Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=O)=[CH:16][CH:15]=3)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:29]>CO>[CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH2:29])=[O:23])=[CH:18][CH:19]=3)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N
Reactant: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 45.8 %

Procedure:
A 20-mL vial was charged with methyl 2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.150 g, 0.38 mmol) in methanol (2 mL). To this mixture was added NH3 (10.8 mL, 7N in methanol, 76.0 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 23 h. The crude reaction solution concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by chromatography on silica using dichloromethane/methanol (10:0 to 96:4) as eluent to afford the title compound (0.066 g, 46%) as a white solid. MW=379.38. M.p. 130-132° C. 1H NMR (DMSO-d6, 500 MHz) δ 7.51 (s, 1H), 7.41 (br s, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.83 (br s, 1H), 5.35 (septet, J=3.0 Hz, 1H), 4.10 (s, 2H), 3.33 (s, 2H), 2.00-1.90 (m, 2H), 1.77-1.66 (m, 4H), 1.65-1.55 (m, 2H); ESI MS m/z 380 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22](B5OC(C)(C)C(C)(C)O5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22]([C:2]5[N:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: NC(=O)c1cc(-c2ncccn2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 100 °C

Procedure:
2-Bromopyrimidine (250 g, 1.572 mmol), 7-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide 429A (140 mg, 0.125 mmol), Pd(Ph3P)4 (76 mg, 0.066 mmol) and Na2CO3 (2M) (0.8 mL, 1.600 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was degassed and heated at 100° C. for 12 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 402.16 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.76 (s, 1H), 9.35 (s, 1H), 9.01 (d, 1H, J=1.5), 8.95 (d, 2H, J=4.9), 8.43 (s, 1H), 8.34 (d, 1H, J=7.9), 7.82 (s, 1H), 7.58 (s, 1H), 7.45 (t, 1H, J=4.7), 7.26(dd, 1H, J=8.0, 1.5), 3.7-3.5 (bm, 8 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:11]2[CH:15]=[N:14][NH:13][N:12]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:40][CH3:41]>CN(C=O)C.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:11]2[CH:15]=[N:14][N:13]([CH2:40][CH3:41])[N:12]=2)[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCC(c1ccc(Cl)cc1)(c1cn[nH]n1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ncc(C(CC)(c2ccc(Cl)cc2)n2ccc3c(NC(=O)OC(C)(C)C)cccc32)n1
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-(1-(4-chlorophenyl)-1-(2H-1,2,3-triazol-4-yl)propyl)-1H-indol-4-ylcarbamate (150 mg, 0.33 mmol) in DMF (5 mL), was added potassium carbonate (91 mg, 0.66 mmol) and iodoethane (62 mg, 0.40 mmol). After stirring for 2 hours, the mixture was diluted with saturated aqueous ammonium chloride (10 mL) and extracted with EA. The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to afford the crude product. The product was purified via column chromatography (50% EtOAc/hexanes) to provide the title product.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Cl)=[N:8][S:9](=[O:11])(=[O:10])[C:4]2=[CH:3][CH:2]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:15]([CH2:16][CH3:17])[C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH3:14]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CCNCC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCN(CC)C1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
10.0 g of pseudosaccharine chloride are initially introduced in 150 ml of toluene. 3.7 g of diethylamine diluted with 25 ml of toluene are added dropwise at room temperature over the course of 30 minutes. After a further 30 minutes, 50 ml of pyridine in 25 ml of toluene are added and the mixture is subsequently stirred at room temperature for 2.5 hours. The solvent is then removed in vacuo and the residue is stirred up with 350 ml of water. The colorless precipitate is filtered off to give 10.1 g (84%) of 3-diethylaminobenzoisothiazole 1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC[C:29]([NH2:31])=[O:30].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH2:18][C:29]([NH2:31])=[O:30])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: NC(=O)CI
