Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C@@H:7]([C:27]([OH:29])=[O:28])[CH2:6]1)=[O:4]>O1CCCC1.C(O)C.[Pd]>[CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C@@H:7]([C:27]([OH:29])=[O:28])[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCN(S(=O)(=O)N2CC=C(c3ccc(F)cc3)CC2)[C@@H](C(=O)O)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3ccc(F)cc3)CC2)[C@@H](C(=O)O)C1
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (1.39 g, 3.16 mmol) [prepared as described in Example 28, Steps 1-4] and 10% Pd/C (0.7g) in 10% tetrahydrofuran/ethanol (45 ml) was stirred under an atmosphere of hydrogen (1 atm) overnight. The reaction mixture was filtered through Celite with excess ethanol and the filtrate was concentrated in vacuo to give 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (88%) as a white solid. This material was converted to N-hydroxy-4-dimethylaminocarbonyl-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide by following the procedure described in Example 28, Step 5 above.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:51]([O:55][C:56]([C:58]1[C:59]2[CH2:67][CH2:66][CH2:65][CH2:64][C:60]=2[S:61][C:62]=1[NH2:63])=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.C(Cl)Cl>[C:51]([O:55][C:56]([C:58]1[C:59]2[CH2:67][CH2:66][CH2:65][CH2:64][C:60]=2[S:61][C:62]=1[NH:63][C:13](=[O:15])[CH2:12][N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3]([C:2]([F:1])([F:17])[F:16])=[N:4]1)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Yield: 75.1 %

Procedure:
(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetic acid (638 mg, 2.57 mmol) was suspended in a solution of DCM (10 mL) and DMF (1 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.17 g, 3.08 mmol) and N,N′-diisopropylethylamine (537 μL, 3.08 mmol) added, followed by 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid tert-butyl ester (651 mg, 2.57 mmol). The resultant mixture was stirred at RT overnight. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography using DCM as eluent, to afford the title compound as a yellow solid (0.93 g, 1.93 mmol, 75%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]([CH3:21])([CH2:19][CH3:20])[C:9]([O:11]CC1C=CC=CC=1)=[O:10]>[Pd].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]([CH3:21])([CH2:19][CH3:20])[C:9]([OH:11])=[O:10]
Reactant: CCC(C)(Oc1ccccn1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(Oc1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 2-(2-pyridyloxy)-2-methylbutanoate (1.6 g, 5.5 mmol) and 10% palladium on carbon (50 mg) in 50 mL of methanol was degassed and filled with hydrogen using a balloon. After stirring at room temperature overnight, the reaction mixture was filtered through CELITE diatomaceous earth and washed with methanol (20 mL), and the filtrate was concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.03 (dd, 1H), 7.64 (ddd, 1H), 6.89 (dd, 1H), 6.76 (dd, 1H), 2.14 (m, 1H), 1.94 (m, 1H), 1.64 (s, 3H), 0.99 (t, 3H). LC-MS: m/e 196 (M+H)+ (1.8 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:19][C:20]2[CH:25]=[CH:24][C:23](/[C:26](/[NH:35]C(OC(C)(C)C)=O)=[N:27]/C(OC(C)(C)C)=O)=[CH:22][CH:21]=2)[C:16]([O-:18])=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26](=[NH:27])[NH2:35])=[CH:24][CH:25]=2)[C:16]([O:46][CH3:45])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)c1ccc(NC(C(=O)[O-])c2cccc(OCc3ccccc3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Nc1ccc(C(=N)N)cc1)c1cccc(OCc2ccccc2)c1
Reaction time: 0.83 h

Procedure:
655 mg of methyl (E)/(Z)-(RS)-(3-benzyloxy-phenyl)-[4-(tert-butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-phenylamino]-acetate were treated in 3 ml of methylene chloride with 3 ml of trifluoroacetic acid and left to stand for 50 min. at room temperature. The solution was evaporated in a vacuum and the residue was chromatographed on silica gel. There were obtained 440 mg of methyl (RS)-(3-benzyloxy-phenyl)-(4-carbamimidoyl-phenylamino)-acetate trifluoroacetate, m.p. 162° C., MS: 390 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.NC1C=CC(C(O)=O)=C(OC)C=1.[NH2:28][C:29]1[C:34]([NH2:35])=[CH:33][CH:32]=[CH:31][N:30]=1>P(Cl)(Cl)(Cl)=O>[ClH:15].[CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12]([Cl:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:35][C:34]2[C:29]([N:28]=1)=[N:30][CH:31]=[CH:32][CH:33]=2
Reactant: Nc1cccnc1N
Reactant: COc1cc(S(=O)(=O)Cl)ccc1C(=O)O
Agent: COc1cc(N)ccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2ncccc2[nH]1
Product: Cl
Temperature: 80 °C

