Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH:6]1[C:8]([O:10]C)=[O:9])=[O:4].CO.[OH-].[Na+]>O>[Cl:19][C:14]1[CH:13]=[C:12]([C:5]2([C:3]([OH:4])=[O:2])[CH2:7][CH:6]2[C:8]([OH:10])=[O:9])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C1CC1(C(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC1(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
A mixture of 31.0 kg 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid dimethyl ester (from Step 2), 40 L water, 35 kg methanol and 18.0 kg 50% caustic soda was warmed to 70-75° C. (under reflux) and maintained at 70-75° C. for 1.5 hours. 10 L water was then added, and the mixture was kept at 75-77° C. for an additional 2 hours. Methanol was slowly distilled off in vacuo to 70° C. to give a heavy suspension, which was then mixed with 80 L water to effect solution. The free dicarboxylic acid was precipitated with 31 kg of 32% hydrochloric acid and extracted with 100 kg ethyl acetate. The lower aqueous phase was separated and washed with 20 kg ethyl acetate. The combined organic phases were washed with 50 L water, and then saturated aqueous sodium chloride. Distillation in vacuo to 80° C. with full vacuum yielded a concentrate of 1-(3,4-dichlorophenyl)-1,2-cyclopropane-dicarboxylic acid, which was used “as is” for the next step, cyclization to the imide. A quantitative yield from the diester was assumed for calculation purposes.
Reaction SMILES: Br[C:2]1[CH:27]=[C:26]([O:28][CH3:29])[C:5]2[NH:6][C:7](=[O:25])[CH:8]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[C:31]([N:33](C)C)=O>[C-]#N.[Zn+2].[C-]#N.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>[C:31]([C:2]1[CH:27]=[C:26]([O:28][CH3:29])[C:5]2[NH:6][C:7](=[O:25])[CH:8]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)#[N:33]
Reactant: CC(=O)N(C)C
Reactant: COc1cc(Br)cc2c1NC(=O)C(NC(=O)OC(C)(C)C)N=C2c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)cc2c1NC(=O)C(NC(=O)OC(C)(C)C)N=C2c1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-Butyl (7-bromo-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate (0.050 g, 0.109 mmol), zinc cyanide (0.013 g, 0.109 mmol), and Pd(Ph3P)4 (0.013 g, 10.86 μmol) were dissolved in DMA (0.543 ml) and heated to 90° C. After 1 h, the reaction was quenched with saturated NaHCO3. The reaction mixture was extracted three times with EtOAc. The combined organic layers were dried with MgSO4 and evaporated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give tert-butyl 7-cyano-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (41 mg, 93%): HPLC RT=1.948 min (H2O/MeOH with TFA, SunFire C18, 5.0 μm, 2.1 mm×30 mm, 4 min gradient, monitored at 220 nm). [M+H+]=407.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.O.C(N(CC)CC)C>[O:1]=[C:2]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:36][CH:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]([OH:47])=[O:46])=[O:21])=[CH:22][CH:23]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (30 mg, 0.1 mmol) was dissolved in DMF (0.5 ml) and 18 mg (0.1 mmol) of carbonyldiimidazol (90% pure) was added and the mixture stirred for 4 h. Phenylalanine (33 mg, 0.2 mmol) was dissolved in of H2O (0.5 ml) together with triethylamine (0.05 ml) and added to the activated acid. This reaction mixture was heated at 75° C. for 2 h. After cooling it was made acidic and diluted 5×with H2O. The precipitate was filtered and washed with H2O and dried under vacuum. FlashTube chromatography using EtOAc/MeOH(7:3) yielded a small amount of 2-[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoylamino]-3-phenyl-propionic acid. The material contained approx. 10% of starting material. 1H NMR (400 MHz, DMSO-d6) δ 8.7 (1H, s), 8.31 (2H, d), 8.21 (1H, d), 7.82 (2H, d), 7.70 (1H, d), 7.62 (1H, t), 7.50 (1H, t), 7.2-7.3(4H, m), 7.17 (1H, t), 4.50 (1H, m), 3.1-3.2 (2H,m).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[C:22](Cl)[CH:23]=[CH:24][C:9]1=2.[CH:40](OC(N1C2C(=CC3CCCC=3C=2)C(NCC2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)CCC1)=O)([CH3:42])[CH3:41]>>[CH:18]([O:17][C:15]([N:11]1[C:10]2[C:9](=[CH:24][C:23]3[CH2:41][CH2:40][CH2:42][C:22]=3[CH:21]=2)[CH:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:38])[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=2)[C:26]2[N:30]=[N:29][NH:28][N:27]=2)[CH2:14][CH2:13][CH2:12]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc(Cl)cc21
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)CCC3
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)CCC3

