Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19]3[S:20][CH:21]=[C:22]([CH2:24][C:25]([O:27]CC)=[O:26])[N:23]=3)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.C1COCC1>[CH:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:10]([C:19]3[S:20][CH:21]=[C:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=3)[CH:9]=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1csc(-c2cnn(C3CCCCC3)c2-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1csc(-c2cnn(C3CCCCC3)c2-c2ccc(F)cc2)n1
Yield: 90.2 %

Procedure:
A mixed solution of the compound (269 mg, 0.65 mmol) obtained in step 3 and 1N aqueous sodium hydroxide solution (0.976 mL, 0.98 mmol) in ethanol (4 mL) and THF (4 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. 1N Hydrochloric acid was added thereto, and the precipitate was collected by filtration, and crystallized from diethyl ether and hexane to give 2-(2-(1-cyclohexyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (226 mg, 0.586 mmol, 90%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH2:15])[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:16]#[N:17])=[C:13]([NH:15][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(sc(N)c2C#N)C1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)N1CCc2c(sc(NC(=O)c3ccccc3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano-4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid ethyl ester (compound A1) and benzoyl chloride.
Reaction SMILES: [C:1]1([CH2:7]C(N)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)C=CC1C=CC=CC=1.C1([CH2:27][CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C=CC=CC=1>>[C:1]1(/[CH:7]=[CH:27]/[CH:28]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Reactant: NC(=O)Cc1ccccc1
Agent: O=CC=Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(/C=C/c1ccccc1)NC(=O)Cc1ccccc1
Yield: 88 %

Procedure:
Compound 46 was prepared from 2-phenylacetamide and cinnamaldehyde using the procedure for compound 44. Yield: 88%. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J=7.6 Hz, 2H), 7.21-7.37 (m, 15H), 6.41-6.45 (m, 1H), 6.27-6.32 (m, 1H), 6.04-6.09 (m, 1H), 3.44-3.52 (m, 4H). LC-MS (ESI): m/z 385.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1.O>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[C@@H:2]([NH:1][C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[C:3]([OH:5])=[O:4]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@@H](C(=O)O)C1Cc2ccccc2C1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](C(=O)O)C1Cc2ccccc2C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.1 %

Procedure:
(2R)-amino(2,3-dihydro-1H-inden-2-yl)ethanoic acid (1.91 g, 10 mmol) was suspended in dioxane (10 ml) and water (10 ml). To this was added triethylamine (1.7 ml) and N-(benzyloxycarbonyloxy)-succinimide (2.54 g) and the reaction mixture was stirred rapidly at room temperature for 2 days. The reaction mixture was poured into water (50 ml) and extracted with chloroform (100 ml). The organic phase was washed with 1N hydrochloric acid (50 ml) and water (50 ml). This was dried over magnesium sulphate and the solvent removed in vacuo to give the title compound (3.06 g, 94%):
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:17])C(F)(F)F.C([OH:20])C.[OH-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([OH:17])=[O:20]
Reactant: CCO
Reactant: O=C(c1cccn1Cc1ccco1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccn1Cc1ccco1

