Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH:10]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:9])=[CH2:8]>O1CCCC1>[C:7](=[C:10]([CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:9])[CH3:8]
Reactant: C=C(C)C(CC=C(C)C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC=C(C)C)=C(C)C

Procedure:
In a nitrogen atmosphere, 3.5 g of potassium t-butoxide was added to a mixture of 38.3 g of al 8.2:81.8 mixture of ethyl 2-isopropenyl-5-methyl-4-hexenoate obtained in Synthesis Example 3 and ethyl 2-isopropylidene-5-methyl-4-hexenoate and 150 ml of tetrahydrofuran at room temperature, and stirred at room temperature overnight. After 60 g of a 25% aqueous solution of sodium hydroxide and 38 g of 99.5% ethanol were added thereto, the resulting mixture was heated to reflux for 7.5 hours with stirring, then subjected to addition of 100 g of a 25% aqueous solution of sodium hydroxide, and refluxed with stirring for further 15 hours. The reaction mixture was poured into ice water, followed by extraction with n-hexane. The extract was discarded. The aqueous phase was neutralized with 10% hydrochloric acid, followed by extraction with diethyl ether. The diethyl ether solution was subjected to typical work-up including washing, drying and concentration to obtain 31.47 g of crude product. The yield was 95.9%.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][CH2:28][C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (13.9 mg, 43.2%), MS (ISP) m/z=403.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 2-methoxyacetic acid
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:18]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:18]3[CH2:19][CH2:20][C:21](=[O:24])[CH2:22][CH2:23]3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1
Reactant: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCC(O)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-1-(4-hydroxycyclohexyl)-2-methylbenzimidazole (see Working Example 49-2) (50 mg, 0.14 mmol) in chloroform (3 mL) was added DDQ (35 mg, 0.16 mmol), and this was stirred overnight at room temperature. After the reaction was complete, this was concentrated, and the residue obtained was purified by silica gel column chromatography to yield the title compound (20 mg, 40% yield) as reddish-brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=1.[NH4+].[Cl-]>C1COCC1>[C:2]1([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:10][CH:11]=2)[OH:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of bromobenzene (0.3 mol) in THF (300 ml) was added dropwise to a mixture of magnesium (0.32 mol) in THF (20 ml). The mixture was stirred and refluxed for 1 hour. A mixture of 4-biphenylcarboxaldehyde (0.3 mol) in THF (500 ml) was added dropwise. The mixture was stirred and refluxed for 2 hours, at room temperature overnight, poured out into a saturated NH4Cl solution and extracted with DCM. The organic layer was separated, washed three times, dried, filtered and the solvent was evaporated. The residue was triturated in hexane, filtered off and purified over silica gel on a glass filter (eluent: CH2Cl2 100%). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 31 g of (±)-α-phenyl(1,1′-biphenyl)-4-methanol (interm. 23).
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[CH3:7][CH:8]([CH:11]=[CH:12][CH:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH:15]=[C:14]1[CH3:21])[CH:9]=[O:10]>CCOCC>[CH3:7][CH:8]([CH:11]=[CH:12][CH:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH:15]=[C:14]1[CH3:21])[CH:9]([OH:10])[CH3:5]
Reactant: CC1=CCCC(C)(C)C1C=CC(C)C=O
Reactant: CI
Agent: C[Mg]I
Agent: [Mg]
Solvent: CCOCC
Product: CC1=CCCC(C)(C)C1C=CC(C)C(C)O
Temperature: 30 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
A solution of methylmagnesium iodide, prepared from 11 g of magnesium shavings and 76 g of methyl iodide, in 700 ml of absolute ether is added dropwise at -10° C. under nitrogen to a solution of 62 g of 2-methyl-4-(2,6,6-trimethyl-2-cyclohexenyl)-3-butenal in 700 ml of ether. The mixture is stirred for 4 hours at 30° C. and then poured on to an excess of ice-cold ammonium chloride solution. The mixture is extracted with ether in the usual manner, the extract is washed neutral with water and dried over anhydrous sodium sulphate to give, after removal of the solvent, 66 g of a yellow, slightly viscous oil which, after distillation in vacuo, yields 52 g of 3-methyl-5-(2,6,6-trimethyl-2-cyclohexenyl)-4-penten-2-ol; b.p.0.008 = 90°; nD20 = 1.4890. This alcohol has a very fine, tenacious sandalwood odour.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][C:24]([OH:26])=O)[CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCN(CC)CC.C(Cl)Cl>[CH2:16]([O:15][C:12]1[CH:11]=[C:10]([CH:22]=[CH:23][C:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])=[O:26])[CH:9]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:13]=1[OH:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOc1cc(C=CC(=O)O)cc(OCCCCCC)c1O
Reactant: Nc1ccccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCOc1cc(C=CC(=O)Nc2ccccc2O)cc(OCCCCCC)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To the solution of 3-(3,5-bishexyloxy-4-hydroxyphenyl) acrylic acid (40 mg, 0.11 mmol) in DMF (1 ml) and Et3N (17 μl), was added 2-aminophenol (13 mg, 0.12 mmol) at 0° C. and was added the solution of BOP (53 mg, 0.12 mmol) in CH2Cl2 (0.6 ml). The solution was stirred for 30 minutes at 0° C. and then was stirred for 1.5 hours at room temperature. And then CH2Cl2 was evaporated in vacuo and the obtained residue was poured into ice water. The residue was extracted with EtOAc and washed with HCl (aq) and NaHCO3 (aq). And then the water was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by column chromatography (EtOAc:Hexane=1:5), yielding 17 mg (34%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:7]([C:20]([F:23])([F:22])[F:21])([OH:19])[CH2:6][C:5]([CH3:25])([CH3:24])[C:4]=2[C:3]=1[OH:26].[C-:27]#[N:28].[Na+].O>CN1CCCC1=O.C(OCC)(=O)C.[Ni](Br)Br>[OH:26][C:3]1[C:4]2[C:5]([CH3:25])([CH3:24])[CH2:6][C:7]([OH:19])([C:20]([F:23])([F:22])[F:21])[CH:8]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:9]=2[CH:10]=[CH:11][C:2]=1[C:27]#[N:28]
Reactant: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccnc2)c2ccc(Cl)c(O)c21
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccnc2)c2ccc(C#N)c(O)c21
Yield: 19.3 %