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with iodoacetamide in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=453.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:20])[CH2:4][O:3]1.[C:26](=O)([O-])[O-].[K+].[K+].IC.C(OCC)(=O)C>CN(C=O)C.[Cl-].[Na+].O>[CH3:26][N:17]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]3[NH:6][C:5](=[O:20])[CH2:4][O:3][C:2]([CH3:1])([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[C:8]=3[CH:9]=2)=[CH:14][CH:15]=[C:16]1[C:18]#[N:19]
Reactant: O=C([O-])[O-]
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1cccs1)OCC(=O)N2
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of 5-[5-methyl-2-oxo-5-(2-thienyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-2-carbonitrile (0.1 g, 0.29 mmol) in anhydrous DMF (5 mL) at rt under nitrogen was added potassium carbonate (1 g, 7.23 mmol) and iodomethane (0.5 mL, 8 mmol). The reaction mixture was stirred for 2 h and treated with brine (30 mL). Ethyl acetate (50 mL) was added and organic layer separated, dried (Mg2SO4), and concentrated. The residue was purified by a flash chromatography on a silica gel column (hexane:ethyl acetate/2:1) to afford the title compound as a white solid (23 mg, 22%): mp 197-198° C.; 1H-NMR (DMSO-d6) δ 10.21 (s, 1H), 7.55 (d, J=4.8, 1H), 7.43 (dd, J=8.4, 1.8 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.01 (d, J=4.1 Hz, 1H), 6.98 (d, J=4.9 Hz, 1H), 6.93 (d, J=3.0 Hz, 1H), 6.31 (d, J=4.1 Hz, 1H), 4.21 (d, J=15.9 Hz, 1H), 4.07 (d, J=15.9 Hz, 1H), 3.65 (s, 3H), 2.04 (s, 3H). MS (ES) m/z 362 ([M−H]−, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[C:35]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C.CN(C)C=O.C[Si](C#C)(C)C.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.ClCCl>[C:35]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2)#[CH:36]
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: C#C[Si](C)(C)C
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1ccc2cc(S(=O)(=O)N3CCN(C(=O)c4ccc(-c5ccncc5)cc4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[(6-bromonaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine (310 mg) and triphenylphosphine (455 mg) in tetrahydrofuran (1.0 ml), triethylamine (3.0 ml), N,N-dimethylformamide (1.0 ml), trimethylsilylacetylene (130 ml) and palladium acetate (13.0 mg) were added, followed by heating under reflux for 2 hours. After the reaction mixture was allowed to cool down to room temperature, dichloromethane (15 ml) and water (30 ml) were added to separate the organic layer. The organic layer thus obtained was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (dichloromethane:acetone=3:1), whereby colorless amorphous was obtained. The resulting product was dissolved in methanol (25 ml), followed by the addition of tetrahydrofuran (5.0 ml) and potassium carbonate (300 mg). The resulting mixture was stirred for 30 minutes. Dichloromethane (30 ml) and water (50 ml) were added to the reaction mixture to separate the organic layer. The organic layer thus obtained was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (dichloromethane acetone=4:1), followed by pulverization and washing in a mixed solvent of dichloromethane, acetone and water, whereby the title compound (210 mg, 75%) was obtained.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][CH:7]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:8]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH:9][C:10](=[O:23])[CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH3:5].[H][H]>CO.[Pd]>[ClH:1].[CH2:32]([O:31][CH:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[C@H:8]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])[NH:9][C:10](=[O:23])[CH2:11][NH2:12])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)CN
Yield: 101.3 %

Procedure:
After N-benzyloxycarbonyl-glycyl-L-argininal dibutylacetal hydrochloride (1.60 g, 3.10 mmols) was dissolved in methanol (250 ml), palladium black (1 g) was added to the solution. The mixture was stirred at room temperature for 2 hours in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give 1.20 g (100%) of glycyl-L-argininal dibutylacetal hydrochloride as oil.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][N:11]([CH2:14][C@H:15]([NH:23][C:24]([O:26][C:27](C)(C)[CH3:28])=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.[C:45](=[O:63])([O:56][CH2:57][C:58]1[S:62][CH:61]=[N:60][CH:59]=1)OC1C=CC([N+]([O-])=O)=CC=1>ClCCl.C(OCC)(=O)C>[CH2:12]([N:11]([CH2:10][C@@H:9]([NH:8][C:45]([O:56][CH2:57][C:58]1[S:62][CH:61]=[N:60][CH:59]=1)=[O:63])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:62][CH:61]=[N:60][CH:59]=1)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:13]
