Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>N1C=CC=CC=1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:23]([C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc(-c2cnc3ccccc3n2)c1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 0.01 mol) in pyridine (10 mL) was cooled to 0° C. and 2-furoyl chloride (1 mL, 0.01 mol) was added dropwise over 10 min. The reaction mixture was stirred overnight at room temperature, diluted with water (50 mL), and stirred until precipitate formed. The solid was filtered, dried, and recrystallized from toluene to afford N-[3-(quinoxalin-2-yl)phenyl]furan-2-carboxamide (2.4 g, 76%). LCMS calculated for C19H13N3O2 (M+H): 316.10. found 316. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.45 (1H, s), 9.51 (1H, s), 8.68 (1H, s), 8.22-7.80 (7H, m), 7.61 (1H, m), 7.40 (1H, m), 6.81 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][Br:44])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(CO)c(C(C)C)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C#Cc2ccc(CBr)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl[4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 123, 180.0 mg, 0.56 mmol) and triphenylphosphine (190.0 mg, 0.73 mmol) in 5 mL CH2Cl2 was cooled to 0° C. and N-bromosuccinimide (130.0 mg, 0.73 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 212.0 mg (98%), was isolated by column chromatography (5-10% EtOAc-hexanes) as a pale-yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]([CH2:24][CH2:25][CH3:26])=[C:22]([C:27]([OH:29])=O)[N:21]=[N:20]3)=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:34]1([NH:36][C:27]([C:22]2[N:21]=[N:20][N:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:12])=[CH:18][CH:17]=3)[C:23]=2[CH2:24][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:33]1
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 182 %

Procedure:
1-(4-{[(3-Phenylpropyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (505 mg, 1.29 mmol) obtained in Example 60b), HOBt (87.8 mg, 0.643 mmol, 0.5 eq.) and cyclopropylamine (0.120 ml, 1.67 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (302 mg, 1.54 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (505 mg, 1.17 mmol, 90.7%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2].CI.[C:24](=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([N:7]([CH3:24])[C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1CCCN2
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)C(=O)N(C)c1c([N+](=O)[O-])ccc2c1CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of the product from Example 87 (0.87 g, 3 mmol), methyl iodide (0.51 g, 3.6 mmol) and cesium carbonate (1.17 g, 3.6 mmol) in 15 mL of acetonitrile was stirred at room temperature for 2 hours. The inorganic salts were removed by filtration and the filtrate evaporated. The residue was dissolved in methylene chloride, filtered and evaporated. The product was then used without further purification (0.86 g, 93% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:26])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=4Br)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH3:27][N:28]1[CH2:32][CH2:31][N:30]([C:19]2[CH:20]=[C:21]([N:30]3[CH2:31][CH2:32][N:28]([CH3:27])[C:29]3=[O:33])[CH:22]=[CH:23][C:18]=2[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[C:6]([CH3:26])=[CH:5][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][N:8]=3)[CH2:11][CH2:12]2)=[O:17])[C:29]1=[O:33]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2Br)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2N2CCN(C)C2=O)CC1
Yield: 25.7 %

Procedure:
Using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](2,4-dibromophenyl)methanone (238 mg) described in Preparation Example 238 and 1-methylimidazolidin-2-one (149 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (66 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.22 (s, br, 1H), 7.74-6.70 (m, 12H), 5.05-4.94 (m, 1H), 3.66-3.52 (m, br, 2H), 3.02-2.83 (m, br, 2H), 2.81-2.58 (m, br, 4H), 2.58-2.36 (m, br, 2H), 2.02-1.66 (m, br, 6H), 1.66-1.46 (m, br, 1H), 1.46-1.35 (m, br, 3H), 1.26 (d, 6H, J=6.0 Hz); ESMS m/e: 535.1 (M+H)+.
Reaction SMILES: [CH3:1][P:2]([C:5]1[N:6]=[C:7]([O:12][CH3:13])[C:8](N)=[N:9][CH:10]=1)([CH3:4])=[O:3].Cl[C:15]1[N:20]=[C:19]([Cl:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:21][C:19]1[C:18]([C:22]([F:24])([F:23])[F:25])=[CH:17][N:16]=[C:15]([C:8]2[C:7]([O:12][CH3:13])=[N:6][C:5]([P:2]([CH3:4])([CH3:1])=[O:3])=[CH:10][N:9]=2)[N:20]=1
Reactant: COc1nc(P(C)(C)=O)cnc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared in Example 33: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, is allowed to stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature and filtered to obtain a white solid. The white solid is washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid is dried under vacuum to yield 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:21][CH:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]=4[OH:32])[CH2:23]3)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:38]([O:37][C:35]([CH2:34][O:32][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[CH2:30][CH2:31][CH:22]([CH2:21][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=1)[CH3:20])[CH2:23]2)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(CC1CCc2c(O)cccc2C1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(CC1CCc2c(cccc2OCC(=O)OC(C)(C)C)C1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 80.6 %