Procedure:
50 mg of the 2-chloro-8,8-dimethyl-5-(pyridin-3-ylamino)-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol that is described in Example 159 is dissolved in 0.12 ml of 1-methyl-2-pyrrolidinone and mixed with 12.6 mg (0.258 mmol) of sodium cyanide and 28.2 mg (0.129 mmol) of nickel(II) bromide. The reaction mixture is brought to reaction in the microwave as described in the literature (J. Org. Chem. 68, 9122 (2003) (200° C., 20 bar). After cooling, the reaction mixture is diluted with ethyl acetate and then a small amount of water is added. The mixture is filtered over Extrelut (mobile solvent ethyl acetate). The solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent methanol/dichloromethane). 9.4 mg (19.2%) of the desired nitrile is isolated.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]>CC(C)=O>[CH:21]([C:20]1[O:24][C:3](=[O:4])[C:5]2=[CH:9][CH:8]=[CH:7][N:6]2[CH:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)C(=O)CBr
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1cn2cccc2c(=O)o1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a slurry of 2-(trichloroacetyl)pyrrole (5.3 g, 25 mmol) and K2CO3 (11 g, 76 mmol) in 100 mL acetone was added a solution of 1-bromo-3-methylbutan-2-one (4.5 g, 27 mmol) in 30 mL acetone. The mixture was stirred for 1 hour at 50° C. before filtering and concentrating under reduced pressure to obtain 3-isopropyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (4.1 g, 93%), which was used in the following step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[CH3:12].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:17]([NH2:18])=[C:16]([N+:22]([O-:24])=[O:23])[C:15]=1[CH3:25].Cl[C:27]1C(C)=CC(N)=C(C)C=1>>[NH2:18][C:17]([CH3:27])([CH2:19][N:7]1[N:6]=[C:5]2[C:9]([CH3:11])=[CH:10][C:2]([Cl:1])=[C:3]([CH3:12])[C:4]2=[N:8]1)[C:16]#[N:22].[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[CH3:12].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:17]([NH2:18])=[C:16]([N+:22]([O-:24])=[O:23])[C:15]=1[CH3:25]
Reactant: Cc1cc(Cl)c(C)cc1N
Agent: Cc1c(Cl)cc(C)c2[nH]nnc12
Agent: Cc1cc(Cl)c(C)c([N+](=O)[O-])c1N
Product: Cc1cc(Cl)c(C)c2nn(CC(C)(N)C#N)nc12