Reactant: CCN(C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
The product from Example 70E (87 mg, 0.17 mmol) in dichloromethane (1.8 mL) was treated with trifluoroacetic acid (1.0 mL) at ambient temperature. After stirring for 2 hours, the mixture was concentrated and treated with aqueous 10% K2CO3 (2.4 mL). The aqueous solution was extracted with ethyl acetate (3×3 mL). The ethyl acetate extracts were combined and treated with 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (100 mg, 0.36 mmol) by extraction with aqueous NaHCO3] in ethyl acetate (6 mL). After heating at 60° C. for 18 hours, the mixture was allowed to cool to ambient temperature and concentrated. The residue was purified by flash column chromatography on silica gel eluting with (chloroform:methanol, 98:2) to provide the title compound (33.5 mg, 31%). 1H NMR (CDCl3) δ 8.76 (s, 2H), 7.85 (s, 2H), 7.32-7.09 (m, 10H), 5.37-5.17 (m, 6H), 4.15 (br s, 2H), 3.61-2.65 (m, 10H), 1.24 (t, 3H); MS (ESI+) m/z 594 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7](=[N:16][OH:17])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Cl[CH2:27][C:28](=[O:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CN(C)C=O>[CH2:33]([O:32][C:30]([CH2:29][C:28](=[O:35])[CH2:27][O:17][N:16]=[C:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
2.57 g (0.01 mol) of the 4,4'-dimethoxybenzophenone oxime as obtained in (1) was dissolved in 5 ml of dimethylformamide and 1.2 g of potassium tert-butoxide was added thereto under ice cooling. The resulting mixture was stirred for ten minutes. Then 1.8 g of ethyl 4-chloroacetoacetate was added thereto and the obtained mixture was stirred at room temperature. After two hours, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethanol. The crude product thus obtained was purified by silica gel chromatography to give 3.1 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:27][CH:28]=[CH:29][CH3:30].[OH-].[Na+]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:27][CH:28]=[CH:29][CH3:30])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: CC=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC=CCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccc(NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: To the stirred mixture of 5.5 g of 4-(4-acetamidophenylamino)-3-amino-5-sulfamoylbenzoic acid, 2.0 g of 1-bromo-2-butene, 30 ml of water and 10 ml of N aqueous sodium hydroxide, 4N aqueous sodium hydroxide is added dropwise in order to keep the pH of the mixture at 7.4 for 17 hours. It is filtered, the filtrate acidified with glacial acetic acid to pH = 4 and the precipitate formed filtered off. It is recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenylamino)-3-but-2-enylamino-5-sulfamoylbenzoic acid melting at about 230° with decomposition.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH2:14][CH3:15])([CH3:13])[CH3:12].CS(C)=O>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]([CH2:14][CH3:15])([CH3:12])[CH3:13])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCC(C)(C)c1ccc(O)cc1
Solvent: CS(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Following procedure A, 4-fluoronitrobenzene (318 mg, 2.25 mmol, 1.00 eq) and 4-tert-pentylphenol (460 mg, 2.28 mmol, 1.24 eq) were dissolved in DMSO (6 mL) Anhydrous K2CO3 (465 mg, 3.37 mmol, 1.49 eq) was added and the reaction mixture was stirred at room temperature for 2 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as colourless solid (533 mg, 1.87 mmol, 83% yield). Rf=0.70 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C17H20NO3+ [M+H]+ 285.1365. found: 285.1359. 1H NMR (400 MHz, CDCl3) δ 8.25-8.14 (m, 2H, aromatic H), 7.44-7.32 (m, 2H, aromatic H), 7.06-6.96 (m, 4H, aromatic H), 1.66 (q, J=7.4 Hz, 2H, Ar—C(CH3)2CH2CH3), 1.31 (s, 6H, Ar—C(CH3)2CH2CH3), 0.71 (t, J=7.4 Hz, 3H, Ar—C(CH3)2CH2CH3). 13C NMR (101 MHz, CDCl3) δ 163.81, 152.24, 146.94, 142.56, 127.91, 126.01, 120.06, 116.99, 37.89, 37.06, 28.63, 9.27.