Procedure:
To a solution of 413 mg of 2-[N-(5,6-diphenylpyrazin-2-yl)-N-methyl(aminomethyl)]-5-hydroxy-1,2,3,4-tetrahydronaphthalene and 210 mg of tert-butyl bromoacetate in 10 ml of acetonitrile, a catalytic amount of potassium iodide and 163 mg of potassium carbonate were added and the mixture was heated at reflux for 4 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 423 mg of the desired compound as a pale orange oily substance.
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].O>C1C=CC=CC=1>[CH2:18]([N:19]([CH2:22][CH2:23][CH:13]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:14]#[N:15])[CH2:20][CH3:21])[CH3:17]
Reactant: CCN(CC)CCCl
Reactant: N#CCc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCN(CC)CCC(C#N)c1cccc2ccccc12

Procedure:
7 g of sodium amide are added in small quantities to 27.11 g of 1-naphthylacetonitrile in 210 ml of anhydrous benzene. The mixture is heated for 2 hours to reflux and 22 g of 2-chlorodiethylaminoethane are added, the heating being continued to reflux for another two and a half hours. Then, the mixture is cooled and 200 ml of water are added. After decanting, the organic phase is extracted by HCl at 10%. The aqueous phase is washed in ether, neutralized with NaOH at 10%, then extracted with ether. After evaporation of the solvents, a red oil is obtained, which is distilled in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[NH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[OH:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]([NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[OH:24])=[O:16])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: CN1CCCc2c(Br)cc(C(=O)O)c(N)c21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCCc2c(Br)cc(C(=O)N[C@H]3CCCC[C@@H]3O)c(N)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (600 mg, 2.10 mmol) in DMF (7 mL) at rt was added (1S,2S)-2-aminocyclohexanol (242 mg, 2.10 mmol), BOP (1.16 g, 2.63 mmol), and Et3N (0.59 mL, 4.21 mmol). The mixture was stirred at rt for 2 h. The resulting solution was quenched with 10% aqueous NaHCO3 and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated to afford 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxamide in pure form.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[C:7]([F:15])[C:5]=2[N:6]=1.C1COCC1.CC(C[Al]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([F:15])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(F)c2nc(Br)sc2c1
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cc(F)c2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a solution of methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate 0.335 g, 1.15 mmol) in toluene (10 mL) and THF (5 mL) was added Dibal-H (4.8 mL, 4.8 mmol) at −78° C. over 10 min. The resulting mixture was allowed to warm to rt and stirred at rt for 3 hr before it was poured into ice cold water (100 mL). The mixture was stirred at rt for 30 min and then filtered through Celite® 545. The organic layer was separated and the aqueous layer was extracted twice with AcOEt. The combined organic phase was dried over anhydrous MgSO4 and concentrated under vacuum. Evaporation of solvent under vacuum gave the title compound (0.269 g, 89% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:6]=1.[Br:17]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:14])[F:15])=[N:5][N:6]=1
Reactant: Cc1nnc(-c2ccccc2C(F)(F)F)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1nnc(CBr)s1
Temperature: 25 °C

