Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[C:18](=[O:31])[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)[N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[Pd]>[C:5]1([S:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[C:18](=[O:31])[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)[N:16]=2)(=[O:10])=[O:9])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2cc1-c1csc(CS(=O)(=O)c2ccc(Cl)cc2)n1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2cc1-c1csc(CS(=O)(=O)c2ccccc2)n1
Reaction time: 8 h

Procedure:
A mixture of 3-[2-(4-chloro-benzenesulfonylmethyl)-thiazol-4-yl]-7-trifluoromethyl-1H-quinolin-2-one (Example 103, 67 mg, 0.14 mmol), 0.5 mL of IPEA, and 0.1 g of Pd-C (10%) in anhydrous DMF (10 mL) was stirred under H2 overnight. The catalysts were filtered through Celite and the filtrate was concentrated. CH2Cl2 was added and precipitates were filtered, washed with MeOH, CH2Cl2 to afford the title compound as a tan solid. MS m/z: 451.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[O:8])=[O:5])[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH:31]3[NH:35][CH2:34][CH2:33][S:32]3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C:7]([N:35]1[CH2:34][CH2:33][S:32][CH:31]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH2:21][CH2:20]1)=[O:8])=[O:5])[CH3:2]
Reactant: Fc1cccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Reactant: CCOC(=O)N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.5 %

Procedure:
0.9 g of ethoxycarbonyl isocyanate is added to a solution of 2 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine in 30 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 18 hours. 3.1 g of ethoxycarbonyl isocyanate are added to the mixture, and the mixture is stirred at room temperature for 2 hours. Water is added to the mixture, and the aqueous mixture is made alkaline with potassium carbonate. The aqueous mixture is extracted with ethyl acetate, and the extract is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, benzene:ethyl acetate=1:1). 1.05 g of N-ethoxycarbonyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained as an amorphous powder.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25](/[CH:28]=[CH:29]/[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
35 mg of tert-butyl trans-(E)-3-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]-cyclohexyl}acrylate (0.07 mmol, 1 eq.) are placed in 1 mL of dichloromethane. 0.5 mL of trifluoroacetic acid (6.73 mmol, 97 eq.) is added and the reaction medium is stirred for 3 hours at room temperature. The solvent is evaporated off. The resin is triturated in ethyl acetate to give 8 mg of trans-(E)-3-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)-phenyl]cyclohexyl}acrylic acid.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)#[N:29]>>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([NH:39][C:25](=[O:26])[CH:24]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH3:10])=[CH:18][CH:19]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1)#[N:29]
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C#N)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-cyanobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (21%); 1H NMR (d6-DMSO) δ 8.09-8.03 (m, 4H), 7.94 (d, J=8.0 Hz, 1H), 7.40-7.07 (m, 12H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 519 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:16][O:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: COc1ccccc1CC1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: COc1ccccc1CC1CCN(c2ccc(C(=O)NCCC(C)C)nn2)CC1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-(2-methoxybenzyl)piperidine. MS (+ESI) m/z 397 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])/[N:4]=[N:5]/[C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:10]([C:19](=[O:21])[CH3:20])[CH:9]=[C:8]([F:22])[C:7]=1[C:23]#[C:24][Si](C)(C)C)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[CH2:29]([N:3]([CH2:1][CH3:2])/[N:4]=[N:5]/[C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:10]([C:19](=[O:21])[CH3:20])[CH:9]=[C:8]([F:22])[C:7]=1[C:23]#[CH:24])[CH3:30]
Reactant: CCN(CC)/N=N/c1c(C#C[Si](C)(C)C)c(F)cc(C(C)=O)c1-c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1c(F)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A solution of 1-{6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-3′,4-difluoro-5-[(trimethylsilyl)ethynyl]biphenyl-2-yl}ethanone (2.0 g, 4.6 mmol) in tetrahydrofuran (39 mL) and methanol (7.7 mL) was treated with powdered potassium carbonate (3.2 g, 23 mmol) and stirred at 0° C. for 2 hours. The reaction mixture was filtered and the filtrate was treated with a few drops of water. The filtrate was concentrated to an oil that was diluted with ethyl acetate (150 mL), washed with water (50 mL) and brine (25 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (1.6 g, 99%) that was used without further purification. LCMS for C20H20F2N3O (M+H)+: m/z=356.2; Found: 355.9.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][S:8]([C:11]1[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.SC1[S:33][CH:34]=[CH:35][N:36]=1>CN(C=O)C>[CH2:28]([O:27][C:13]1[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=[C:11]([S:8][C:7]2[S:33][CH:34]=[CH:35][N:36]=2)[N:12]=1)[CH2:29][CH3:30]
Reactant: Sc1nccs1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Sc2nccs2)nc2oc(-c3cccc(C)c3)nc12
Temperature: 100 °C
Yield: 12.6 %