Procedure:
1-Furfurylpyrrole (2.3 g, 15.6 mMol), 15 ml of trifluoroacetic anhydride (22.35 g, 106 mmol), 50 ml of nitromethane and 25 ml anhydrous diethylether were combined in a 100 ml round bottom flask. The mixture was stirred overnight under positive argon. The reaction was heated and the excess solvents distilled off. The mixture was evaporated to dryness under reduced pressure to give 3.9 g of a dark oil. The oil was distilled in a Kugel-rohr apparatus. The fraction collected at 80° C. to 90° C. at 0.2 mm Hg pressure gave 3.0 g of the colorless oil. 1-(2-furanylmethyl)-2-trifluoroacetyl-1H-pyrrole. This oil was combined with 50 ml ethylalcohol in a 100 ml round bottom flask equipped with a reflux condenser. The mixture was heated to reflux. Sodium hydroxide, 3.0 g in 15 ml of water, was added, and the reaction mixture was refluxed for 3 hours. The ethanol was distilled off and 50 ml of water was added. The mixture was cooled and acidified by addition of 5.0 g malonic acid. A precipitate formed which was collected by filtration. The solid precipitate was recrystallized from acetonitrile to give the title compound a white powder, mp =117° C. to 118° C., infrared spectrum absorption at 3400 cm-1, 1675 cm-1, 1530 cm-1, 1440 cm-1, 750 cm-1.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]1([C:20]2[CH:24]=[CH:23][S:22][C:21]=2[CH:25]=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C)C>CC(C)=O>[C:14]1([C:20]2[CH:24]=[CH:23][S:22][C:21]=2[C:25]([OH:3])=[O:26])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1sccc1-c1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)c1sccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
8N Jones' reagent (ca. 10 ml) was added dropwise to a solution of 3-phenylthiophen-2-aldehyde (5) (0.58 g, 3.1 mmol) in 32 ml of acetone, until an orange colour persisted. The mixture was stirred at room temperature for 18 hrs. Isopropanol (5 ml) was added to remove the excess Jones' reagent and the mixture was then filtered, the organic solvents were evaporated under vacuum and extracted with ethyl acetate (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was then chromatographed using 95/5 chloroform/methanol, thus giving the compound (6) (0.44 g, 1.36 mmol, 46% yield) (M. Pt. 200–202° C.). 1H-NMR (CDCl3) ä 6.87–7.37 (m, 5H, Ph-H) 7.05 (d J=5.0 Hz, 1H, th-H4), 7.53 (d J=5.0 Hz, 1H, th-H5).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[CH2:15]([NH2:17])[CH3:16]>C(Cl)Cl>[Cl:14][C:4]1[N:3]=[C:2]([NH:17][CH2:15][CH3:16])[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=1
Reactant: CCN
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Solvent: ClCCl
Product: CCNc1nc(Cl)cc2ncn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (1.5 g, 6.5 mmol) in DCM (10 mL) was added an aqueous ethylamine solution (70%, 8 mL, 6.368 g, 141.3 mmol). After stirring for 8 hours at room temperature, the reaction mixture was evaporated under reduced pressure to afford the title compound. ESI-MS m/z 239.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]3[C:14]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH:18][C:5]3=[CH:4][C:3]1=2.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40].Cl>C(Cl)Cl>[C:39]([N:18]1[C:5]2[C:6](=[CH:7][C:8]3[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:32])([CH3:1])[C:3]=3[CH:4]=2)[C:14]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)=[N:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)Nc1ccccc1N=C3c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2N=C(c2ccc(C(=O)O)cc2)c2cc3c(cc21)C(C)(C)CCC3(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution 4-(7,7,10,10-tetramethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]-cyclohepta[1,2-b]naphthalen-12-yl)benzoic acid (27) (0.47 mmol) and pyridine (1.2 mmol) in CH2Cl2 (4 mL) is treated with acetyl chloride (1.0 mmol) and stirred at room temperature for 6 h. The mixture is poured into 1 N HCl and extracted with EtOAc. The extract is washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting solid is purified by reversed-phase HPLC (0.1% TFA, 30-100% gradient CH3CN) to give the acid (29).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2N=C(N)S[CH:12]=2)[CH2:3][CH2:2]1.[NH2:14][C:15]1[S:16]C(C(OCC)=O)=C[N:19]=1>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[S:16][C:15]([NH2:19])=[N:14][CH:12]=2)[CH2:5][CH2:6]1
Reactant: Nc1nc(CN2CCOCC2)cs1
Reactant: CCOC(=O)c1cnc(N)s1
Product: Nc1ncc(CN2CCOCC2)s1

Procedure:
5-(morpholinomethyl)thiazol-2-amine 61 was prepared using the same synthetic sequence outlined above for 4-(morpholinomethyl)thiazol-2-amine employing ethyl 2-aminothiazole-5-carboxylate 60 as the starting material.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]3)[NH:9][CH2:8][CH2:7][C:6]2=1.C([N:44]1[CH:48]=[C:47]([C:49](O)=[O:50])[N:46]=[CH:45]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]3([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][CH2:18][CH2:19]3)[N:9]([C:49]([C:47]3[NH:46][CH:45]=[N:44][CH:48]=3)=[O:50])[CH2:8][CH2:7][C:6]2=1
Reactant: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C2c3[nH]c4ccc(Cl)cc4c3CCN2C(=O)c2cnc[nH]2)CCC1

Procedure:
1.84 g of the compound of Example 1, 1.8 g of N-tritylimidazole-4-carboxylic acid, 1.92 ml of diisopropylethylamine and 1.76 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate are stirred at ambient temperature for 24 hours. After dilution with 500 ml of water, filtration, and extraction with dichloromethane, the organic phases are dried and filtered and then concentrated under reduced pressure. Crystallisation of the residue in an ethanol-diethyl ether-hydrogen chloride mixture enables the expected compound to be isolated.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(NC[C@H]1CCNC1)c1cc2ccc(Cl)cc2s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2ccc(Cl)cc2s1

