Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])(=[NH:14])=[O:13]>>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:14]=[S:12]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([O:20][CH3:21])=[O:19])([CH3:11])=[O:13])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: COC(=O)c1cccc(S(C)(=N)=O)c1
Product: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1

Procedure:
In a manner similar to that described in Example 480 (step 6), 5-bromonicotinic acid and methyl 3-(S-methylsulfonimidoyl)benzoate were reacted to give the title compound.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:28]=[N:27][N:26]([CH3:29])[C:25]=1[C:30]([OH:32])=O.[N:33]1([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:47]=[C:43]3[CH:42]=[C:41]([NH2:54])[N:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C.C(OCC)(=O)C>[N:33]1([C:39]2[N:44]3[CH:45]=[C:46]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:47]=[C:43]3[CH:42]=[C:41]([NH:54][C:30]([C:25]3[N:26]([CH3:29])[N:27]=[CH:28][C:24]=3[Cl:23])=[O:32])[N:40]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: Cn1ncc(Cl)c1C(=O)O
Reactant: Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc(Cl)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.5 %

Procedure:
Under an atmosphere of nitrogen, N—N-diisopropylethylamine (121 mg) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 120 mg) were added to a solution of 4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 0.31 mmol, Art-Chem B000148) in DMF (3 ml). After 30 min, 5-morpholin-4-yl-2-phenyl-imidazo[1,2-c]pyrimidin-7-ylamine (110 mg, 0.37 mmol) was added, and the black solution was stirred at r.t. overnight. The reaction mixture was taken up in ethyl acetate and washed with water. After drying (Na2SO4), the solvent was evaporated and the title compound (2 mg, 1.1%) was isolated by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=438.2 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])[CH3:2].[OH-].[K+].[CH2:16](Br)[C:17]#[CH:18]>[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]([CH2:7][C:8]1[N:9]=[CH:10][CH:11]=[CH:12][N:13]=1)[CH2:18][C:17]#[CH:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)NCc1ncccn1
Reactant: C#CCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCN(Cc1ncccn1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
18.1 g (0.1 mol) of 2-ethoxycarbonylaminomethyl-pyrimidine are added to a suspension of 20 g (0.3 mol) of pulverized KOH and 1.1 g (5 mmol) of triethylbenzylammoniumbromide in 200 g of toluene, and then 18 g (0.12 mol) of propargylbromide (80% solution in toluene) at room temperature. The mixture is subsequently stirred for 15 hours at room temperature, the salts are filtered off with suction, the filtrate is washed with brine, dried with MgSO4 concentrated and distilled. The reaction product is identical with that of example Z1b.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([CH2:13][N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN(c2ccccc2)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Methanesulfonyl chloride (0.77 mL, 1.13 g, 9.9 mmol) was added dropwise to a stirred, cooled (0° C.) solution of N-phenyl-1-t-butoxycarbonylpiperidine-4-methylamine (2.61 g, 9 mmol) and pyridine (1.09 mL, 1.07 g, 13.5 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 16 h. The mixture was cooled in ice and 4-dimethylaminopyridine (220 mg, 1.8 mmol), pyridine (1.09 mL, 1.07 g, 13.5 mmol) and methanesulfonyl chloride (0.77 mL, 1.13 g, 9.9 mmol) were added. The mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, aqueous sodium hydrogen carbonate (saturated, 50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×50 mL), aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane (2:1, 30 mL) to give the title compound as a colorless solid (2.96 g, 89%), δH (250 MHz, CDCl3) 7.46-7.31 (5H, m), 4.06 (2H, m), 3.56 (2H, d, J 7.2 Hz), 2.85 (3H, s), 2.60 (2H, m), 1.71 (2H, m), 1.57 (1H, m), 1.43 (9H, s), and 1.05 (2H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([NH:10][C:11](=[O:22])[CH:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:13])[CH:7]=[N:8][CH:9]=1)=O.[OH-].[NH4+:24]>>[CH2:15]([O:14][CH:12]([CH3:13])[C:11]([NH:10][N:6]1[C:5]([C:3]([NH2:24])=[O:2])=[CH:9][N:8]=[CH:7]1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cncn1NC(=O)C(C)OCc1ccccc1
Agent: [OH-]
Product: CC(OCc1ccccc1)C(=O)Nn1cncc1C(N)=O
Temperature: 60 °C
Yield: 100 %