Procedure:
The titled compound was prepared in a manner analogous to the procedure for the preparation of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, from Step 2 to Step 3) by replacing isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with (+/−)-isopropyl-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate (prepared above) in Example 46 Step 2. MS (ES−): 581 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[NH:55])[C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([NH:33]C(OCC[Si](C)(C)C)=O)=[CH:28][C:27]=3[NH:43][C:44](=[O:54])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=[O:52])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:33][C:29]1[CH:30]=[C:31]([CH3:32])[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([C:12]3[CH:11]=[C:10]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[NH:55])[S:14][C:13]=3[S:15][CH3:16])(=[O:18])=[O:19])[CH:21]=2)=[C:27]([NH:43][C:44](=[O:54])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=[O:52])[CH:28]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2NC(=O)NCCCCCC(=O)O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)NCCCCCC(=O)O)c1
Temperature: 40 °C
Yield: 57.3 %

Procedure:
A solution of 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid ((Example 259: step b) 0.422 g, 0.506 mmol) in dry THF (20 mL) was treated with tetrabutylammonium fluoride (1 M in hexanes, 3.39 mL, 3.39 mmol) and stirred at 40° C. 4 h. Solvents were evaporated in vacuo. The residue was taken up in CH2Cl2 and washed with water (4×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (4% MeOH in CH2Cl2) afforded the product 6-(3-{4-amino-3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-hexanoic acid (0.200 g, 57%) as an off-white solid. The material was combined with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.252 g, 0.870 mmol) and acetic acid (0.5 mL) in MeOH (10 mL) and was stirred at 40° C. 2 h. The solvent was removed in vacuo. Silica gel chromatography (4% MeOH in CH2Cl2 then 10% MeOH in CH2Cl2) afforded the title compound (0.215 g, 80%) as a white solid. 1H-NMR (CD3OD): δ 8.22 (s, 1H), 8.06 (m, 1H), 7.89 (m, 1H), 7.72 (m, 1H), 7.69 (m, 1H), 7.53 (m, 1H), 7.32 (m, 1H), 3.01 (m, 2H), 2.66 (s, 3H), 2.27 (t, 2H, 7.4 Hz), 1.97 (s, 3H), 1.57 (m, 2H), 1.54 (s, 18H), 1.51 (s, 9H), 1.37 (m, 2H), 1.27 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[O:7][C:6]2[C:8]3[C:13]([CH:14]=[CH:15][C:5]=2[CH:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=2)[C:3]=1[C:24]#[N:25])=[CH:12][CH:11]=[CH:10][CH:9]=3>C(OCC)(OCC)OCC>[Cl:23][C:18]1[CH:17]=[C:16]([CH:4]2[C:3]([C:24]#[N:25])=[C:2]([N:1]=[CH:2][O:7][CH2:6][CH3:5])[O:7][C:6]3[C:8]4[C:13]([CH:14]=[CH:15][C:5]2=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: N#CC1=C(N)Oc2c(ccc3ccccc23)C1c1ccc(F)c(Cl)c1
Solvent: CCOC(OCC)OCC
Product: CCOC=NC1=C(C#N)C(c2ccc(F)c(Cl)c2)c2ccc3ccccc3c2O1
Reaction time: 24 h

