Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:10]2O)([CH3:6])([CH3:5])[CH3:4].[C:22]([C:26]1[CH:34]=[C:33]2[C:29]([CH:30](O)[N:31]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:32]2=[O:35])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].O.C[O:43][CH2:44][CH2:45]OC>C(OCC)(=O)C>[C:3]([C:7]1[CH:8]=[C:9]2[C:13]([C:12](=[O:16])[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:10]2[CH2:45][C:44]([O:35][CH2:32][CH3:33])=[O:43])=[CH:14][CH:15]=1)([CH3:6])([CH3:5])[CH3:4].[C:22]([C:26]1[CH:34]=[C:33]2[C:29](=[CH:28][CH:27]=1)[CH:30]([CH2:45][C:44]([O:16][CH2:12][CH3:13])=[O:43])[N:31]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:32]2=[O:35])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)CN1C(=O)c2cc(C(C)(C)C)ccc2C1O
Reactant: COCCOC
Reactant: CC(C)CN1C(=O)c2ccc(C(C)(C)C)cc2C1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC1c2cc(C(C)(C)C)ccc2C(=O)N1CC(C)C
Product: CCOC(=O)CC1c2ccc(C(C)(C)C)cc2C(=O)N1CC(C)C
Temperature: 20 °C

Procedure:
Ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are prepared as described in Example 2, starting with 2.9 g of 60% sodium hydride in 200 cm3 of 1,2-dimethoxyethane, 15.2 cm3 of triethyl phosphonoacetate and 9.6 g of a mixture of 5-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydoxy-2-isobutyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 110 cm3 of water and then 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 100 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is separated out by HPLC chromatography on a 10 μm WHELK-01SS chiral column, eluting successively with heptane/isopropanol mixtures (90/10 and then 50/50 by volume). The fractions comprising the first regioisomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40° C. 1.81 g of ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous gray oil (Rf=0.43, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)). The fractions comprising the second regioisomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40° C. 3.53 g of ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous gray oil. (Rf=0.38, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH:12](O)[CH2:13][O:14][C:8]3=[CH:7][C:6]=2[CH2:5][C:4]1=[O:16])[CH3:2].FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]3[CH:12]=[CH:13][O:14][C:8]3=[CH:7][C:6]=2[CH2:5][C:4]1=[O:16])[CH3:2]
Reactant: CCN1C(=O)Cc2cc3c(cc21)C(O)CO3
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)Cc2cc3occc3cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of 30.3 g. (0.138 mole) of 5-ethyl-3-hydroxy-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole in 950 ml. of acetonitrile at 25° C. was added 7 ml. of a 10% solution of trifluoroacetic acid in acetonitrile, and the reaction was allowed to stir at room temperature for 12 hours. The clear solution was evaporated to give a quantitative yield of the product. A small sample was recrystallized from hexane, m.p. 112°-113° C.
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].[OH-].[Na+].[C:9]([C:14]1[C:15](=[O:30])[CH2:16][CH:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[CH2:18][C:19]=1[OH:20])(=O)[CH2:10][CH2:11][CH3:12].C(O)C>O>[CH2:2]([O:5][N:6]=[C:9]([C:14]1[C:19](=[O:20])[CH2:18][CH:17]([C:21]2[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])[CH2:16][C:15]=1[OH:30])[CH2:10][CH2:11][CH3:12])[CH:3]=[CH2:4]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCON=C(CCC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Yield: 76.3 %