Procedure:
Compound 9 (8.2 g, 27 mmol) and ammonium hydroxide (100 mL) were mixed and heated to 60° C. for two hours. The reaction mixture was concentrated in vacuo to give compound 10 (7.8 g, 100% yield) as white solid. LC-MS: m/z 289 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][C@H:19]1[CH2:24][NH:23][C@H:22]([CH3:25])[CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:20]3[CH2:21][C@@H:22]([CH3:25])[NH:23][CH2:24][C@@H:19]3[CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Product: C[C@@H]1CN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)[C@@H](C)CN1
Yield: 5.6 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and trans-2,5-dimethylpiperazine (114 mg, 1.0 mmol) were reacted according to GP4 to give 1.9 mg of the title compound (160FE33A). MS (ESI) 341 (MH+). Purity for MH+ (UV/MS) 100/82.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[N:8])[CH:2]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[CH3:9][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7](=[NH:8])[O:13][CH2:11][CH3:12]
Reactant: CCO
Reactant: Cc1cccc(C#N)c1
Agent: Cl
Product: CCOC(=N)c1cccc(C)c1

Procedure:
Ethyl 3-methylbenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, m-tolunitrile (25.2 g, 0.215 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 41.7 g (97%) of the target compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3].[Br:12]Br.C([O-])(O)=O.[Na+]>C(OCC)C>[Br:12][CH2:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Yield: 67.9 %

Procedure:
2,5-Dichloroacetophenone (20.9 g, 0.11 mol) was dissolved in diethyl ether (300 mL) and the reaction mixture was cooled to 0° C. Bromine (5.66 mL, 0.11 mol) was added slowly dropwise and the reaction mixture was allowed to warm to room temperature over 20 minutes. The reaction mixture was treated with saturated aqueous NaHCO3 solution (250 mL). The organic layer was separated, dried over MgSO4 and concentrated in vacuo, yielding the title compound (20.0 g, 68%) as a yellow oil. δH (d6-DMSO) 7.94 (dd, J 2.2, 0.3 Hz, 1H), 7.61 (m, 2H), 4.88 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([OH:18])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:53][C:54]1[CH:55]=[C:56]([NH:61][C:62](=[O:74])[C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([C:69]([C:72]#[N:73])([CH3:71])[CH3:70])[CH:64]=2)[CH:57]=[CH:58][C:59]=1[CH3:60]>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([NH:53][C:54]1[CH:55]=[C:56]([NH:61][C:62](=[O:74])[C:63]2[CH:68]=[CH:67][CH:66]=[C:65]([C:69]([C:72]#[N:73])([CH3:70])[CH3:71])[CH:64]=2)[CH:57]=[CH:58][C:59]=1[CH3:60])=[O:18]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: Nc1c(C(=O)O)sc2ncc(-c3ccco3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2ncc(-c3ccco3)nc2c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
A solution of 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylic acid 59 (66 mg, 0.253 mmol), HATU (106 mg, 0.278 mmol) and DIPEA (0.104 mL, 0.632 mmol) in DMF (2 mL) was stirred at rt for 30 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (83 mg, 0.253 mmol) was added and stirred overnight at 80° C. Quenched in 2N HCl solution, the resulting precipitate was collected and dried. Purification by HPLC gave the title compound 7-amino-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxamide 60 (47 mg, 34%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.23 (s, 3H), 6.79 (dd, J=1.6 and 3.5 Hz, 1H), 7.01 (s, 2H), 7.27 (d, J=8.2 Hz, 1H), 7.46 (d, J=3.5 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (m, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.95 (m, 1H), 8.01 (m, 1H), 8.05 (m, 1H), 9.16 (s, 1H), 9.48 (s, 1H), 10.33 (s, 1H). (m/z)=537 (M+H)+.
Reaction SMILES: C1(N(C)[C:8]2[C:9](C)=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH:33]=O)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13]CC2C(=O)NC(C)=CC=2C)=[O:12])CCCCC1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:40]1[CH2:41][CH2:42][N:37]([CH2:33][C:30]2[N:29]=[CH:28][C:27]([C:25]3[CH:26]=[CH:8][CH:9]=[C:10]([CH:24]=3)[C:11]([NH2:13])=[O:12])=[CH:32][CH:31]=2)[CH2:38][CH2:39]1
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1cccc(-c2ccc(CN3CCOCC3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a stirred solution of compound 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (1 equiv.) and morpholine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl)-5-(6-(morpholinomethyl)pyridin-3-yl)benzamide (0.089 g, 53% yield). LCMS: 558.35 (M+1)+; HPLC: 96.52% (@254 nm) (Rt; 4.375; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (s, 1H), 8.18 (t, 1H), 8.01 (d, 1H, J=6.8 Hz), 7.49 (d, 1H, J=8 Hz), 7.33 (s, 1H), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=3.6 Hz), 3.59-3.61 (m, 6H), 2.75 (m, 1H), 2.65 (s, 3H), 2.43 (bs, 4H), 2.21 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.70 (bs, 4H), 1.53-1.56 (m, 1H), 1.42-1.44 (m, 1H), 1.09-1.23 (m, 4H).
Reaction SMILES: ClC1C=C([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=C(Cl)C=1.Br[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:20][C:21]=1[F:26]
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reactant: Fc1cc(Br)ccc1Cl
Product: O=C(Cc1ccccc1)c1ccc(Cl)c(F)c1
Yield: 18.2 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 4-bromo-1-chloro-2-fluorobenzene, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to afford Intermediate 16 (200 mg, yield 18.2%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])(=O)=O.CN(C=O)C.[N-:34]=[N+:35]=[N-:36].[Na+]>C(OCC)(=O)C>[N:34]([CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:10][CH2:11][N:12]([CH3:13])[C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCN=[N+]=[N-]
Temperature: 80 °C

