Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
4-bromo triphenylamine 7.6 g(23.45 mmol), aniline 21.85 g(0.235 mol), sodium tert-butoxide 6.76 g(70 mmol), Pd2(dba)3[(tris(dibenzilidene acetone)dipalladium(0))] 0.86 g(0.938 mmol) and tri(tert-butyl)phosphine 0.23 g(1.173 mmol) in 500 ml round bottom flask were dissolved with toluene 200 ml, and refluxed for 12 hours. After the reaction was terminated, the reaction solution was cooled to room temperature, and 200 ml of distilled water was added thereto to extract an organic layer. The organic layer was dried over MgSO4, concentrated, and purified by silica gel column chromatography. The eluate was concentrated and dried to give N,N,N′-triphenyl-p-phenylenediamine (6.71 g, 85%).
Reaction SMILES: C(=O)(O[CH2:6][CH3:7])OCC.C[O-].[Na+].[CH:12]([O:14][CH:15]1[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1)=[O:13]>O>[CH:12]([O:14][C:15]1([CH:7]2[CH2:6][CH2:18][CH2:17][CH2:16][CH2:15][CH2:22][CH2:21]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: CCOC(=O)OCC
Reactant: O=COC1CCC=CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=COC1(C2CCCCCCC2)CCCCCCC1
Temperature: 85 °C

Procedure:
Into a 2 liter reaction flask equipped with heating mantle, stirrer, Bidwell water trap, reflux condenser, thermometer and nitrogen blanket apparatus is placed 1,000 ml (8.4 moles) of diethyl carbonate, and 25 grams (0.45 moles) of sodium methoxide. The resulting mixture is heated to 85° C. While maintaining the reaction mass at 85°-86° C. over a period of 1 hour, 695 grams (4.5 moles) of a composition containing a major proportion of 4-cyclooctenyl formate having the structure: ##STR77## and a minor proportion of bicyclooctanyl formate having the structure: ##STR78## produced according to Example I, is added while removing ethyl formate reaction product from the reaction mass using the Bidwell trap. At the end of the 1 hour period, the reaction mass is stirred at a temperature of 85°-86° C. for an additional 1 hour.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Br.[C:23]([NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][NH:32][CH2:31]2)(=[O:25])[CH3:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:23]([NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][N:32]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:31]2)(=[O:25])[CH3:24]
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2c(c1)CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 62.1 %

Procedure:
447 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 436 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.C=CC=CC.[Br:19]N1C(=O)CCC1=O>>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccccc2)n1
Solvent: C=CC=CC
Product: BrCc1cccc(-c2ccccc2)n1

Procedure:
2-Methyl-6-phenylpyridine, obtainable from 1,3-pentadiene and benzonitirle via the procedure of Janz and McColloch [J. Am. Chem. Soc., 77 (1955), 3413] is treated with N-bromosuccinimide to give 2-bromomethyl-6-phenylpyridine. The bromomethyl compound is treated with 1-methyl-2-cyanopyrrolidine, and the resulting salt is rearranged using sodium amide in liquid ammonia and decyanated with sodium borohydride in ethanol according to the procedures described in Example 1. The product can be purified by distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([O:15]C)=[O:14])=[CH:4][CH:3]=1.BrC1C=C(C(OC)=O)C=NC=1.FC1C=CC(B(O)O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cncc(-c2ccc(F)cc2)c1
Agent: COC(=O)c1cncc(Br)c1
Agent: OB(O)c1ccc(F)cc1
Product: O=C(O)c1cncc(-c2ccc(F)cc2)c1