Procedure:
Allyloxyamine hydrochloride (0.72 g) and then a solution of sodium hydroxide (0.25 g) in water (3 ml) were added to a stirred mixture of 2-butyryl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.78 g; 5.9 mmole) and 95% ethanol. The progress of the reaction was monitored using thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the ethanol was removed by evaporation using a rotary evaporator and the residue was extracted with dichloromethane. The organic extract was washed with aqueous 5% hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure using a rotary evaporator to give the product, 2-[1-(allyloxyimino)butyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.6 g) as an oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[C:15](Cl)=[N:14][C:13]2[C:8](=[CH:9][C:10]([N+:18]([O-:20])=[O:19])=[C:11]([F:17])[CH:12]=2)[N:7]=1.[CH3:21][OH:22]>>[CH3:1][O:2][C:6]1[C:15]([O:22][CH3:21])=[N:14][C:13]2[C:8](=[CH:9][C:10]([N+:18]([O-:20])=[O:19])=[C:11]([F:17])[CH:12]=2)[N:7]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc2nc(Cl)c(Cl)nc2cc1F
Reactant: CO
Agent: [Na+]
Agent: [Na]
Product: COc1nc2cc(F)c([N+](=O)[O-])cc2nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium methoxide which was prepared from dried methanol 75 mL and metallic sodium 1.332 g, was added 2,3-dichloro-6-fluoro-7-nitroquinoxaline 4.778 g under ice-cooling and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water, then the resulting precipitation was collected and washed with water. The aqueous layer was extracted with chloroform, then the combined product was purified with alumina column chromatography and crystallized from acetone/hexane, to give the title compound (white crystal) 3.342 g.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[OH-:14].[Na+].[NH2:16]O.Cl>>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[N:16][OH:14]
Reactant: NO
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: ON=Cc1cccc(OC(F)(F)F)c1
Yield: 96.5 %

Procedure:
In a similar manner as described in Preparation Example 1, by using 3-(trifluoromethoxy)benzaldehyde (38.03 g, 200.0 mmol), sodium hydroxide (12.00 g, 300.0 mmol) and hydrochloric acid hydroxylamine (16.6 g, 240 mmol), a white solid required compound (39.74 g, 193 mmol, 97%) was obtained.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1([CH3:24])[C:18]2[C:11]([CH:12]=[C:13]3[C:17]=2[CH:16]=[N:15][N:14]3[CH2:19][CH:20](O)[CH3:21])=[C:10]([CH3:23])[CH:9]=[CH:8]1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:20]([CH3:21])[CH2:19][N:14]1[C:13]2=[CH:12][C:11]3[C:18]([C:7]([CH3:24])([CH3:6])[CH:8]=[CH:9][C:10]=3[CH3:23])=[C:17]2[CH:16]=[N:15]1)=[N+:33]=[N-:34]
Reactant: CC1=C2C=c3c(cnn3CC(C)O)=C2C(C)(C)C=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2C(C)(C)C=C1
Yield: 63.1 %

Procedure:
1 ml (12.5 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.6 g (6.2 mmol) of (RS)-1-(4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol and 3.5 ml (25 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 60 ml of anhydrous dimethylformamide, treated with 0.81 g (12.5 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The yellow oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.1 g (63%) of (RS)-1-(2-azido-propyl)-4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: [CH2:1]([C@@:4]1(CC)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:33]2[CH2:35][CH2:34]2)[CH2:25][NH:26][S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=C.C[N+]1([O-])CC[O:43]CC1.[C:47]([OH:51])(C)([CH3:49])[CH3:48]>C1COCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C@@H:24]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][NH:26][S:27]([CH:30]3[CH2:32][CH2:31]3)(=[O:29])=[O:28])[C:5](=[O:36])[C@:4]([CH2:48][CH:47]([OH:51])[CH2:49][OH:43])([CH2:1][CH3:2])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC[C@]1(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide (Example 254, Step A, 80 mg, 0.139 mmol) in THF (375 μL), water (250 μL) and t-butanol (208 μL) was treated with 4-methylmorpholine N-oxide (57.0 mg, 0.486 mmol) followed by 2.5% osmium tetroxide in t-butanol (45.6 μL, 3.47 μmol). After stirring at ambient temperature for 16 h, the mixture was diluted with ethyl acetate and washed with water and sat. aq. NaCl solution. The organic layer was dried over sodium sulfate and concentrated to provide the title compound as a mixture of diastereomers (85 mg) which was used directly in the next step. Mass Spectrum (ESI) m/z=609.1 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-:20])[C:10]=2[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc2cccnc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.2 %