Procedure:
2-(3-(tert-Butoxycarbonyl(methyl)amino)-1-(5-chloro-2-methylphenyl)propoxy)ethyl methanesulfonate (414 mg, 0.95 mmol) was dissolved into anhydrous DMF (15 mL), solid NaN3 (186 mg, 2.86 mmol) was added and the reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, the organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to the crude product (270 mg, 74%), which was used for next step without purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:14][CH:13]=1.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([CH:30]([CH2:32][NH2:33])[OH:31])=[CH:25][C:24]=1[Cl:34]>CN(C=O)C>[NH2:22][C:23]1[C:24]([Cl:34])=[CH:25][C:26]([CH:30]([OH:31])[CH2:32][NH:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:14][CH:13]=2)=[CH:27][C:28]=1[Cl:29]
Reactant: NC(=O)Cc1ccc(CCCOCCCCCCBr)cc1
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)cc1
Yield: 38.5 %

Procedure:
4-[3-[(6-Bromohexyl)oxy]propyl]benzeneacetamide (950 mg) was added to a stirred solution of 4-amino-α-(aminomethyl)-3,5-dichloro-benzenemethanol (900 mg) and DEA (650 mg) in DMF (10 ml) at 100° under nitrogen. After 1 h the solvent was evaporated and the residue was partitioned between 8% sodium bicarbonate (20 ml) and ethyl acetate (20 ml). The organic layer was washed with water and brine, dried and concentrated in vacuo to give a yellow solid which was triturated with ether to give the title compound as an off-white powder (510 mg) m.p. 104°-106°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C([O-])([O-])=O.[Na+].[Na+].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.C1C=CN=C(C2C=CC=CN=2)C=1.C([O-])(O)=O.[Na+]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:16]1([N:1]2[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1cc[nH]n1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccn(C2CC2)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Methyl 1H-pyrazole-3-carboxylate (4 g, 31.7 mmol) was dissolved in dichloroethane (160 ml). Na2CO3 (6.72 g, 63.4 mmol) and cyclopropylboronic acid (5.44 g, 63.4 mmol) were added to the solution. The resulting mixture was heated to 70° C. and a hot solution of bipyridine (4.92 g, 31.6 mmol) and Cu(OAc)2 (5.72 g, 31.6 mmol) in dichloroethane (40 ml) was added. The mixture was stirred at 70° C. under an oxygen atmosphere overnight. Saturated aqueous solution of NaHCO3 was added to the reaction mixture and extracted with EtOAc. The organic layer was evaporated and the residue was purified by flash chromatography. Yield 2.5 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.04-1.09 (m, 2H), 1.17-1.23 (m, 2H), 3.64-3.69 (m, 1H), 3.91 (s, 3H), 6.78 (d, 1H), 7.46 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH3:29])=[C:17](/[F:28])\[CH:18]=[CH:19]\[C:20](\[CH3:27])=[CH:21]\[C:22]([O:24]CC)=[O:23])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([O:3][C:4]1[C:5](/[C:16](/[CH3:29])=[C:17](/[F:28])\[CH:18]=[CH:19]\[C:20](\[CH3:27])=[CH:21]\[C:22]([OH:24])=[O:23])=[CH:6][C:7]2[CH:8]=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OCC)C(C)(C)CC=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C=CCC2(C)C
Temperature: 60 °C