Procedure:
Five grams of 2-methoxy-4-chlorosulfonyl-benzoic acid (prepared from 4-amino-2-methoxy-benzoic acid via the corresponding diazonium compound) were dissolved in 400 ml of phosphorus oxychloride and heated to 80° C. for 30 minutes. Then, 3.6 mg of 2,3-diaminopyridine were added, and the mixture was refluxed for four hours. The reaction mixture was concentrated by evaporation in vacuo and re-evaporated with toluene, and the solid residue was processed further without any other purification.
Reaction SMILES: [CH:1](=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11].[OH-:13].[Na+]>O.[Ag-]=O>[C:1]([OH:13])(=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11]
Reactant: CCC=CCCC=CC=CC=O
Reactant: [OH-]
Agent: O=[Ag-]
Agent: [Na+]
Solvent: O
Product: CCC=CCCC=CC=CC(=O)O
Temperature: 20 °C

Procedure:
2,4,8-Undecatrienal was added to a suspension of silver (I) oxide (1.1 eq) in water. The mixture was stirred at 20° C. and concentrated sodium hydroxide solution (equal weight to the aldehyde), was added over 30 minutes allowing the batch to exotherm to 60° C. The solution was filtered through celite, and the aqueous filtrate acidified to pH 1 with hydrochloric acid solution, to give 2,4,8-undecatrienoic acid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C.ClCCl.O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:38]2[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]2)=[N:11][CH:10]=1)=[O:23]
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCC(O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 70 h
Yield: 79.6 %

Procedure:
A mixture of 10.0 g (20.5 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide, 3.1 g (31 mmol) 4-hydroxypiperidine, 10.6 ml (62 mmol) N-ethyldiisopropylamine and 0.13 g (1.0 mmol) 4-(N,N-dimethylamino)-pyridine was stirred at 140° C. for 70 h. After cooling to room temperature the residue was dissolved in a mixture of dichloromethane and water. The layers were separated and the aqueous layer was extracted with four portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated to give 11.1 g of crude product. Flash chromatography afforded 9.0 g (80%) of the title compound as a white solid. MS m/e (%): 552 (M+H+, 100), M.p. 150-152°C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]1[C@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][CH2:17][CH2:16]1.[C:29]1([C:35]2[CH:48]=[CH:47][C:38]([C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH:45]=O)=[O:40])=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl>C(O)(=O)C.ClCCCl>[C:29]1([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][N:18]3[C@@H:19]4[C@@H:24]([C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20]4)[CH2:15][CH2:16][CH2:17]3)=[O:40])=[CH:47][CH:48]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCCCCN1CCC[C@@H]2c3ccccc3CC[C@@H]21)c1ccc(-c2ccccc2)cc1
Reaction time: 16 h
Yield: 68.4 %