Reaction SMILES: B(OC(C)C)(OC(C)C)OC(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Li])CCC.Cl.C(=O)([O-])[O-].[Na+].[Na+].[NH2:43][C:44]1[C:45]([C:51]([O:53][CH3:54])=[O:52])=[N:46][C:47](Br)=[CH:48][N:49]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:43][C:44]1[C:45]([C:51]([O:53][CH3:54])=[O:52])=[N:46][C:47]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:48][N:49]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)cnc1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Triisopropyl borate (2.7 mL, 11.6 mmol) was added to a solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine in (1.24 g, 3.87 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 548-550) in anhydrous tetrahydrofuran (25 mL) at −78° C. under an atmosphere of nitrogen, followed by dropwise addition of n-butyllithium (9.8 mL, 15.5 mmol). The resulting mixture was stirred at −78° C. for 30 min, then allowed to warm to room temperature. HCl (3 M aq, 7.8 mL, 23.2 mmol) was added and the mixture was stirred at room temperature for 10 min. Sodium carbonate (4.1 g, 38.7 mmol) was added followed by the addition of methyl 3-amino-6-bromo-2-pyrazinecarboxylate (0.79 g, 3.4 mmol; described in: H. Ellingson, J. Amer. Chem. Soc. 1949, 2798) and Pd(dppf)Cl2 (95 mg, 0.12 mmol). The resulting mixture was heated at 55° C. overnight. Silica was added, the solvent was evaporated and the crude mixture was purified by column chromatography on silica using chloroform/methanol, (99:1), as the eluent to give 0.923 g (69% yield) of the base as a yellow solid: 1HNMR (DMSO-d6) δ 9.0 (s, 1H), 8.22 (d, J=7 Hz, 2H), 7.80 (d, J=7 Hz, 2H), 7.62 (br s, 2H), 3.90 (s, 3H) 2.91 (m, 4H), 2.36 (m, 4H), 2.12 (s, 3H); 13C NMR (DMSO-d6) δ 166.2, 155.1, 145.8, 140.33, 127.5, 134.0, 128.1, 125.7, 109.1, 53.5, 52.3, 45.7, 45.2; MS (ESP) m/z 392 (M++1).
Reaction SMILES: Cl.[CH:2]1[C:14]2[C:13](=[CH:15][C:16]3[CH:24]=[CH:23][C:19]([CH:20]([NH2:22])[CH3:21])=[CH:18][CH:17]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.C[CH:27]([NH2:42])[C:28]1C=[CH:32][C:31](CCC2C=CC=CC=2)=[CH:30][CH:29]=1>>[CH:11]1[C:12]2[C:13](=[CH:15][C:16]3[CH:17]=[CH:18][C:19]([CH:20]([N:22]=[C:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:42]4)[CH3:21])=[CH:23][CH:24]=3)[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccc(C=C2c3ccccc3-c3ccccc32)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(C=C2c3ccccc3-c3ccccc32)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting ρ-(fluoren-9-ylidenemethyl)-α-methylbenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above results in the formation of 2-[[1-[ρ-(fluoren-9-ylidenemethyl)phenyl]ethylimino]]-hexahydro-1H-azepine, having a M.P. of 265.5°-7.5° C. (dec.)
Reaction SMILES: [C:1]([NH:6][C:7]1[O:8][CH:9]=[C:10]([CH3:12])[N:11]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.O>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:6]([C:7]1[O:8][CH:9]=[C:10]([CH3:12])[N:11]=1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1coc(NC(=O)C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1coc(N(Cc2cccc(Cl)c2)C(=O)C(C)C)n1
Temperature: 70 °C

Procedure:
2-iso Butyramido-4-methyloxazole (11.1 g., 0.066 mol) prepared in a manner similar to that described in Example 20, was dissolved in dry dimethylformamide. Solid potassium carbonate (10.47 g., 0.076 mol) and 3-chlorobenzyl bromide (15.6 g., 0.076 mol) were added and the stirred mixture was heated at 70° C for 2 hours, cooled and poured into cold water. The solution was extracted with ether and the extract was dried over magnesium sulphate and evaporated. The residue b.p. distilled to give the product, 12.3 g., b.p, 115°-120° C/0.08 mm.
Reaction SMILES: Br.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1.[OH-].[Na+].C(O)(=O)C>C(OCC)(=O)C>[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)C(=O)N(Cc1cccnc1)CC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1c2cc(O)ccc2CCN1Cc1cccnc1
Yield: 46.7 %

Procedure:
To 84 ml of 47% aqueous hydrogen bromide was added 11.3 g of 3,4-dihydro-7-methoxy-2-(3-pyridylmethyl)-1 (2H)-isoquinolinone, and the mixture was refluxed under heating for 4.5 hours. After ice cooling, the mixture was neutralized with aqueous sodium hydroxide, made weakly acidic with acetic acid and shaken with ethyl acetate. The organic layer was washed with water and saturated brine in order, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 5.00 g of the titled compound.