Procedure:
65.3 Using general method H, 6-chloro-benzo[b]thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(6-chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 523.2 ([M−H]−)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])[C:14]([CH3:33])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:40](I)[CH3:41]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]3[C:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([C@H:24]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:25]([O:27][CH2:40][CH3:41])=[O:26])[C:14]([CH3:33])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2nc(-c3cccc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(Br)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-2-(2-(3-bromophenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid (104 mg, 0.191 mmol) in DMF, was added Cs2CO3 (152 mg, 0.467 mmol), ethyl iodide (30 μL, 0.343 mmol). The reaction was stirred at room temperature for 2hs. The reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, dry over MgSO4, filtered, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C28H27BrClNO3S: 572.1 (M+H+); Found: 572.2 (M+H+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1>>[Cl:19][C:17]1[CH:18]=[C:13]([NH2:12])[CH:14]=[C:15]([Cl:21])[C:16]=1[O:20][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1

Procedure:
3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine was synthesized (65%) from 2,6-dichlorobenzothiazole (259) and 4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described in Example 417. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.47 (dd, J=8.7, 2.2 Hz, 1H), 6.73 (s, 2H), 5.88 (s, 2H). MS (EI): m/z 345 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+].[CH3:19]CCCCC.CI.CCOCC>CN(C)C=O.O>[CH3:19][N:4]1[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:6][C:2]([CH3:1])=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(C)c(C(=O)OCC)[nH]1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOCC
Product: CCOC(=O)c1cc(C)c(C(=O)OCC)n1C
Temperature: 0 °C

Procedure:
The diethyl 3-methylpyrrole-2,5-dicarboxylate obtained in Step A was taken up in dried N,N-dimethylformamide (100 ml) and added dropwise over 10 minutes, under nitrogen to an ice-cooled suspension of washed (hexane) sodium hydride (from 16.2 g, 0.41 m of 60% sodium hydride in mineral oil dispersion) in dried N,N-dimethylformamide (400 ml). The resulting mixture was then stirred without cooling for 1 hour, recooled in an ice-bath and treated dropwise over ca. 15 minutes with methyl iodide (30.3 ml, 0.49 m). After stirring for an additional 30 minutes, the mixture was slowly poured into a separatory funnel containing ether (0.5 liter) and water (1 liter). The separated ether layer was washed with water and saturated sodium chloride solution, dried, and concentrated to a tan solid. Purification via chromatography (silica gel/hexane-EtOAc) yielded diethyl 1,3-dimethylpyrrole-2,5-dicarboxylate (75 g) as a white solid, m.p. 48°-48.5° C.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=O.[C:9]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:11][CH2:12][CH3:13])=[O:10]>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])/[CH:14]=[CH:7]/[C:6]1[CH:5]=[CH:4][S:3][C:2]=1[Br:1])[CH3:13]
Reactant: O=Cc1ccsc1Br
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccsc1Br
Yield: 93.8 %