Procedure:
2-Amino-3-(5-chloro-4,7-dimethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile [1.3 g, Rf=0.2 (1:1 EA/heptane)] was prepared using a procedure similar to that described in Example 1, part a and b, except starting from 5-chloro-4,7-dimethyl-1H-benzotriazole. 5-Chloro-4,7-dimethyl-1H-benzotriazole (4 g, 85%) was prepared using a procedure similar to that described in Example 11, part a, except starting from 4-chloro-3,6-dimethyl-2-nitroaniline. 4-Chloro-3,6-dimethyl-2-nitroaniline (6.1 g) was prepared using a procedure similar to that described in Example 39, part a, b and c, except starting from 4-chloro-2,5-dimethylaniline (10 g).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([S:14](F)(=[O:16])=[O:15])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:35]S(O)(=O)=O>>[C:1]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([S:14]([Cl:35])(=[O:16])=[O:15])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: O=C(Nc1ccccc1)c1ccccc1
Product: O=C(Nc1ccc(S(=O)(=O)Cl)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
N-benzoylsulfanilyl chloride was prepared as starting material for N-benzoylsulfanilyl fluoride in the following manner: A 15 gm (0.076 mole) portion of benzanilide was added with stirring to 26 ml (0.38 mole) of chlorosulfonic acid at 0° C. The mixture was then allowed to stir at 60° C for two hours, then cooled to room temperature and poured into ca 200 gm of ice. The sulfonyl chloride was recovered by filtration and recrystallized from chlorobenzene, giving 9.1 gm (41% yield) with mp 176°-178° C. The assigned structure was in agreement with the chemical analysis and the NMR and IR spectra.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23]CC)=[O:22])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH3:26])([CH3:27])[C:21]([OH:23])=[O:22])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)(C)CCCCOc1cccc(OCCCCCn2ccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(CCCCOc1cccc(OCCCCCn2ccnc2)c1)C(=O)O
Yield: 98 %

Procedure:
A mixture of 3.5 g ethyl 6-[m-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoate, 20 ml of 1N NaOH solution and 20 ml ethanol was heated under reflux overnight. Ethanol was distilled off under reduced pressure, and concentrated hydrochloric acid was added to the remaining aqueous solution to lower its pH down to about 4.0. The pasty solid which separated out was extracted with chloroform, and the extract was washed with water and dried. The solvent was distilled off, and the crude product thus obtained was purified by silica gel column chromatography, affording 3.2 g of 6-[m-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoic acid.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH2:27][CH3:28])=[C:13]([C:15]2[NH:16][C:17](=[O:25])[C:18]3[N:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:14]=1>>[CH2:27]([O:26][C:12]1[CH:11]=[CH:10][C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:14][C:13]=1[C:15]1[NH:16][C:17](=[O:25])[C:18]2[N:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:28]
Reactant: CCOc1ccc(N)cc1-c1nc2cccnc2c(=O)[nH]1
Reactant: CC(C)S(=O)(=O)Cl
Product: CCOc1ccc(NS(=O)(=O)C(C)C)cc1-c1nc2cccnc2c(=O)[nH]1