Procedure:
172 mg (0.70 mmol) of the compound from Example 72A together with 251 mg (1.41 mmol) of N-bromosuccinimide and 12 mg (0.07 mmol) of 2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride were heated under reflux for 8 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 33 mg (15% of theory) of the target compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33]>CN(C=O)C.CCOC(C)=O>[N:34]1([C:32](=[O:33])[CH2:31][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:22][C:21]4([CH3:24])[CH2:23][CH:17]3[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]4)=[O:15])=[CH:12][CH:13]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NCC(=O)N3CCOCC3)cc2)C1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (0.5 g, 1.34 mmol) in dry DMF (40 ml) was added sodium hydride (80 mg, 3.33 mmol in 60% mineral oil) and the mixture was stirred for 30 min. 2-Chloro-1-morpholin-4-yl-ethanone (264 mg, 1.61 mmol) was added and the stirring was continued for an additional 1 hr. at 50° C. The reaction was quenched by addition of water (50 ml) and extracted with diethyl ether (2×25 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (20 ml) and TFA (10 ml) was added. The resulting mixture was stirred for 4 hrs. at room temperature and evaporated in vacuo. The residue was purified by column chromatography (silica gel) using first EtOAc (500 ml) followed by 4% TEA in EtOAc as eluents. Semi-pure fractions were collected and evaporated to dryness affording 0.4 g as an oil which was dissolved in EtOAc (25 ml) and washed with water (2×25 ml), dried (Na2SO4), filtered and evaporated in vacuo affording 180 mg (34%) of the title compound as a oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F>C1COCC1.C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccc3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
A slurry of 334 mg (374 mg of 60% in oil, 9.35 mmol) of sodium hydride in 5 mL THF was treated with a solution of 1.0 g (8.5 mmol) of indole in 5 mL THF, followed by stirring at ambient temperature for 15 min. The solution was then treated with 1.35 g (8.5 mmol) of 3,4-difluoronitrobenzene. The solution was stirred at ambient temperature for 48 h, followed by concentration in vacuo to afford brown oil which was dissolved in ethyl acetate and washed with water. Drying (Na2SO4) and concentration in vacuo afforded an oil which was chromatographed over 100 g of 230-400 mesh silica gel, eluting with 20% (v/v) ethyl acetate in hexane. These procedures afforded 1.1 g (51%) of the title compound as a yellow solid. 1H NMR (CDCl3): δ 8.23, 7.74, 7.40, 7.35, 7.30, 6.80.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7])[N:9]=1)#[N:27]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(OC3CCCCC3)cc2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(OC3CCCCC3)ccc12

Procedure:
Prepared from 1-Cyano-6-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 28e (94% yield). MS-(+)-ion: M+1=370.32.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(C(F)(F)F)c4)c(C(=O)O)s3)c2cc1OC
Yield: 58.1 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-trifluoromethylphenylboronic acid (28.5 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid (26.1 mg, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.90 (br.s. 1H); 8.82 (s, 1 H); 8.37-8.47 (m, 2 H); 7.87 (s, 1 H); 7.82 (d, 1 H); 7.72 (t, 1 H); 7.39 (s, 1 H); 3.87 (s, 3 H); 3.85 (s, 3 H). MS 450 m/z (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:40]([O:39][CH:35]([O:36][CH2:37][CH3:38])[C@@H:34]([N:22]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:13])[CH3:43])[CH3:42])[CH3:41]
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 100 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]2=[N:3]1.[CH2:13]1[S:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>>[CH3:1][N:2]1[N:6]=[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[C:13]3[S:19][C:17](=[O:18])[NH:16][C:14]3=[O:15])=[CH:10][C:4]2=[N:3]1
Reactant: Cn1nc2ccc(C=O)cc2n1
Reactant: O=C1CSC(=O)N1
Product: Cn1nc2ccc(C=C3SC(=O)NC3=O)cc2n1

Procedure:
Following the general method as outlined in Example 1, starting from 2-Methyl-2H-benzotriazole-5-carbaldehyde (intermediate 33) and thiazolidinedione, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCCCCCCCCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCCCCCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 12-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 9-aminononanol. MS obsd. (ESI+) [(M+H)+] 495, 1H NMR (400 MHz, CD3OD) δ ppm 8.11-8.09 (dd, J=1.2 Hz, 1 H), 7.92 (s, 1 H), 7.85-7.83 (d, J=7.6 Hz, 1 H), 7.71-7.67 (m, 2 H), 7.61-7.57 (m, 2 H), 5.92 (s, 1 H), 5.28 (s, 2 H), 4.52 (s, 2 H), 3.74 (s, 2 H), 3.50-3.46 (t, 2 H), 2.92-2.89 (t, 2 H), 2.46 (s, 3 H), 1.73-1.63 (m, 4 H), 1.50-1.38 (m, 10 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: COCCNS(=O)(=O)c1ccc(Br)cc1
Yield: 93.5 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and 2-methoxyethyl amine (1.62 g, 22 mmol) to give the title compound (5.5 g, 95%) as an off-white crystalline solid. MS (ISP) 294.1[(M+H)+].