Procedure:
A solution of the aldehyde of Example 23(c) (4.334 g, 22.7 mmol) and (carboethoxymethylene)triphenylphosphorane (8.708 g, 25.0 mmol, Aldrich) in THF (40 mL) was stirred for 17 h. The solution was then evaporated, taken into ether (53 mL) and vacuum filtered. The filtrate was evaporated and the residue purified by flash chromatography on silica gel (20% ethyl acetate/hexanes) to give (E)-3-(2-Bromo-thiophen-3-yl)-acrylic acid ethyl ester 4 (5.559 g, 21.3 mmol, 94%) as a slightly yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:8]3=[CH:7][C:6]=2[C:5](Cl)=[N:4][N:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([NH:23][C:2]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:8]3=[CH:7][C:6]=2[C:5]([NH:3][CH2:2][CH2:11][CH2:6][CH3:5])=[N:4][N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: COc1cccc2cc3c(Cl)nnc(Cl)c3cc12
Product: CCCCNc1nnc(NCCCC)c2cc3c(OC)cccc3cc12
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 1,4-dichloro-6-methoxybenzo[g]phthalazine (3.94 mmol) and n-butylamine (25 mL) was treated in an autoclave at 130° C. for 6 h. After cooling to room temperature, the excess n-butylamine was evaporated to dryness under vacuum and the residue was extracted with chloroform (2×50 mL). The resulting extracts were concentrated and purified by flash chromatography on silica gel 60 Merck (200-400 mesh), using a mixture of chloroform, benzene, methanol (v/v, 1:0.5:0.2) as eluent. The removal of the solvents from the fraction of Rf=0.11 afforded 0.67 g (48%) of 1,4-bis(n-butylamino)-6-methoxy-benzo[g]phthalazine as a brown solid, melting at 178°-180° C., which shows the following physical properties:
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([Cl:37])[CH:28]=3)[C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)[C:14]3[CH:38]=[C:39]([CH3:47])[C:40]([C:43]([F:46])([F:45])[F:44])=[C:41]([CH3:42])[C:13]2=3)[CH2:7][CH2:6]1.[OH-].[Na+]>CO.O.Cl>[Cl:37][C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=1)[CH2:26][N:19]([C:20]1[N:21]=[N:22][N:23]([CH3:25])[N:24]=1)[C@H:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH2:11][CH:8]2[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:48])=[O:2])[CH2:6][CH2:7]2)[C:13]2[C:41]([CH3:42])=[C:40]([C:43]([F:44])([F:45])[F:46])[C:39]([CH3:47])=[CH:38][C:14]1=2
Reactant: COC(=O)CC1CCC(CN2CCC[C@H](N(Cc3cc(Cl)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)c(C)c32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCC(CC(=O)O)CC1)CCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid methyl ester (0.1 mmol) in methanol (1 mL), add 4N sodium hydroxide (0.5 mL). Heat the mixture at 60° C. for 3 h. Dilute the cooled mixture with water and 1N HCl to bring the pH to 6-7 and extract with CH2Cl2 (3×15 mL). Combine the organic layers, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by chromatography (elution with 5%-10% methanol in EtOAc) to afford the title compound. MS (ES+): 687 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[O:19][CH3:20])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[O:19][CH3:20])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(F)c(F)c2OC)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc(F)c(F)c1F

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(3,4,5-trifluoro-2-methoxy-phenyl)-methanone (Example 196) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C18H21N5O4SF3 [(M+H)+] 460.1261, observed 460.1267.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:19]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Yield: 70.3 %

Procedure:
Benzenesulfonamide (3.14 g, 20 mmol) was dissolved in DMF (100 mL) and NaH (60% in oil, 40 mmol, 1.60 g) was added. The reaction was stirred until the gas evolution ceased. 2,4-Difluoronitrobenzene (18 mmol, 2.9 g, 2 mL) was added and the reaction mixture was stirred over night at 35° C. The reaction mixture was poured into HCl (1M aq, 100 mL) and extracted with toluene (25 mL×5). The organic phase was dried (MgSO4) and concentrated and re-crystallized from EtOH to give a first crop of 3.75 g of a yellow solid. A second crop of 0.20 g was collected from the EtOH remains. Yield 3.95 g, 13.3 mmol (74%). MS (posES-FIA) m/z=found: 296. Calc: 296.0.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=O)[CH:17]=3)[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=2)[N:5]=1)([CH3:3])[CH3:2].[NH2:33][NH2:34]>O1CCOCC1>[CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:33][NH2:34])=[O:21])[CH:17]=3)[NH:12][CH:11]=2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)c(-c1nccc(C(C)C)n1)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: NN
Solvent: C1COCCO1
Product: CC(C)c1ccnc(-c2c[nH]c3ccc(C(=O)NN)cc23)n1
Temperature: 90 °C
Yield: 44.4 %

Procedure:
A light-yellow mixture of methyl 3-(4-isopropylpyrimidin-2-yl)-1-tosyl-1H-indole-5-carboxylate (1.37 g, 3.05 mmol) in anhydrous hydrazine (2.39 mL, 76 mmol) and dioxane (1 mL) was heated in an oil bath at 90° C. for 3 h. The mixture was cooled to RT, treated with 20 mL of ice cold H2O. The precipitated pink solid was filtered, rinsed with 2×5 mL of water and 2×20 mL of EtOAc. The filtrate was transferred to a separatory funnel. The aqueous layer was discarded. The EtOAc layer was concentrated to half of its volume. The precipitated brown solid was filtered, rinsed with 2×2 mL of Et2O. The above obtained pink solid and brown solid were combined and dried in a vacuum oven at 40° C. for 18 h to afford 3-(4-isopropylpyrimidin-2-yl)-1H-indole-5-carbohydrazide (400 mg). This material was used in next step without further purification. MS (ESI, pos. ion) m/z: 296.1 (M+1).