Procedure:
15.3 g of methyl 5-(4-fluorophenyl)nicotinate (obtainable by Suzuki coupling of methyl 5-bromopyridine-3-carboxylate with 4-fluorobenzeneboronic acid analogously to Example 1 or 2) are saponified by conventional methods to give 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.O>[ClH:15].[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A slurry of 6-hydroxy-naphthalene-1-carboxylic acid (0.100 g, 0.531 mmol), 4-chloro-6,7-dimethoxy-quinoline (0.143 g, 0.638 mmol) and Cs2CO3 (0.519 g, 1.59 mmol) in 2.66 mL of DMSO under argon was stirred for 15 min at RT. The mixture was heated to 140° C. in a microwave. After 1 h, the reaction was diluted with ca. 2.7 mL of water. 6N HCl was added dropwise until the solution was at pH 3-4. The resulting precipitate was filtered and washed with acetone to afford the titled compound as a tan solid.
Reaction SMILES: [ClH:1].CCOC(C)=O.[Br:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[CH:17]=[CH:18][CH:19]=1)=[O:13]>CCOC(C)=O>[ClH:1].[Br:8][CH2:9][CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cccc(C(=O)NCCBr)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCCBr)c1cccc(CCC2CCNCC2)c1
Reaction time: 8 h

Procedure:
4 M hydrogen chloride/EtOAc solution (5 ml) was added to an EtOAc (15 ml) solution of the crude tert-butyl 4-[2-(3-{[(2-bromoethyl)amino]carbonyl}phenyl)ethyl]piperidine-1-carboxylate at room temperature, followed by stirring overnight. The solvent was evaporated under reduced pressure to obtain N-(2-bromoethyl)-3-(2-piperidin-4-ylethyl)benzamide hydrochloride (1.27 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26](O)=[O:27])=[CH:9]2.[CH2:29]([S:36][CH:37]([CH:40]([O:43][CH3:44])[O:41][CH3:42])[CH2:38][NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CCCCCC.C(OCC)(=O)C.CN(C)C=O>[CH2:29]([S:36][CH:37]([CH:40]([O:41][CH3:42])[O:43][CH3:44])[CH2:38][NH:39][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=1)(=[O:17])=[O:18])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.9 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxylic acid (2.3 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (1.7 g), 1H-1,2,3-benzotriazol-1-ol (1.2 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.6 g) and N,N-dimethylformamide (70 mL) was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80-80:20) to give the title compound (3.2 g, yield 89%) as a colorless oil.
Reaction SMILES: [C:1]([C:9]1[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[S:27]>>[C:2]1([C:1]([C:9]2[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:31]4[S:25][C:26](=[S:27])[NH:28][C:29]4=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccc(C(=O)c3ccccc3)cc2)cc1
Reactant: O=C1CSC(=S)N1
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccc(C(=O)c3ccccc3)cc2)cc1

Procedure:
The 4-(4-benzoylbenzyloxy)benzaldehyde was coupled with rhodanine to yield the title compound by admixing the 4-(4-benzoylbenzyloxy)benzaldehyde (2.09 g, 6.3 mmol) with rhodanine (1.0 g, 7.5 mmol), sodium acetate (1.8 g, 22 mmol) and acetic acid (75 ml) in a 250 ml flask. The reaction mixture was heated to reflux and refluxed overnight.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[N+]([O-])(O)=O.[N+:22]([O:25][CH2:26][CH2:27][NH2:28])([O-:24])=[O:23].[CH3:29][N:30]1[CH:34]([C:35](O)=[O:36])[CH2:33][S:32][C:31]1=[O:38]>O1CCCC1>[N+:22]([O:25][CH2:26][CH2:27][NH:28][C:35]([CH:34]1[CH2:33][S:32][C:31](=[O:38])[N:30]1[CH3:29])=[O:36])([O-:24])=[O:23]
Reactant: NCCO[N+](=O)[O-]
Reactant: CN1C(=O)SCC1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Product: CN1C(=O)SCC1C(=O)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
1.33 ml of triethylamine and 0.36 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 402 mg of N-(2-nitrooxyethyl)amine nitrate and 326 mg of 3-methyl-2-oxothiazolidine-4-carboxylic acid in 35 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 3.5 hours, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with ethyl acetate, and the resulting mixture was washed with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The crystalline residue was recrystallized from ethanol, to give 247 mg of the title compound as colorless crystals, melting at 105°-106° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([N:19](CC)[CH2:20][C:21]4C=CC(OC)=CC=4)[C:16]4=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:15]4[N:14]=3)[CH:10]=2)[N:5]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)[CH:4]=1)#[N:2].[C:49]1([O:55]C)[CH:54]=CC=C[CH:50]=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH2:20][CH3:21])[C:16]4=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:15]4[N:14]=3)[CH:10]=2)[N:5]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:50][C@@H:49]([OH:55])[CH3:54])[CH2:38][CH2:37]2)[CH:4]=1)#[N:2]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2ccc3c(c2)c(C#N)cn3C2CCN(C(=O)OC(C)(C)C)CC2)nn2c(C#N)cnc12
Reactant: COc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1nc(Nc2ccc3c(c2)c(C#N)cn3C2CCN(C[C@H](C)O)CC2)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 4-(3-cyano-5-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-1H-indol-1-yl)piperidine-1-carboxylate (500 mg, 0.503 mmol) was mixed with ANISOLE (0.5 mL, 4.58 mmol) and DCE (5 mL). TFA (1 mL, 12.98 mmol) was added. The mixture was stirred at 25° C. for 24 hrs. LC/MS showed product formation. The mixture was concentrated to dryness, diluted with MeOH and applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents left 2-((3-cyano-1-(piperidin-4-yl)-1H-indol-5-yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as solid.
Reaction SMILES: [NH:1]([C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:7]2[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26](O)=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26](=[O:27])[NH:2][NH:1][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:7]2[CH:6]=[CH:5][N:4]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: NNc1nccc2nc(C(F)(F)F)nn12
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2nc(C(F)(F)F)nn12)Cc1cc(F)c(F)cc1F