Procedure:
2-Amino-4-(3-chloro-4-fluorophenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (3.12 g) was heated, under reflux, in triethyl orthoformate (40 ml) for 24 hours. A fraction coming over at 80° to 140° C. was distilled off and more triethyl orthofomate (40 ml) was added, and the refluxing was continued for a further 24 hours. The solution was evaporated to dryness. The gummy residue was dissolved in chloroform and passed through a column of `flash` silica using 30% hexane in chloroform as eluant. The fractions containing product were bulked, evaporated and triturated with ethyl acetate to give white crystals of 4-(3-chloro-4-fluorophenyl)-2-ethoxymethyleneamino-4H-naphtho[1,2-b]pyran-3-carbonitrile, m.p. 146°-148° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][N:27]([C@H:35]([CH3:38])[CH2:36][OH:37])[C:28]3=[O:34])=[O:21])[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(Cl)Cl>CN(C)C1C=CN=CC=1>[CH3:39][S:40]([O:37][CH2:36][C@H:35]([N:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:32]([CH3:33])[C:23]=2[NH:22][C:20](=[O:21])[CH2:19][C:11]2[CH:12]=[CH:13][C:14]([C:15]([F:18])([F:16])[F:17])=[C:9]([F:8])[CH:10]=2)[C:28]1=[O:34])[CH3:38])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.2 g, 0.002 mol) was added to a solution of (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(2-(1-hydroxypropan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)acetamide (0.5 g, 0.001 mol), methanesulfonyl chloride (0.16 g, 0.0014 mol) and 4-dimethylaminopyridine (10 mg, 0.0001 mol) in methylene chloride (10 mL, 0.2 mol). The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the mixture was purified via flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]=2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])=O)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:55]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Na].[OH-:59]>C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].C(N(CC)CC)C>[NH2:55][C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:25]=2[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])=[O:59])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Reactant: [OH-]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](N)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (250 mg) was dissolved in toluene (5 ml), diphenylphosphoryl azide (0.15 ml) and triethylamine (94 μl) were added and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled to room temperature, 8M aqueous sodium, hydroxide solution (0.56 ml) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and the mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) and ethyl acetate-methanol (10:1) was concentrated under reduced pressure to give the object product (155 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14](Cl)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2].[CH3:21][NH2:22]>>[CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:22][CH3:21])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2]
Reactant: CCCCCP(=O)(OCC)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Product: CCCCCP(=O)(OCC)c1ccc(NC)c([N+](=O)[O-])c1

Procedure:
Prepared analogously to Example 7b from ethyl(4-chloro-3-nitro-phenyl)-n-pentyl-phosphinate and methylamine solution.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH2:18][CH2:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>C(O)C.O>[CH2:21]([C:18]1[C:17](=[O:20])[C:7]2[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=[C:11]3[C:6]=2[N:5]([CH:19]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]3=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc2c3c(c1)c1ccc(Br)cc1n3CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(=O)c(Cc3ccccc3)cn3c4cc(Br)ccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
9-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 101, step 6 was suspended in ethanol (12 ml), and benzaldehyde (103 mg) and sodium hydroxide (190 mg) dissolved in water (1 ml) were added to the suspension. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (217 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16].C[O-].[Na+].[C:22](O)(=[O:24])C.C(OCC)(=O)C>CO.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([O:24][CH3:22])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1NC(C)=O
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1NC(C)=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
256 mg (1.0 mmol) of 2-acetylamino-5-fluoro-4-nitro-benzoic acid methyl ester are dissolved in 5.1 ml of refluxing methanol abs. and cooled to 23° C. whereby some of the material recrystallizes. 81 mg (1.5 mmol) of sodium methanolate are added and the mixture is stirred under argon at room temperature for 16 hours. Acetic acid is added until a pH value of 5 is reached, the resulting mixture is distributed between ethyl acetate and water, the organic phase is separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on 100 g of silica gel (0.04-063 mm) with toluene-ethyl acetate (3:1), fraction size 12 ml. The fractions 37-46 are combined and evaporated, yielding 77 mg (28%) of 2-acetylamino-5-methoxy-4-nitro-benzoic acid methyl ester as yellowish crystals, m.p. 141-143° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[I-].[Na+].CN(C=O)C.Cl[CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]([CH3:39])[N:27]=[C:28]2[C:37]=1[C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:30]=[C:29]2[NH2:38]>O>[NH2:38][C:29]1[C:28]2=[N:27][N:26]([CH3:39])[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[C:37]2[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:30]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 70.2 %

Procedure:
Potassium phthalimide (4.90 mg, 26.4 mmol), sodium iodide (495 mg, 3.30 mmol), and DMF (22 mL) were added to 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (4.00 g, 13.2 mmol, prepared as described in Parts A-F of Examples 454-489), and the reaction was heated at 90° C. for two hours under a nitrogen atmosphere and allowed to cool to ambient temperature. Water (100 mL) was added and a precipitate formed and was isolated by filtration to yield 3.7 g of 2-[4-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3 (2H)-dione that was used in the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:16]C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[F:16][C:7]1[CH:2]=[C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Reactant: Fc1cccc(CBr)c1
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1cccc(F)c1
Yield: 80 %

