Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[CH2:11][CH2:10][N:9]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
A solution of 3-phenylpyrrolidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and butanoyl chloride (266 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(3-phenylpyrrolidin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 378 mg of colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.[Cl:12][C:13]1[CH:18]=[C:17](I)[CH:16]=[C:15]([Cl:20])[CH:14]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O1CCOCC1.C1COCC1.C(OCC)C.[Cu]I>[ClH:12].[Cl:12][C:13]1[CH:18]=[C:17]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:2]2)[CH:16]=[C:15]([Cl:20])[CH:14]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Agent: [Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1cc(Cl)cc(-n2ccc(-c3ccccn3)c2)c1
Temperature: 110 °C

Procedure:
A solution of 2-(1H-pyrrol-3-yl)pyridine (0.072 g, 0.5 mmol), 1,3-dichloro-5-iodobenzene (0.163 g, 0.6 mmol), 1,10-phenanthroline (0.360 g, 2 mmol) and potassium phosphate (0.223 g, 1.05 mmol) in dioxane were degassed for 10 min, then copper (I) iodide (0.038 g, 0.2 mmol) was added and the mixture degassed a further 10 min. The mixture was heated to 110° C. for 4 h. The reaction mixture was quenched with brine, extracted with EtOAc (3×25 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4, concentrated in vacuo and the residue was chromatographed on silica gel eluting with EtOAc:hexane (1:4) to afford a white solid. The crude material was dissolved in THF (5 mL), 1.2 eq. of 1M HCl in diethyl ether was added and the resulting precipitate was filtered to obtain 2-[1-(3,5-dichlorophenyl)-1H-pyrrol-3-yl]pyridine hydrochloride as a white solid. 1H-NMR (CD3OD, 300 MHz) δ 8.60 (d, 1H), 8.50 (dd, 1H), 8.41 (dd, 1H), 8.34 (d, 1H), 7.80-7.69 (m, 3H), 7.59 (dd, 1H), 7.50-7.49 (m, 1H), 7.11-7.09 (dd, 1H). MS (ESI) 289.0 (M++H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[CH:17][CH:16]=2)=O)[CH2:8][CH3:9].O>O1CCCC1>[CH:32]([C:29]1[CH:28]=[CH:27][C:26]([S:23]([NH:22][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH2:11][NH:10][CH2:7][CH2:8][CH3:9])=[CH:21]3)(=[O:24])=[O:25])=[CH:31][CH:30]=1)([CH3:34])[CH3:33]
Reactant: CCCNC(=O)c1cc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNCc1cc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a suspension of lithium aluminiumhydride (590 mg, 15.54 mmol) in tetrahydrofuran (THF) (40 ml, dried over Al2O3) at −5 to 0° C. a solution of 5-(4-isopropyl-benzenesulfonylamino)-1H-indole-2-carboxylic acid propylamide (1.03 g, 2.59 mmol) in THF (10 ml) was added. After complete addition the mixture was allowed to warm to room temperature and was heated to reflux for 3 h. At 0° C. THF and then water were added. The mixture was dried with Na2SO4. The filtered solution was evaporated and the residue was purified by column chromatography (toluene:THF:methanol, 4:1:1+2.5% triethylamine) to give the product as a yellow powder (240 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]\[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Solvent: CC#N
Product: CC(C)(C)O/N=C(/CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 91.8 %

Procedure:
207 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(tert-butoxyimino)ethyl]-2-(trifluoromethyl)benzamide in 4 ml of acetonitrile was irradiated with light for 8 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 5:5) to obtain 190 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:3]=1
Reactant: Cc1ccccc1-c1coc2cc(O)cc(Cl)c2c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccccc3C)coc2c1
Yield: 89.1 %