Procedure:
The title compound was prepared using 2-propyl-sulphonyl chloride and 2-(5-amino-2-ethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (Example 20), following the procedure of Example 12, and was obtained as a hydrated solid (59%), m.p. 211°-213° C. Found: C,54.98; H,5.07; N;14.21. C18H20N4O4S;0.25 H2O requires C,55.02; H,5.26; N,14.26%.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.O1CCCC1.CC(C)([O-])C.[K+].Cl[CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[N:3]=1
Reactant: CS(=O)(=O)CCCl
Reactant: Brc1cc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1ccc(Br)n1
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a solution of 3-bromo-1H-pyrazole obtained in Step C of Example 6 (600 mg) in N,N-dimethylformamide (40 mL) was added potassium tert-butoxide tetrahydrofuran solution (1 M, 6.12 mL) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added 1-chloro-2-(methylsulfonyl)ethane obtained in Step A (873 mg) at room temperature, and the mixture was stirred for 2 hr. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (730 mg).
Reaction SMILES: FC(F)(F)C(C(F)(F)F)(C1C=CC2NCCCCC=2C=1)O.[F:22][C:23]([F:48])([F:47])[C:24]([C:43]([F:46])([F:45])[F:44])([C:26]1[CH:27]=[CH:28][C:29]2[N:35]([C:36](=[O:41])[CH2:37][C:38](=O)[CH3:39])[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:42]=1)[OH:25]>S(=O)(=O)(O)O>[F:46][C:43]([F:44])([F:45])[C:24]([C:26]1[CH:27]=[C:28]2[C:29]3=[C:30]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[C:36](=[O:41])[CH:37]=[C:38]2[CH3:39])[CH:42]=1)([OH:25])[C:23]([F:48])([F:47])[F:22]
Reactant: CC(=O)CC(=O)N1CCCCc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Agent: O=S(=O)(O)O
Agent: OC(c1ccc2c(c1)CCCCN2)(C(F)(F)F)C(F)(F)F
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CCCC2

Procedure:
By the method shown in Example 14, α,α-bis(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-7-methanol is converted to α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-7-methanol, m.p. 169°-171°, which is cyclized by heating in sulfuric acid (in this instance at 120° for 24 hours) to give 5,6,7,8-tetrahydro-10-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1-methyl-3H-azepino[3,2,1-ij]quinolin-3-one, m.p. 197°-198°.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br)#[N:2].C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]>CC#N.CCOC(C)=O.O>[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=3[C:1]#[N:2])[S:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc2cc(N(Cc3ccccc3C#N)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Cyanobenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>C1C=CC=CC=1.[Hg]>[C:7]1([C:5]2([OH:6])[CH:3]3[CH2:2][CH:1]2[CH2:4]3)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1ccccc1)C1CCC1
Agent: [Hg]
Solvent: c1ccccc1
Product: OC1(c2ccccc2)C2CC1C2
Yield: 29.8 %

Procedure:
A stirring solution of cyclobutyl(phenyl)methanone (3.0 g, 18.8 mmol) in 800 ml of benzene was irradiated with a 1000 W mercury arc lamp for 48 h at room temperature in a nitrogen atmosphere. The solution was concentrated and the residue (3.1 g) was purified by column chromatography (10%-25% ethyl acetate in petroleum ether) to give the desired product as a white solid (0.9 g, 5.6 mmol, yield: 30%). 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.28 (m, 5H), 3.04 (s, 2H), 2.82 (dd, J1=10.2 Hz, J2=2.4 Hz, 1H), 2.09 (s, 1H), 1.78 (d, J=2.4 Hz, 1H), 1.50 (d, J=3.3 Hz, 1H), 1.33 (dd, J1=9.9, J2=3.3 Hz, 1H).
Reaction SMILES: [ClH:1].CCOC(C)=O.[CH3:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1>CCOC(C)=O>[ClH:1].[ClH:1].[CH3:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[N:14]=1
Reactant: Cc1cccc(N2CCC(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCC(CCC3CCNCC3)CC2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 4 M hydrogen chloride/EtOAc solution (2 ml) was added to an EtOAc (10 ml) solution of tert-butyl 4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidine-1-carboxylate (650 mg), followed by stirring at room temperature for 2 days. The reaction liquid was concentrated to obtain 2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridine dihydrochloride (644 mg) as a yellow amorphous substance.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH:13]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1>>[CH:2]1([CH2:5][O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:13])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1OCC1CC1
Agent: Cl
Product: N[C@@H]1CCCC[C@@H]1OCC1CC1

