotary evaporation. Dilute brine (200 mL) was added, followed by extraction with EtOAc (4×100 mL). The organic phase was washed with 100 mL portions of cold 0.5M citric acid, 5% NaHCO3 and brine. Solvent removal led to 2.2 g (quantitative) of (9) as an oil, which was used directly in the next step. An analytical sample was chromatographed on silica gel, eluting with 3.5% EtOH/CHCl3 : 300 MHz NMR δ 1.1-1.7 (m+s, 21 H), 2.3-3.3 (m, 10 H), 3.60 (t, 2 H, J=7), 4.6 (br s, 1 H), 4.67 (s, 2 H), 4.80 (s, 2 H), 6.0 (br s, 1 H), 7.25-7.40 (m, 10 H). Anal. calcd. for C33H50N4O6 : C, 66.19; H, 8.42; N, 9.36. Found: C, 66.27; H, 8.40; N, 9.33.
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][N:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[Cl:23][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(c1ccc(CO)nc1)N(C1CCCC1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(CCl)nc1)N(C1CCCC1)C1CCCC1
Reaction time: 0.17 h

Procedure:
To a solution of the title product of Example C (1.44 g, 5 mmol) in chloroform (30 mL), phosphorus pentachloride (1.04, 5 mmol) was added. The contents were immersed in an oil-bath at 70° C. and the temperature raised to reflux. After 18h, the pinkish colored reaction solution was cooled to room temperature. The reaction was diluted with water (75 mL) and solid potassium carbonate (2.2 g) added. The contents were stirred for about 10 min until no more effervescence was observed. More water (100 mL) was added and the reaction solution extracted with methylene chloride. The organic layer was separated, dried (MgSO4) and filtered. After removal of solvent, 1 6 g of the title product was isolated as an off-white solid. The compound was used in Example 1 without any further purification. 1H NMR (CDCl3) 1,2-2.2 (m, 16H), 3.6-3.9 (m, 2H), 4.7 (s, 2H), 7.53 (d,J=8 Hz, 1H), 7.74 (dd,J=3,8 Hz, 1H), and 8.56 ppm (d,J=3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]3([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: Fc1ccc(C2(CBr)OCCO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC2(c3ccc(F)cc3)OCCO2)C1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.2 mmol) was dissolved in 5 mL of NMP. KOH (896 mg, 15 mmol) was added at RT under nitrogen atmosphere and the reaction mixture was stirred for 5 min. 2-Bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane (886 mg, 3.4 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-2% MeOH:DCM.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: COCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a stirred solution of 2-methoxy-1-phenylethanone (1.0 g, 6.66 mmol) in ethanol was added sodium borohydride (0.28 g, 7.32 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with sat. ammonium chloride solution, concentrated. Extracted with ethyl acetate, washed with brine, dried, and concentrated to yield 0.8 g of 2-methoxy-1-phenylethanol.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([CH3:17])[C:12](OCC)=O)[NH:7][C:6]=2[C:5]([F:18])=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:43]=[CH:42][C:24]([C:25]([NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])=[CH:23][C:22]=1[NH:44][CH3:45]>CN1C(=O)N(C)CCC1>[F:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([C:12]3[N:44]([CH3:45])[C:22]4[CH:23]=[C:24]([C:25]([NH:27][CH2:28][CH2:29][O:30][C:31]5[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=5[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])[CH:42]=[CH:43][C:21]=4[N:20]=3)[CH3:17])[NH:7][C:6]=2[C:5]([F:18])=[C:4]([F:19])[CH:3]=1
Reactant: CCOC(=O)C(C)c1nc2c(F)cc(F)c(F)c2[nH]1
Reactant: CCOC(=O)c1ccccc1OCCNC(=O)c1ccc(N)c(NC)c1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)c1ccccc1OCCNC(=O)c1ccc2nc(C(C)c3nc4c(F)cc(F)c(F)c4[nH]3)n(C)c2c1
Temperature: 195 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
Ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionate (988 mg, 3.63 mmol) and ethyl 2-[2-(4-amino-3-methylaminobenzoylamino)ethoxy]benzoate (1.3 g, 3.63 mmol) were combined and placed under vacuum for 4 hours and then further combined with DMPU (4 ml). The mixture was stirred until in solution, evacuated overnight under high vacuum to remove residual gases, heated to 195° C. under a nitrogen stream for 4 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica (stepwise gradient of 100% hexane to 100% ethyl acetate) and further purified by crystallization from MeOH/THF/water to provide ethyl 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carbonylamino}ethoxy}benzoate (1.0 g, 49%) as a white crystalline solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:31][CH2:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: NCC1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNCC2CCCCC2)c1
Yield: 73.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-((cyclohexylmethylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), cyclohexylmethanamine (0.057 mL; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.045 g (73%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>CC(O)=O.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1Cl
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
4-Amino-2-(2-chloro-phenylamino)-3-fluoro-5-nitro-benzoic acid methyl ester 5b (0.30 g, 0.88 mmol) is suspended in AcOH (5 mL) and zinc dust (0.29 g, 4.42 mmol) is added. After 15 minutes, the reaction is complete. The reaction mixture is diluted with ethyl acetate and filtered through Celite. The filtrate is washed with water, saturated NaHCO3, 10% K2CO3 and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 0.13 g (48%) pure desired product as an whitish brown foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:30]=[N:31][CH:32]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:9]2[C:10]3[N:11]=[C:2]([C:27]4[CH:28]=[C:29]([NH:33][S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[CH:30]=[N:31][CH:32]=4)[CH:3]=[CH:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:14]=1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: Clc1ccc2ncnc(Oc3cccnc3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(Oc4cccnc4)c3n2)c1)c1ccccc1
Temperature: 25 °C
Yield: 125.9 %