Procedure:
In 1 l of acetone was suspended 114 g of 5-chloro-7-hydroxy-3-(2-methylphenyl)-4-oxo-4H-1-benzopyran, and 60.4 g of anhydrous potassium carbonate and 73.0 g of ethyl bromoacetate were added thereto, followed by refluxing for 1.5 hours. After cooling, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Recrystallization of the residue from ethanol gave 132 g of the entitled compound having a melting point of 122° to 123° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])=[CH:20][CH:19]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:27]([CH2:26][CH2:25][CH2:24][C:21]3[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=3)[C:28]2=[O:29])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(Nc2ncccc2C=O)c1
Reactant: CCOC(=O)CCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2c(=O)c(CCCc3ccncc3)cc3cccnc32)c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-cyanophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(4-pyridyl)pentanoate (1.2 eq., prepared in Synthetic Example 10) and LDA (1.2 eq.) to obtain 1-(3-cyanophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 202 to 203.5° C./DMF.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(C)cc(C=Nc2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3,5-dimethylbenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 59%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](NC2C=CC=C(F)C=2)(C(N)=O)[CH2:13][CH2:12]1.[BH4-].[Na+].C(N)=[O:32]>>[CH3:1][C:2]1([CH3:28])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[O:32])[CH2:13][CH2:12]1
Reactant: NC=O
Reactant: CC1(C)C2CCC(CCN3CCC(Nc4cccc(F)c4)(C(N)=O)CC3)C1C2
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)C2CCC(CCN3CCC(=O)CC3)C1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 29.3 g (76 mmol) of (29a) in 400 ml formamide was heated for 2 h at 200° C. The solution turned from yellow to black. The reaction was monitored by 1H-NMR. After completed reaction the mixture was cooled to room temperature and poured into ice-water (800 g). The mixture was extracted with DCM (6×1 l). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in 1.2 l of methanol and 4.3 g (114 mmol) of sodiumborohydride were added portion wise. The mixture was stirred for 1 h at room temperature and another hour at 60° C. The reaction mixture was cooled to room temperature and quenched with 25 ml of water. The solvent was evaporated in vacuo. The residue was dissolved in 750 ml of ammonia and extracted with DCM (7×1.5 l). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 24.8 g of crude product, which was purified by column chromatography (SiO2, heptane:EtOAc, 1:1→1:3). Trituration with Et2O of the eluated product yielded 3.44 g (8.6 mmol, 11.3% from compound (26)) of compound (30a) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:31])[N:14]([C:15]4[C:16]([CH3:30])=[N:17][N:18]([CH2:20][C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:32]([O:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[CH3:33]>>[CH2:32]([O:34][C:35]1[N:40]=[CH:39][C:38]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[NH:12][C:13](=[O:31])[N:14]([C:15]5[C:16]([CH3:30])=[N:17][N:18]([CH2:20][C:21]([N:23]6[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]6)=[O:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:37][CH:36]=1)[CH3:33]
Reactant: CCOc1ccc(B(O)O)cn1
Reactant: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Product: CCOc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(CC(=O)N6CCN(C)CC6)nc5C)c4c3c2)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 133.1.1) and 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany) to give the title compound as a white solid. (HPLC: tR 2.27 min (Method A); M+H=527 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.69 (s, br, 1H), 8.71 (s, 1H), 8.45-8.42 (m, 1H), 8.08-8.03 (m, 2H), 7.96-7.88 (m, 2H), 7.74-7.71 (m, 1H), 6.81-6.67 (m, 1H), 5.27-5.11 (m, 2H), 4.32 (q, 2H), 3.58-3.38 (m, 4H), 2.38-2.26 (m, 4H), 2.19 (s, 3H), 1.92 (s, 3H), 1.31 (t, 2H))
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1.[CH2:28]([NH2:30])[CH3:29]>CN(C)C(=O)C>[CH2:28]([NH:30][CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1)[CH3:29]
Reactant: CCN
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CCNC/C=C/[C@H]1CC[C@H](CCN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with ethylamine in N,N-dimethylacetamide at room temperature to yield trans-N-{2-[4-(3-ethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 433 (MH+).
Reaction SMILES: C([O:8][C:9](=[O:50])[CH2:10][C@H:11]([NH:29][C:30](=[O:49])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:48])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C1C=CC=CC=1>CO>[CH3:47][S:44]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([NH:29][C@H:11]([C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:10][C:9]([OH:50])=[O:8])=[O:49])=[O:48])(=[O:46])=[O:45]
Reactant: CCCCCCCCCCCCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCNC(=O)CCCCCNS(C)(=O)=O
Solvent: CO
Product: CCCCCCCCCCCCCCNC(=O)[C@H](CC(=O)O)NC(=O)CCCCCNC(=O)CCCCCNS(C)(=O)=O
Yield: 359 %

Procedure:
35 mg of the ester compound thus obtained was dissolved in 10 ml of methanol and after treating the mixture in the same manner as in Example 26, 110 mg of (S)-3-[6-(6-methanesulfonamidohexanamido)hexanamido]-3-tetradecylcarbamoylpropionic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10]C(=O)C.O.C(O)CC.[Cl-]>Cl.CC(O)=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10]
Reactant: CC(=O)Nc1c(Cl)ccc(C)c1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(N)c1Cl
Yield: 90.1 %

Procedure:
N-(2,6-Dichloro-3-methylphenyl)acetamide (22 g) was suspended in HCl (5.0 N, 100 mL), H2O (300 mL) and propanol (or AcOH, 20-50 mL). The mixture was refluxed for several hr after which the solution was cooled, chloride (3×200 mL). The organic extractions were combined, washed with water, dried over MgSP4, and concentrated to give 16 g of product as a low melting solid (m.p. 36°-38° C.). 1H NMR (CCl4) δ6.97 (d, 9.0), 6.46 (d, 9.0 Hz, 1H), 2.28 (s, 3H, CH3)
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH:19]([NH:21][N:22]1[C:26]([SH:27])=[N:25][N:24]=[N:23]1)=[O:20].CS(O)(=O)=O.N>C(#N)C.O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:26]3[N:22]([NH:21][CH:19]=[O:20])[N:23]=[N:24][N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: O=CNn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)O
Agent: N
Solvent: CC#N
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
2.45 g of 7β-aminocephalosporanic acid and 1.31 g of 1-formamido-5-mercapto-1H-tetrazole were dissolved in 13 ml of acetonitrile, and 4.32 g of methanesulfonic acid were added dropwise thereto at room temperature under stirring. The mixture was stirred at room temperature for 30 minutes and then at 50° C. for 4 hours. 15 ml of water were added to the reaction mixture, and said mixture was adjusted to pH 5 with 28% ammonia. The resultant precipitates were collected by filtration, washed with water and acetone, and then dried. 2.43 g of 7β-amino-3-[(1-formamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid were obtained as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([C:6]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:7]=23)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:8]3[C:9]=2[C:5]([CH:6]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:7]23)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c3c(n4c2c1CCNCC4)CCCCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc2c3c1CCNCCN3C1CCCCCC21
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.4 %