Procedure:
Sodium triacetoxyborohydride (170 mg, 0.8 mmol) was added to a stirred mixture of cis-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (D8b, 100 mg, 0.5 mmol), 4-(4-phenylbenzoylamino)butyraldehyde (143, 0.54 mmol) and acetic acid (1 drop) in 1,2-dichloroethane (8 ml) at room temperature. After stirring for 16 h, dichloromethane (10 ml) was added and the mixture was then washed with saturated aqueous K2CO3 (2×20 ml) and brine (20 ml). Drying (Na2SO4) and evaporation in vacuo afforded an oil which was purified by preparative TLC on Kieselgel using 10% methanol-ethyl acetate as eluent to give the title compound as a gum (150 mg, 68%). Mass spectrum: found M+ 438.2679; C30H34N2O requires 438.2671.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[ClH:27].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:18]([CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: c1ccc(CCNCc2ccccc2OCCCN2CCOCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=S(=O)(c1ccc(Cl)cc1)N(CCc1ccccc1)Cc1ccccc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[[2-[3-(4-Morpholinyl)propoxy]phenyl]methyl]benzeneethanamine (14g, see Example 31C) is reacted with 9.2 g of p-chlorobenzenesulfonyl chloride in 130 ml of chloroform. A solution of the amine in chloroform is added dropwise at 10°-15° C to a stirred solution of the p-chlorobenzenesulfonyl chloride in chloroform. After the addition, the solution is stirred for 1 hour at room temperature and maintained for about 1 hour at room temperature. The chloroform is evaporated, and the residue is rubbed under ether. The resulting solid is taken up in acetonitrile, diluted with ether, rubbed and stored at a reduced temperature for several days, yielding 21.2 g of material, melting point 156°-158° C. Recrystallization from 130 ml of isopropanol yields 17 g of the title compound, melting point 163°-165° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24](O)=[O:25])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1[CH:32]=[N:31][C:30]2N(O)N=[N:35][C:29]=2[CH:28]=1.[CH3:37]CN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:35][C:29]1[CH:28]=[CH:27][CH:32]=[CH:37][C:30]=1[NH:31][C:24]([C:19]1[N:20]=[CH:21][C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1)[CH:23]=2)=[O:25]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)O)ncc3c2)CC1
Reactant: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)Nc4ccccc4N)ncc3c2)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A mixture of 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylic acid (214 mg, 0.6 mmol), amine (65 mg, 0.6 mmol), HOAT (122 mg, 0.9 mmol), EDCI (229 mg, 1.2 mmol), and DIPEA (155 mg, 1.2 mmol) in DMF(5 mL) was stirred at 55° C. overnight. The mixture was quenched with water (20 mL) and extracted with EA(25 mL×2). The combined organic layers were separated, dried, filtered, and concentrated to a residue, which was purified by Pre-TLC to afford compound tert-butyl 4-(3-(2-aminophenylcarbamoyl)-isoquinolin-7-yl)piperazine-1-carboxylate (201 mg, 75%) as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:9][CH2:10][N:11]1[C:20]2[C:19](=[O:21])[N:17]([CH3:18])[C:16](=[O:22])[N:15]([CH3:23])[C:14]=2[N:13]=[CH:12]1.C(N(CC)CC)C.CCCCCCC.C(Cl)Cl>C(Cl)Cl>[C:1]([O:9][CH2:10][N:11]1[C:20]2[C:19](=[O:21])[N:17]([CH3:18])[C:16](=[O:22])[N:15]([CH3:23])[C:14]=2[N:13]=[CH:12]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: Cn1c(=O)c2c(ncn2CO)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCCCC(=O)OCn1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
To 0.71 g (0.0053 mole) of hexanoyl chloride in 10 ml of CH2Cl2 there was added 1.10 g (0.0052 mole) of 7-hydroxymethyl theophylline; no reaction occurred and the reaction mixture was a suspension. Then 0.58 g (0.0057 mole) of triethylamine was added and a clear, colorless solution was obtained. The solution was stirred at room temperature for 15 minutes then concentrated in vacuo. The residue was titrated with 200 ml ether and filtered. The filtrate was concentrated in vacuo to give an oil which was titrated with heptane CH2Cl2 (50:10). The resulting suspension was filtered while hot and concentrated to 20 ml, then cooled to room temperature. A gelatinous mass precipitated which was filtered and dried to give 0.70 g (mp 67°-72° C., 43% yield) of the desired product.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)[O:4]1.[CH2:10]([C:17](O)=O)[C:11](CC(O)=O)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O>[CH2:20]([N:27]1[CH:6]2[CH2:5][CH2:17][CH:10]1[CH2:11][C:3](=[O:4])[CH2:7]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CC(=O)CC(=O)O
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: O
Product: O=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This was prepared according to the reported method (Chem. Abs., 1958, 53, 432e). A mixture of 2,5-dimethoxytetrahydrofuran (13 ml, 0.1 mol), 2 drops of c-HCl and water (10 ml) was stirred at room temperature for 1 h, then treated with water(10 ml), acetone-1,3-dicarboxylic acid (14.6 g, 0.1 mol), and benzylamine (10.9 ml, 0.1 mol). After the initial foaming had subsided, the pH was adjusted to 5 with 1N HCl, and stirring was continued for 14 h. The reaction mixture was adjusted to pH 1, washed with ethyl acetate, filtered through celite, and then adjusted to pH 12 with NaOH, and extracted with ethyl acetate. The extract was dried over Na2SO4 and concentrated to afford 14.5 g (67% crude) of an oil, which was used for next reaction without further purification.
Reaction SMILES: O1CCCC1.[H-].[Na+].Cl.Cl[CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14].[CH2:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23](C#N)[CH2:22][C:21]2[CH:32]=[CH:33][CH:34]=[CH:35][C:20]1=2)[CH3:18].[CH3:36][N:37](C)C=O>>[CH2:13]([N:12]([CH2:15][CH3:16])[CH2:11][CH2:10][CH:22]1[C:21]2[CH:32]=[CH:33][CH:34]=[CH:35][C:20]=2[N:19]([CH2:17][CH3:18])[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([C:36]#[N:37])[C:24]=2[CH2:23]1)[CH3:14]
Reactant: CCN(CC)CCCl
Reactant: CCN1c2ccccc2CC(C#N)c2ccccc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCC1Cc2c(C#N)cccc2N(CC)c2ccccc21
Reaction time: 3 h