Procedure:
113 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine were added to a solution of 34 mg of 2-mercaptothiazole in 3 ml of DMF. The mixture was heated to 100° C. in a microwave reactor for 15 min. After cooling and filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 14 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[O:17]([CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[NH2:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCOc1ccccc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cnc2ccccc2c1NCCOc1ccccc1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
3-Nitro-N-(2-phenoxyethyl)quinolin-4-amine (6.0 g, 19 mmol), 5% platinum on carbon (1.5 g) and ethyl acetate (300 ml) were placed in a hydrogenation flask. The mixture was shaken overnight under a hydrogen pressure of 40 psi (2.8 Kg/cm2). The reaction mixture was filtered and the catalyst was washed with ethyl acetate. The filtrate was dried (MgSO4), filtered, and concentrated under vacuum to near dryness. Hexane was added and the resulting precipitate was collected by vacuum filtration to provide 4.9 g of N4-(2-phenoxyethyl)quinoline-3,4-diamine as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([S:17]([NH:20][C:21]3[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=3)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1.C(=O)([O-])O.[Na+].[C:36](O)(=[O:38])[CH3:37]>C(OC(=O)C)(=O)C>[C:36]([O:1][CH2:2][CH:3]([CH3:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([S:17]([NH:20][C:21]3[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=3)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:38])[CH3:37]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)CO)cc1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)COC(C)=O)cc1
Temperature: 25 °C

Procedure:
2-[4-(3-hydroxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide from Example 19 (100 mg) was heated in a mixture of acetic acid (0.5 ml) and acetic anhydride (0.5 ml) to 80° C. for 10 minutes and allowed to cool to ambient temperature. After 16 hours excess saturated aqueous sodium hydrogen carbonate was added cautiously and the product extracted into ethyl acetate (3×20 ml). The combined organic extract was dried (MgSO4) and evaporated. The residue was purifed by elution with a gradient of 0-30% ethyl acetate/hexane through a silica gel Mega Bond Elut column (1 g) to give 2-[4-(3-acetoxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (70 mg) as a white foam; 1H NMR (CDCl3): 0.98 (d, 3H), 1.58 (s, 3H), 2.11 (s, 3H), 2.1-2.3 (m, 1H), 2.51 (q, 1H), 2.85 (q, 1H), 3.80 (s, 3H), 3.97 (m, 2H), 6.69 (s, 1H), 7.2 (d, 2H), 7.29 (d, 2H), 8.67 (d, 1H), 8.80 (dd, 1H); mass spectrum (+ve ESP): 471.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[N:21]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccc(F)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A mixture of (S)-2-tertbutoxycarbonylaminopropionic acid (480 mg, 2.53 mmol), 3-fluoro-N2-phenylbenzene-1,2-diamine (466 mg, 2.30 mmol), HOAt (345 mg, 2.53 mmol), 4-methylmorpholine (560 μL, 5.07 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (486 mg, 2.53 mmol) in DCM (15 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between additional DCM and an aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo and the resulting residue (1.0 g) was dissolved in AcOH (20 mL) and stirred for 18 h at 70° C. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) affording [(S)-1-(7-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as a yellow/orange oil (631 mg, 77%). LCMS: RT 3.64 min [M+H]+ 356.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7](=[O:14])[NH:6][CH:5]=1.CI.[CH3:17]C(=O)OCC>CN(C=O)C>[Br:3][C:4]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:17])[CH:5]=1
Reactant: O=c1[nH]cc(Br)c2ncncc12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2ncncc2c1=O
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Sodium hydride (21 mg, 0.53 mmol, 60% in mineral oil) was added to the title compound of step 2 (100 mg, 0.44 mmol) in DMF (10 mL) at 0° C. After stirring 0.5 h, MeI (126 mg, 0.88 mmol) was added and stirring continued at 0° C. for 2 h. Following extractive work up with EA, the title compound (80 mg, yield: 75.3%) was obtained as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.47 (s, 1H), 9.46 (s, 1H), 8.53 (s, 1H), 3.54 (s, 3H). LCMS: 240.0, 242.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].[C:26]1([C:32]2[N:33]=[C:34](/[CH:37]=[N:38]/[C:39]3[CH:44]=[CH:43][C:42]([CH2:45]O)=[CH:41][CH:40]=3)[S:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:45][C:42]1[CH:41]=[CH:40][C:39](/[N:38]=[CH:37]/[C:34]2[S:35][CH:36]=[C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:33]=2)=[CH:44][CH:43]=1)[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: COC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: OCc1ccc(/N=C/c2nc(-c3ccccc3)cs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(N(Cc2ccc(/N=C/c3nc(-c4ccccc4)cs3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (364 mg, 1.0 mmol), (4-{[(1E)-(4-phenyl-1,3-thiazol-2-yl)methylene]amino}phenyl)methanol (297 mg, 1.0 mmol) and triphenylphosphine (393 mg, 1.5 mmol) in tetrahydrofuran (4 mL) was added diethyl azodicarboxylate (40% toluene solution, 660 mg, 1.5 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was purified by silica gel column chromatography (5%-70% ethyl acetate/hexane) to give a yellow oil containing the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (187 mg) in anhydrous DCM (5 ml) and triethylamine (111 ul) was added cyclopropanesulfonyl chloride (65 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature over 4 hours. Aqueous work-up and purification on silica gave 2-chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine (159 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 413. NMR (DMSO): 0.90-0.92 (2H, m), 0.97-1.00 (2H, m), 2.53-2.58 (4H, m), 2.60-2.64 (1H, m), 3.20-3.23 (4H, m), 3.74-3.77 (4H, m), 3.80 (2H, s), 3.88-3.91 (4H, m), 7.08 (2H, br), 7.52 (1H, s), 9.08 (2H, s) MS (ESI+): MH+ 517.22 (50%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9]2
Reactant: O=C1Cc2cccc([N+](=O)[O-])c2N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-nitroindoline-2-one in methanol (1.0 gm/60 mL), added Pd/C (300 mg, 30 wt %). H2 gas maintained with pressure using hydrogen gas balloon, solution stirred for 4 hours at RT. The catalyst was removed by filtration over celite. The filtrate was concentrated in vacuo to give crude product, which was washed with diethyl ether to afford compound 7-aminoindolin-2-one; YD: 76.77%; mp: 248-251° C.; Rf: 0.6 (CHCl3:MeOH: 9.0:1.0). 1H NMR (DMSO-d6) 200 MHz, δ: 3.382 (s, 2H), 4.794 (s, 2H), 6.453-6.498 (m, 2H), 6.673 (t, J=8.0 Hz, 1H), 9.906 (s, 1H). MS (ESI): m/z 146.8 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH3:2].[CH3:16][O:17][CH:18]([O:22][CH3:23])N(C)C>CO>[CH3:16][O:17][CH:18]([O:22][CH3:23])[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][C:4]2[N:3]([CH2:1][CH3:2])[CH2:7][CH2:6][N:5]=2)[CH2:15][CH2:14]1
Reactant: CCN1CCN=C1CCC1CCNCC1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CCN1CCN=C1CCC1CCN(C(OC)OC)CC1