Procedure:
A mixture of 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 0.348 mmol) (Intermediate 8), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.150 g, 0.418 mmol) (Intermediate 2), PdCl2(dppf)-CH2Cl2Adduct (0.057 g, 0.070 mmol) and 1N aq. sodium bicarbonate (0.70 ml, 0.70 mmol) in dioxane (1.74 ml) was subjected to microwave irradiation for 30 min at 120° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was diluted water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (EtOAc only) to give N-(5-(4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.20 g, 13%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 7.45-7.49 (2H, m), 7.51-7.56 (1H, m), 7.61 (1H, dd, J=8.4 and 4.8 Hz), 7.84-7.87 (2H, m), 7.92-7.95 (1H, m), 8.38 (1H, d, J=2.8 Hz), 8.45 (1H, s), 8.49-8.51 (2H, m), 8.53 (1H, dd, J=4.8 and 1.2 Hz), 8.66 (1H, d, J=2.4 Hz), 8.73 (1H, s), 9.06 (1H, d, J=2.0 Hz). m/z=457 [M+1]+.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:28])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[F:29][C:30]1[CH:31]=[C:32]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[N:44][C:45]=3[NH2:47])[NH:40][N:39]=2)[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=1>>[NH2:47][C:45]1[N:44]=[CH:43][N:42]=[C:41]2[N:40]([CH:2]([C:4]3[O:5][C:6](=[O:28])[C:7]4[C:12]([C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]5[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]5)=[CH:18][CH:19]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:39]=[C:38]([C:32]3[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=[C:30]([F:29])[CH:31]=3)[C:46]=12
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCN(C)CC2)cc1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCN(C)CC4)cc3)c3ncnc(N)c23)c1
Yield: 8 %

Procedure:
The title compound was made in a similar way as that of example 134, step a, from 3-(1-hydroxyethyl)-4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one (Intermediate B46, 750 mg, 1.982 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 565 mg, 2.18 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one (98 mg, 0.158 mmol, 7.98% yield) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C(O)C.Cl>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc([N+](=O)[O-])c3)c2c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(N)c3)c2c1
Yield: 37.4 %

Procedure:
N-[3-(3-Aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 49 from 200 mg of N-[3-(3-nitrophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide, 6 ml of ethanol, 73 mg of powdered iron, 100 ml of distilled water and 40 μl of 12 N hydrochloric acid. 70 mg of N-[3-(3-aminophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of light yellow crystals melting at 154° C. (analysis C20H18N4O4S2 % calculated C, 54.29; H, 4.10; N, 12.66; O, 14.46; S, 14.49. % found C, 53.03; H, 4.26; N, 11.63; S, 13.22).