Procedure:
To a mixture of 3 parts of 5-ethyl-10,11-dihydro-5H-dibenz[b,f]azepine110-carbonitrile with approximately 30 parts of tetrahydrofuran and 5 parts of N,N-dimethylformamide is added 6 parts of sodium hydride, followed by 3 parts of 2-chloro-N,N-diethylethanamine hydrochloride. The resultant mixture is heated at the boiling point under reflux with stirring while thin layer chromatography is employed to monitor the reaction which ensues, additional sodium hydride being introduced as indicated thereby. After approximately 3 hours, when no 5-ethyl-10,11-dihydro-5H-dibenz[b,f]azepine-10-carbonitrile is detectable, excess sodium hydride is destroyed by adding water until evolution of hydrogen ceases, whereupon solvent is removed by vacuum distillation. The residue is partitioned between ether and water. The ethereal phase, dried over magnesium sulfate and stripped of solvent by vacuum distillation, affords 10-[2-(diethylamino)ethyl]-5-ethyl-10,11-dihydro-5H-dibenz[b,f]azepine-l-carbonitrile as a clear yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][O:4][CH2:3]1.CCN(C(C)C)C(C)C.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[S:23]([O:1][C:2]1[CH2:3][O:4][CH2:5][CH2:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:24])=[O:22]
Reactant: CCOC(=O)C1CCOCC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)COCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (1.0 g, 5.81 mmol) in DCM (30 mL) was added DIPEA (1.22 mL, 6.97 mmol) and Tf2O (1.08 mL, 6.39 mmol) at −78° C., then it was warmed up to room temperature and stirred at room temperature for 2 h, the solution was diluted with DCM, washed with Sat. NaHCO3, brine, dried and concentrated to give ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate as crude product (2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]([O:17][CH3:18])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[NH2:24][C:25]1[C:26]([F:33])=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])(O)=O.[Na+]>C1COCC1>[F:33][C:26]1[C:27]([OH:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:13](=[O:15])[C:12]1[CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[C:10]([CH3:19])[C:11]=1[O:17][CH3:18]
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)O
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Temperature: 70 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
To 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (1.09 g, 4.19 mmol, 1.1 eq) was added SOCl2 (10 mL, 12.6 mmol, 3.0 eq). The reaction was heated to 70° C. and stirred for 6 h, then the solvent was removed. The residue obtained was dissolved in THF (10 mL) and added to a mixture of 3-amino-2,4-difluorophenol (intermediate X(a)) (0.405 g, 2.8 mmol, 1.0 eq) and NaHCO3 (1.17 g, 13.9 mmol, 5 eq) in THF (8 mL) at 0° C. The reaction was warmed to room temperature, stirred for 2 h then quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine dried (Na2SO4) and evaporated in vacuo. The crude residue obtained was purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1) to give the title compound as a white solid (209 mg, 19%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:38])[C:34]([OH:37])([CH3:36])[CH3:35])[NH:28][C:27](=[O:39])[CH2:26]2>>[CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](/[CH:17]=[C:26]3\[C:27](=[O:39])[NH:28][C:29]4[C:25]\3=[CH:24][C:23]([F:22])=[C:31]([NH:32][C:33](=[O:38])[C:34]([OH:37])([CH3:35])[CH3:36])[CH:30]=4)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4cc(NC(=O)C(C)(C)O)c(F)cc43)c(C)c2C1=O
Yield: 62.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide 9b as starting materials to obtain (Z)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide 9 (39 mg, yield 62.4%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][CH2:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[C:5]=2[C:3]([OH:2])=[O:4])=[O:24])=[CH:22][CH:21]=1
Reactant: COC(=O)c1[nH]c2ccccc2c1CNC(=O)c1ccc(C)cc1
Reactant: BrCc1cccc2ccccc12
Product: Cc1ccc(C(=O)NCc2c(C(=O)O)n(Cc3cccc4ccccc34)c3ccccc23)cc1

Procedure:
Using general procedure B, 3-[(4-methyl-benzoylamino)-methyl]-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 447.3 ([M−H]−).
Reaction SMILES: C(O)(C)C.[NH2:5][C:6]1[S:7][C:8]([CH2:11][CH3:12])=[N:9][N:10]=1.[Br:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1>O>[BrH:13].[CH2:11]([C:8]1[S:7][C:6](=[NH:5])[N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:19][CH:20]=2)[N:9]=1)[CH3:12]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCc1nnc(N)s1
Solvent: O
Solvent: CC(C)O
Product: Br
Product: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Yield: 110.1 %

Procedure:
To a mixed solution of 7.5 ml of isopropyl alcohol and 2.5 ml of water, 2.7 g of 2-amino-5-ethyl-1,3,4-thiadiazole and 1.3 g of 4'-bromomethyl-2-cyanobiphenyl were added, followed by heating under reflux for 2 hours. After the reaction mixture was cooled, the crystals so precipitated were collected by filtration, washed successively with isopropyl alcohol and diethyl ether and then dried, whereby 2.11 g of the title compound was obtained.