Procedure:
To 50 mL of chloroform, 5.00 g of 3-bromo-1,5-naphthyridin was dissolved, 6.40 g of m-chloroperbenzoic acid was added thereto, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, a 5% aqueous sodium thiosulfate solution and chloroform were added, and the organic layer was separated, washed sequentially with a 5% aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of ethyl acetate:hexane=1:1 to obtain 1.95 g of 3-bromo-1,5-naphthyridin-5-oxide as a light yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.N[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.C([N:27](CC)CC)C>C(Cl)(Cl)Cl>[CH2:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:9]2[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=2[C:6]([NH2:27])=[O:7])[CH2:13][CH2:14]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(I)cc1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 4-iodobenzoyl chloride was dissolved in chloroform (40 mL) and added to a flask containing 4-amino-1-benzyl-piperidine (2.29 g, 12.1 mmol) in chloroform (75 mL) and triethylamine (20 mL). The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The resulting slurry was washed with water (100 mL). The organics were dissolved in CHCl3 (100 mL), separated from the aqueous layer and dried over anhydrous Na2SO4. The solvent was removed to give a solid (yield, 86%), m.p. 206° C. m/e=420 (M+). 1H R (δ ppm): 1.47-1.60 (m, 2H, CH2); 1.97-2.11 (m, 2H, CH2); 2.15-2.19 (m, 2H, CH2); 2.81-2.85 (m, 2H, CH2); 3.49 (s, 2H, benzyl CH2); 3.91-3.97 (m, 1H, CH); 5.98-6.00 (d, 1H, NH); 7.22-7.30 (m, 5H arom); 7.43-7.45 (d, 2H, J=8 Hz, para substituted arom); 7.73-7.76 (d, 2 H, J=8 Hz, para substituted arom). 13C NMR (δ ppm): 32.23, 47.19, 52.25, 63.01, 127.14, 128.27, 128.49, 129.14, 134.18, 137.75, 138.14, 166.02)
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([N+:36]([O-:38])=[O:37])[CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[C:28]([N+:36]([O-:38])=[O:37])[CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 4-bromo-1-isopropoxy-2-nitrobenzene (see step (a) above), followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=[C:10]([O:23][CH3:24])[CH:9]=1)[CH3:3].[CH2:26]([O:28][C:29]1[CH:34]=[C:33]([CH:35]=O)[CH:32]=[C:31]([O:37][CH2:38][CH3:39])[C:30]=1[C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[CH3:27].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([O:23][CH3:24])[CH:11]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:35][C:33]3[CH:32]=[C:31]([O:37][CH2:38][CH3:39])[C:30]([C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)=[C:29]([O:28][CH2:26][CH3:27])[CH:34]=3)[CH2:20][CH2:21]2)[CH:13]=1)[CH3:3]
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reactant: CCOC(=O)COc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)COc1cc(OC)cc(C(=O)NC2CCN(Cc3cc(OCC)c(-c4ccc(F)cc4)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), [3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-acetic acid ethyl ester hydrochloride (example 250b) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 609.3 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:5]1([N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][N:13]([C:1](=[O:3])[CH3:2])[CH2:12][C:11]=3[CH:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:7]1
Reactant: c1ccc(-c2cc3c(n2C2CC2)CCCNC3)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCc2c(cc(-c3ccccc3)n2C2CC2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.9 g. of acetyl chloride in 25 ml. of chloroform is added to a cooled solution of 11.0 g. of 1-cyclopropyl-2-phenyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine and 5.0 g. of triethylamine in 50 ml. of dry chloroform. The mixture is stirred at ambient temperature for 20 hours, washed with water, dried, and concentrated to provide 1-cyclopropyl-2-phenyl-5-acetyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine as an oil. The oil is treated according to the manipulative procedure described above in Example 2, to give crystals, m.p. 85°C. dec., of 1-cyclopropyl-2-phenyl-5-ethyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine oxalate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][S:36][C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[NH2:39].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:35][S:36][C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[NH:39][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CSc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4SC)cc3)c2cc1OC
Yield: 14 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (131 mg) was dissolved in toluene (13 ml) with heat, after the addition of triethylamine (2.6 ml), triphosgene (152 mg) was added, and the admixture was refluxed with heat for 2 minutes. 2-Methylthioaniline (0.11 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 10 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with chloroform, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (4/1) to obtain 29 mg of the title compound (yield: 14%).
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26](F)[C:27](F)=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=CC=CC=3N=2)=CC=1.[CH3:66][O:67][C:68](=[O:80])[C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[C:71]([C:76]([F:79])([F:78])[F:77])[CH:70]=1>>[CH3:66][O:67][C:68](=[O:80])[C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:71]([C:76]([F:78])([F:77])[F:79])[CH:70]=1
Reactant: COC(=O)c1ccc(N)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 22, intermediate d), from [2-(4-chloro-phenyl)-benzoimidazol-1-yl]-cyclohexyl-acetic acid (Ex. 39/40, int. b) and 4-amino-3-trifluoromethyl-benzoic acid methyl ester to give the product as a light yellow solid (57%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH2+:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[Cl-:2].[C:6]1([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH2+:14]3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)[NH2+]CC2
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccccc3)CCC1)[NH2+]CC2