Procedure:
The title compound was prepared as described for B4 using 3-fluorobenzyl bromide (1.250 g, 8.64 mmol), magnesium (0.231 g, 9.51 mmol) and diethyl oxalate (2.52 g, 17.30 mmol) in the form of colorless oil in 80% yield and used instantly in next step.
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:30]([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]([NH:50][C:51]([NH:53][C@@H:54]([C:62](O)=[O:63])[CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:52])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:36])([CH3:33])([CH3:32])[CH3:31].[F:65][C:66]1[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:67]=1[CH2:68][NH2:69]>C(Cl)Cl.CN(C=O)C>[C:30]([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]([NH:50][C:51]([NH:53][C@@H:54]([C:62](=[O:63])[NH:69][CH2:68][C:67]1[CH:70]=[CH:71][C:72]([F:74])=[CH:73][C:66]=1[F:65])[CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:52])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: NCc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)N[C@H](CC1CCCCC1)C(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)N[C@H](CC1CCCCC1)C(=O)NCc1ccc(F)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N-Methylmorpholine (53 μl, 0.48 mmol), 1-hydroxybenzotriazole (28 mg, 0.208 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.8 mg, 0.192 mmol) were added in the stated sequence to a solution of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((R)-1-carboxy-2-cyclohexyl-ethyl)-ureido]-hexanoate (80 mg, 0.16 mmol) and 2,4-difluorobenzylamine (22.9 mg, 0.16 mmol) in 3 ml of CH2Cl2 and 1 ml of DMF, and the mixture was stirred at RT for about 14 h. Extraction with CH2Cl2/H2O, drying of the organic phase with MgSO4 and evaporation afforded tert-butyl (S)-6-tert-butoxycarbonylamino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzylcarbamoyl)-ethyl]-ureido}-hexanoate as crude product. The entire crude product was dissolved in 4 ml of CH2Cl2, 1 ml of TFA was added and, after 4 h, a further 0.5 ml of TFA was added, and deprotection was carried out at RT for about 10 h. Purification of the deprotected crude product by preparative HPLC afforded 25 mg (27%) of (S)-6-amino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzylcarbamoyl)-ethyl]-ureido}-hexanoic acid trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:30]1[CH:46]=[CH:45][C:33]2[N:34]=[C:35]([NH:37][CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[S:36][C:32]=2[CH:31]=1.C(=O)(O)[O-].[Na+]>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.C(O)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:30]2[CH:46]=[CH:45][C:33]3[N:34]=[C:35]([NH:37][CH2:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[S:36][C:32]=3[CH:31]=2)=[CH:4][N:3]=1
Reactant: Brc1ccc2nc(NCC3CCCCC3)sc2c1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2Cl)cc1
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: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(NCC5CCCCC5)sc4c3)cnc2Cl)cc1
Temperature: 85 °C

Procedure:
A reaction tube was charged with N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (157 mg, 0.369 mmol), 6-bromo-N-(cyclohexylmethyl)benzo[d]thiazol-2-amine (80 mg, 0.246 mmol), Pd(PPh3)4 (14.2 mg, 0.012 mmol), 2.0 M aqueous sodium bicarbonate (0.246 mL, 0.492 mmol) and 0.98 mL ethanol. The tube was sealed and the mixture was heated at 85° C. for 2.5 h. The reaction was concentrated, dissolved in 90/10 CH2Cl2/MeOH and passed through a silica plug. The filtrates were concentrated and the crude material was purified by reverse phase chromatography to provide N-(2-chloro-5-(2-(cyclohexylmethylamino)benzo[d]thiazol-6-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide as a slightly yellow solid (7 mg, 5.2%). MS (ESI pos. ion) m/z calc'd for C21H27ClN4O3S2: 543.1/545.1. found 543.0/545.0.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([NH2:16])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:24](=[S:26])=[S:25].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>C(O)C>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][S:25][C:24]([N:2]2[C@H:3]([C:14]([NH2:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:26])=[CH:30][CH:29]=1
Reactant: S=C=S
Reactant: ClCc1ccc(Cl)cc1
Reactant: NC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Yield: 71 %

Procedure:
In the same manner as described in Example 53, (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxamide (0.71 g), triethylamine (0.46 ml), carbon disulfide (0.22 ml), 70% ethanol (20 ml) and 4-chlorobenzyl chloride (0.53 g) are reacted and treated to give the title compound (0.97 g, 71%) as white powder.