Procedure:
By the procedure of Example 9, Step A, 5-hydrazino-2-(trifluoromethyl)[1,2,4]triazolo[1,5-c]pyrimidine (Intermediate 42) was acylated with (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3). Purification by flash chromatography on silica gel (1-5% methanol in dichloromethane) afforded the title compound as a light tan solid, mp 159-161° C. LC-MS 534 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].BrC1C=C([F:25])C=CC=1O.BrCC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:25])=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Agent: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(F)cc1Br

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-bromo-4-fluorophenol and tert-butyl bromoacetate, the title compound was obtained as a white solid in quantitative yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: CC1CCCCN1CCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCCN1CCCOc1ccc(N2CCNCC2)cc1
Yield: 74.5 %

Procedure:
1,1-Dimethylethyl 4-(4-{[3-(2-methyl-1-piperidinyl) propyl]oxy}phenyl)-1-piperazinecarboxylate (E76a) (1.66 g) was dissolved in dry dichloromethane (25 ml) and stirred under nitrogen. 50% Trifluoroacetic acid in dichloromethane (5 ml) was added, and the mixture was stirred at room temperature for 4 h. Saturated sodium bicarbonate solution was then added and the mixture was extracted with dichloromethane. The organic phase was separated using a hydrophobic frit, and evaporated in vacuo, however, most of the product was in the aqueous phase. The product was removed from the aqueous phase using an OASIS cartridge, washing with water and eluting with methanol, and further purified using an aminopropyl bond elut cartridge, eluting with dichloromethane and then SCX cartridge, eluting with 50% [0.880 ammonia-methanol (1:9)]-dichloromethane to give the title compound (0.94 g). LCMS RT=1.01 min, ES+ve m/z=318 (M+H)+
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[H][H]>O1CCCC1.C(O)C.[Ni]>[C:1]([N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[NH2:20])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2N)CC1

Procedure:
A solution of 59 g of 1-carbethoxy-4-(2-nitro-4-chloroanilino)-piperidine in 270 ml of tetrahydrofuran and 96 ml of absolute ethanol was hydrogenated under normal pressure and at room temperature, using 15 g of Raney nickel as a catalyst. When the uptake of hydrogen had ended, the mixture was filtered and the filtrate was evaporated. Melting point: 150° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1C=O.FC1C=CC(CS(C2C=C3C(=CC=2)NC(=O)C3)(=O)=O)=CC=1.N1CCCCC1>C(O)C>[CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][CH:3]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Agent: O=C1Cc2cc(S(=O)(=O)Cc3ccc(F)cc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 166.4 %