Procedure:
1-(1-(4-Chlorophenyl)cyclobutyl)-7-(2-(propylsulfonamido)ethoxy)-1,2,3,4-tetrahydroisoquinolinium chloride (187 mg, 0.374 mmol, example 4), triethylamine (91 mg, 0.897 mmol), Pd/C (11.95 mg, 0.011 mmol) were suspended in dry MeOH (5 ml) and treated with hydrogen gas at ambient pressure for 14 h. The solvent was removed and the residue was purified by column chromatography using silica gel dichloromethane/methanol (97:3→95:5) as the eluent. The product was transferred into the hydrochloride with isopropylether and HCl dissolved in isopropanol (6%). The product was obtained as a white powder (68.0 mg, 0.146 mmol, 39%.)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:13]([CH3:15])[CH3:12])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.2 %

Procedure:
To a stirring solution of 8.0 g (49.6 mmol) of 4-trifluoromethylaniline in 80 mL of 1,2-dichloroethane at RT is added 4.0 mL (54.6 mmol, 1.1 equiv) of acetone, 5 drops of glacial acetic acid, and 13.7 g (64.5 mmol, 1.3 equiv) of sodium triacetoxyborohydride. The solution is stirred at RT for 72 h, cooled to 0° C., and then quenched by addition of H2O (200 mL). The organic layer is separated, washed with brine (1×200 mL), dried (MgSO4) and the solvents removed in vacuo to afford 10.1 g of crude (4-trifluoromethyl-phenyl)-isopropyl amine. A solution of 2.0 g (9.5 mmol) of this material in 50 mL of DCM is cooled to 0° C. and 1.5 mL (10.8 mmol, 1.5 equiv) of triethylamine is added, followed by dropwise addition of 0.90 mL (10.3 mmol, 1.05 equiv) of bromoacetyl bromide. The solution is stirred at RT for 4 h and then poured into Et2O (200 mL). The organics were washed with 1N HCl (2×50 mL), brine (1×50 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane 1/10 as eluent afforded 2.09 g of the title compound: 1HNMR (CDCl3, 300 MHz) δ7.78 (d, 2H, J=8.5), 7.40 (d, 2H, J=8.5), 5.01 (m, 1H), 3.51 (s, 2H), 1.08 (d, 6H, J=6.9).