Procedure:
To a solution of ethyl (2E,4E,6E)-7-(3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound A-67, 4.0 mg, 0.01 mmol) in ethanol (0.2 mL) and THF (1 mL) was added 1M NaOH (0.05 mL, 0.05 mmol). The mixture was heated to 60° C. for 5 h and was cooled to room temperature, acidified with 1M HCl, extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexanes) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:32])[CH2:18][C:17]3=[O:22])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCNCC2=O)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1
Reaction time: 16 h

Procedure:
120 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopiperazin-1-yl)benzamide was dissolved in 2 mL of DMF and then treated with 53 mg of paraformaldehyde, 187 mg of sodium triacetoxyborohydride and 0.2 mL of AcOH. After stirring 16 h, the reaction mixture was evaporated and the crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methyl-2-oxopiperazin-1-yl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COCCOC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOCc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a mixture of ethyl 3-[({4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (175 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (1.00 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (143 mg, 82%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[NH2:19][OH:20].[OH-].[K+].CO>C1COCC1>[OH:20][NH:19][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10]
Reactant: NO
Reactant: COC(=O)CCCCCS(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCCCCS(=O)c1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 6-(4-chloro-benzenesulfinyl)-hexanoic acid methyl ester (2.0 g, 7 mmol) in distilled THF (40 mL) containing 50% aqueous hydroxylamine (4.1 mL, 62 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (12 mL, 1M, 12 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (40 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×50 mL) and the combined extracts were washed with brine (75 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (1.8 g, 89%) as a white powder, mp 125° C.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ccc3ccc4nc(N)[nH]c(=O)c4c3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ccc3ccc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1

Procedure:
A solution of methyl 4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoate (0.54 g, 1.2 mmoles) in 0.1N NaOH (30 ml) was stirred at room temperature under a nitrogen atmosphere for 19 hrs. After this time, the solution was acidified (pH 4) with 1N HCl to cause precipitation of the product which was filtered and dried to give 4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoic acid as a light brown solid. (0.46 g, 86%) 1HNMR(DMSO-d6, 200 MHz) δ: 7.28(d, J=8.9 Hz, 1H, Ar); 7.30(dd, J=8.3, 2 Hz, 1H, Ar); 7.37(br s, 2H, NH2); 7.82(d, J=8.6 Hz, 1H, Ar); 7.95-8.06(m, 5H, Ar); 9.38(d, J=2 Hz, 1H, Ar); 10.85(s, 1H, NH). Anal. Calculated for C19H14N4O5.4/5 HCl .11 /10H2O: C, 49.68; H, 3.73; N, 12.20. Found: C, 49.61; H, 3.78; N, 12.30.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5](Cl)[S:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1>>[NH2:1][C:2]1[CH:6]=[C:5]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:12])[CH:18]=2)[S:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: Clc1ccccc1
Product: Nc1cc(-c2cccc(Cl)c2)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from 3-chlorobenzene boronic acide and 3b by following the procedure in example 3c. This compound is a white solid: MS (ES) 289 (M+H)+; 1H NMR (400 MHz, CD3OD) δ7.62 (s 1 H), 7.53 (m, 1 H), 7.40 (m, 2 H), 6.92 (s, 1 H).