Procedure:
A solution of 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidine (0.66 g, 0.0031 M) in methanol (6 ml) and dimethylformamide dimethylacetal (6 ml) was heated at 90° C. for 6 hrs. Removal of the excess of dimethylformamide dimethylacetal gave 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal. The solution of the piperidine carboxaldehyde dimethylacetal in chloroform (5 ml) was then added to a mixture of 6-aminopenicillanic acid (0.6 g, 0.0028 M) and diisopropylethylamine (0.5 ml) in chloroform (6 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs. The solvent was removed and water (10 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified from about pH 3 to about 3.5 was purified on Sephadex LH B 20 columns to give [2S-(2-alpha,5alpha, 6beta)]-6-[[[4-[2-(1-ethyl-4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.46 g, 35% yield).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][CH3:34])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:43])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][CH3:34])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: CCCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCn1nc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a solution of 2-(6-chloro-1-propyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (38 mg, 0.06 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 10% MeOH/CH2Cl2 to afford 10 mg (32%) of 2-[6-chloro-1-propyl-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid. MS: (M+Na)+=513; mp=219-221° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.93 (s, 1H), 9.13 (s, 1H), 8.71 (d, J=9.1 Hz, 1H), 8.46 (dd, J=7.6, 2.6 Hz, 2H), 8.03 (s, 1H), 7.25 (d, J=9.1 Hz, 1H), 4.43-4.78 (m, 5H), 4.16-4.27 (m, 1H), 4.05-4.13 (m, 1H), 3.78-3.91 (m, 1H), 1.86-1.96 (m, 2H), 1.39 (dd, J=6.6, 4.3 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-(3-nitrophenyl)-acrylamide (1.1 g, 5.61 mmol), iron powder (1.88 g, 33.7 mmol), FeSO4 (3.12 g, 11.2 mmol), Celite® (1.0 g) and H2O (45 mL) was heated to reflux with stirring for 2 h. The reaction mixture was cooled to RT and the solution was made basic to pH 13-14 by the addition of 2N NaOH. The reaction mixture was diluted with EtOAc and water. The solution was filtered to remove the solids and the solids were washed with EtOAc. The aqueous layer was extracted three times with EtOAc (100 mL) and the combined organics were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography using EtOAc as the solvent to give N-(3-aminophenyl)acrylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:14][C:15]1[C:16]([Cl:34])=[CH:17][C:18]([F:33])=[C:19]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:31])[CH3:30])[CH:24]=2)[CH:20]=1>N1C=CC=CC=1>[Cl:34][C:16]1[CH:17]=[C:18]([F:33])[C:19]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:30])[CH3:31])[CH:24]=2)=[CH:20][C:15]=1[NH:14][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CN(C)c1cccc(C(=O)Nc2cc(N)c(Cl)cc2F)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)c(F)cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.9 %

Procedure:
A mixture of 3,4-dimethoxybenzoyl chloride (0.5 g), N-(5-amino-4-chloro-2-fluorophenyl)-3-dimethylaminobenzamide (0.781 g) and pyridine (8 ml) was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous copper sulphate solution. The organic phase was washed in turn with water and a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.328 g);