Procedure:
To a solution of 6-chloro-2,3,4,5,10,11,12,13-octahydro-1H,9H-cyclohepta[b][1,4]diazocino[7,8,1-hi]indole (0.20 g, 0.69 mmole) in acetic acid (50 mL) was added excess sodium cyanoborohydride (0.21 g, 3.45 mmole) and the reaction mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 5% methanol in methylene chloride) provided 67 mg of the title compound. This compound was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 168-170° C. MS (ESI) m/z 291 ([M+H]+).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, light yellow solid (73 mg, 63%), MS (ISP) m/z=467.3 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-chloro-benzoic acid.
Reaction SMILES: COC1C=C2C(=C(N3CCNCC3)C=1)N=C(C)C=C2.C([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([O:44][CH3:45])[CH:36]=[C:37]3[C:42]=2[N:41]=[CH:40][C:39]([CH3:43])=[CH:38]3)[CH2:29][CH2:28]1)C1C=CC=CC=1.C(N1CCN(C2C=C(OC)C=C3C=2N=C(C)C=C3)CC1)C1C=CC=CC=1>>[CH3:45][O:44][C:35]1[CH:36]=[C:37]2[C:42](=[C:33]([N:30]3[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]3)[CH:34]=1)[N:41]=[CH:40][C:39]([CH3:43])=[CH:38]2
Reactant: COc1cc(N2CCN(Cc3ccccc3)CC2)c2ncc(C)cc2c1
Agent: COc1cc(N2CCN(Cc3ccccc3)CC2)c2nc(C)ccc2c1
Agent: COc1cc(N2CCNCC2)c2nc(C)ccc2c1
Product: COc1cc(N2CCNCC2)c2ncc(C)cc2c1

Procedure:
The title compound was prepared by the same method used for the preparation of 4-(6-methoxy-2-methylquinolin-8-yl)piperazine, except 1-benzyl-4-(6-methoxy-3-methylquinolin-8-yl)piperazine (0.32 g, 0.92 mmol) was substituted for the 1-benzyl-4-(6-methoxy-2-methylquinolin-8-yl)piperazine. The title compound was isolated in nearly quantitative yield and used with purification in the subsequent reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][S:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][S:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cscc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cscc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.6 %

Procedure:
A solution of 4-(4-methoxycarbonylthiophen-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (200 mg, 620 μmol, 1.0 eq.) in EtOAc (25 mL) was combined with Pd(OH)2/C (70 mg) under hydrogen (1 atm). MeOH (10 mL) was added and the resulting solution was stirred for 20 hours at room temperature. The solution was then stirred for an additional 16 hours while the temperature was maintained at 40° C. in an oil bath. The solids were filtered and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield 4-(4-methoxycarbonylthiophen-3-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[CH2:10][CH2:11][NH:12][C:13]([CH:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][O:18][C:17]([CH3:24])([CH3:23])[O:16]1)=[O:14].[C:26](O)(=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[C:26]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[CH2:10][CH2:11][NH:12][C:13]([CH:15]1[C:20]([CH3:21])([CH3:22])[CH2:19][O:18][C:17]([CH3:24])([CH3:23])[O:16]1)=[O:14])(=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)Nc2ccccc2O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Oc1ccccc1NC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 67 %

Procedure:
N-(2-Hydroxyphenyl)-3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propanamide (350 mg) and 282 mg of oleic acid were reacted in the same manner as in Example 15 to obtain 411 mg of the title compound (yield: 67%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:22])=[O:21]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cn(S(=O)(=O)c2c(Cl)cccc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 2,6-dichlorophenylsulfonyl chloride (0.589 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(2,6-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.658 g, 93%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:28])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH:23]=[CH:24][CH:25]=1)([F:18])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNC(=O)Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 59 (5.09 g, 10 mmol) in ethanol (30 mL) was added 2N NaOH (18 mL, 35 mmol). The mixture was stirred at room temperature for 3 hours. The crude reaction was concentrated and the residue was diluted with ethyl acetate (50 mL) and washed with water (2×25mL). The aqueous layer was acidified to pH 2 with HCl and then extracted with ethyl acetate (2×50 mL). The organic layers were dried (Na2SO4) and the solvent removed under reduced pressure. The titled compound was obteined (4.23 g, 88%).