Procedure:
3-Methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c (80 mg, 0.26 mmol) and 5-(4-fluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 65a (72 mg, 0.24 mmol) were dissolved in 2.5 ml of ethanol, and added with 42 μA of piperidine the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 3 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-(5-(4-fluorobenzylsulfonyl)-2-oxoindolin-3-ylidene)methyl)-3-methyl-5-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 69 (120 mg, yield 85.7%) as an orange solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].N[C@@H:16](C(C)C)CO>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH:13]([CH3:16])[CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CC(C)[C@H](N)CO
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: Cl
Product: CC(C)[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-2-amino-3-methylbutan-1-ol in the first step (A1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.[CH3:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1[NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1B1OC(C)(C)C(C)(C)O1.Br[C:37]1[N:42]=[C:41]([CH2:43][NH:44][C:45]2[C:50]([CH:51]([CH3:53])[CH3:52])=[CH:49][CH:48]=[CH:47][C:46]=2[CH:54]([CH3:56])[CH3:55])[CH:40]=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH:54]([C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([CH:51]([CH3:53])[CH3:52])[C:45]=1[NH:44][CH2:43][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[CH2:12][NH:11][C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[CH3:8])[N:42]=1)([CH3:56])[CH3:55]
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(CNc2c(C(C)C)cccc2C(C)C)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 27.2 g (95.0 mmol) of Na2CO3×10H2O, 410 ml of water and 120 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 14.2 g (38.0 mmol) of 2-methyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 13.3 g (38.0 mmol) of N-[(6-bromopyridin-2-yl)methyl]-2,6-diisopropylaniline, and 2.19 g (1.90 mmol) of Pd(PPh3)4 in 500 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate-triethylamine=100:20:1, vol.). Yield 10.1 g (52%) of a yellow powder. Anal. calc. for C36H39N3: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.28; H, 7.73; N, 8.09. 1H NMR (CDCl3): δ 7.91 (d, J=8.4 Hz, 1H, 4-H in naphthyl), 7.89 (m, 1H, 8-H in naphthyl), 7.79 (m, 1H, 4-H in Py), 7.66 (d, J=8.4 Hz, 1H, 3-H in naphthyl), 7.47 (m, 1H, 7-H in naphthyl), 7.36-7.42 (m, 4H, 3, 5-H in Py and 5, 6-H in naphthyl), 7.04-7.10 (m, 3H, 3, 5-H in ortho-tolyl and 4-H in 2,6-diisopropylphenyl), 7.01 (m, 2H, 3, 5-H in 2,6-diisopropylphenyl), 6.61 (m, 1H, 4-H in ortho-tolyl), 6.52 (m, 1H, 6-H in ortho-tolyl), 4.22-4.35 (m, 4H, CH2N), 4.02 (br.s, 1H, NH), 3.93 (br.s, 1H, NH), 3.28 (sept, J=6.8 Hz, 2H, CHMe2), 2.09 (s, 3H, Me in ortho-tolyl), 1.16 (d, J=6.8 Hz, 6H, CHMeMe′), 1.14 (d, J=6.8 Hz, 6H, CHMeMe′).
Reaction SMILES: [CH2:1]([N:5]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([OH:21])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:22]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)=[C:8]([O:21][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCC2CO2)c1
Temperature: 60 °C
Yield: 35.2 %

Procedure:
In 15 ml of 1-methyl-2-pyrrolidone were dissolved 0.76 g (2.13 mmol) of 5-[2-(4-dibutylamino-2-hydroxyphenyl)vinyl]thiophene-2-carboaldehyde and 0.8 g (5.84 mmol) of epibromohydrin. To this mixture was added 0.59 g (4.27 mmol) of anhydrous potassium carbonate and the mixture was stirred with heating at 60° C. for 4 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography. From the earlier fraction, 0.31 g of 5-[2-[4-dibutylamino-2-(oxiranylmethoxy)phenyl]vinyl]thiophene-2-carboaldehyde was obtained. From the later fraction, 0.45 g of 5-[2-[2-(3-bromo-2-hydroxypropoxy)-4-dibutylaminophenyl]vinyl]thiophene-2-carboaldehyde was obtained.