Procedure:
This compound was prepared as HCl salt by using procedures analogous to those described for the synthesis of Example 55, Step 2 starting from tert-butyl cis-2-(cyclopropylmethoxy)cyclohexylcarbamate. Analytic LCMS (M+H)+: m/z=144.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([NH:14][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ClC1C=C(C=CC=1S(NCCC)(=O)=O)C(O)=O.Cl.Cl.[CH3:37][C:38]1[N:42]([CH:43]2[CH2:49][CH:48]3[N:50]([CH2:51][CH2:52][C:53]4([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)[CH:45]([CH2:46][CH2:47]3)[CH2:44]2)[C:41]2[CH:65]=[CH:66][CH:67]=[CH:68][C:40]=2[N:39]=1.CC1N(C2CC3N(CCC4(C5C=CC=CC=5)CCN(C(C5C=CC=CC=5S(NC(=O)OC(C)(C)C)(=O)=O)=O)CC4)C(CC3)C2)C2C=CC=CC=2N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([NH:14][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12])=[C:6]([C:7]([N:56]2[CH2:55][CH2:54][C:53]([CH2:52][CH2:51][N:50]3[CH:45]4[CH2:46][CH2:47][CH:48]3[CH2:49][CH:43]([N:42]3[C:41]5[CH:65]=[CH:66][CH:67]=[CH:68][C:40]=5[N:39]=[C:38]3[CH3:37])[CH2:44]4)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:58][CH2:57]2)=[O:9])[CH:10]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: CCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)O
Agent: CCCNS(=O)(=O)c1ccc(C(=O)O)cc1Cl
Agent: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2ccccc2)CC1
Yield: 11 %

Procedure:
The title compound was prepared from a mixture of 5-chloro-2-[(propylamino) sulfonyl]benzoic acid and 3-chloro-4-[(propylamino) sulfonyl]benzoic acid 2e and endo 2-methyl-1-(8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-chloro-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-aza bicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-N-propylbenzenesulfonamide 5 as a white solid (15 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ (8.12, 1H, J=8.0 Hz), 7.65 (m, 1H), 7.52 (m, 1H), 7.41-7.12 (m, 9H), 5.10 (t, 1H, J=6.0 Hz), 4.59 (m, 1H), 4.20 (m, 1H), 3.48-3.19 (m, 6H), 2.89 (q, 1H, J=6.6 Hz), 2.56 (s, 3H), 2.55-2.32 (m, 3H), 2.17 (m, 1H), 1.93-1.64 (m, 10H), 1.61 (m, 1H), 1.50 (m, 2H), 0.882 (t, 3H, J=7.3 Hz). ES-LCMS m/z 690.33 (M+2H). Analytical HPLC (Method Y) Rt 5.39 (93.34%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([CH3:16])[CH:12]([NH2:15])[CH2:13][NH2:14])=[CH:3][CH:2]=1.N.Cl[CH2:19]Cl>>[NH:14]1[CH2:13][CH:12]([CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[CH3:16])[N:15]=[CH:19]1
Reactant: CC(c1ccnc2ccccc12)C(N)CN
Reactant: ClCCl
Agent: N
Product: CC(c1ccnc2ccccc12)C1CNC=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To 3-Quinolin-4-yl-butane-1,2-diamine (1.54 g, 7.16 mmol) in 5 ml of dichloromethane, formidic acid ethyl ester hydrochloride (1.57 g, 14.3 mmol) was added. The reaction mixture was stirred overnight at room temperature. Aqueous ammonia (2 ml) was added to the reaction mixture and was partitioned between EtOAc (2×5 ml) and water. The organic layer was dried, filtered and concentrated to give 1.16 g (73%) of the product as a syrup which was used for the subsequent step.