Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:37])=[C:19]([CH:36]=2)[O:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30]C(=O)OCC)=S)=[N:25][CH:26]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(O)C.Cl.NO.C([N:47](CC)C(C)C)(C)C>CO>[NH2:47][C:28]1[N:27]=[C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:36]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:16]=[CH:17][C:18]=3[CH3:37])=[CH:26][N:25]2[N:30]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Temperature: 60 °C
Yield: 35 %

Procedure:
To a solution of the above-mentioned crude product, ethyl ({5-[5-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)-2-methylphenoxy]pyridin-2-yl}carbamothioyl)carbamate, in methanol (100 mL)/ethanol (100 mL) were added hydroxylamine hydrochloride (5.08 g, 73.1 mmol) and N,N-diisopropylethylamine (15.3 mL, 87.8 mmol), and the mixture was stirred with heating at 60° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL, 50 mL). The combined organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (NH silica gel, hexane/ethyl acetate=30/70→0/100), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (1.81 g, 35%) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[C:13]([C:18](=O)[CH3:19])[C:12]=2[OH:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:22]([C:24]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[S:25])[NH2:23].CN(C)C=O>Cl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[C:13]([C:18](=[N:23][NH:22][C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)=[S:25])[CH3:19])[C:12]=2[OH:21])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCn1nc(C(C)=O)c(O)c1-c1ccc(C(C)(C)C)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C(C)=NNC(=S)Nc2ccc(C(=O)O)cc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Yield: 71.6 %

Procedure:
1-[5-(4-tert-Butylphenyl)-1-ethyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.1718 mmol, 49.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.1718 mmol, 36.3 mg) were stirred with dimethylformamide (3 mL) and two drops of concentrated hydrochloric acid at room temperature for 21 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (59 mg, yield 72%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[F:9][C:10]([F:38])([F:37])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>O1CCCC1.O>[OH:3][NH:2][C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:20]2[CH2:21][CH2:22][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:38])([F:37])[F:9])[CH:12]=3)[CH2:18][CH2:19]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.24 g, 3.4 mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO3 (0.40 g, 4.8 mmol) in water (6 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a suspension of (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in tetrahydrofuran (5 mL) and the mixture was stirred at ambient temperature for 0.5 hours. The mixture was poured into water (25 mL), the precipitate was filtered, washed with water, ether, and dried to give the title compound (0.23 g, 73%). M.p. 178-179° C. 1H NMR (DMSO-d6, HMDSO), δ: 2.95-3.10 (4H, m); 3.23-3.40 (4H, m, overlapped with a signal of water); 6.62 (1H, d, J=15.9 Hz); 7.09 (1H, d, 3=7.7 Hz); 7.16 (1H, s); 7.19 (1H, d, J=8.0 Hz); 7.40 (1H, t, 3=7.7 Hz); 7.54 (1H, d, J=15.9 Hz); 7.80 (2H, d, J=8.4 Hz); 7.83 (2K, d, J=8.4 Hz); 9.35 (1H, br s); 10.72 (1H, br s). HPLC analysis on Omnispher 5 C18 column: impurities 3.5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M acetate buffer (pH 5.0), 50:50; sample concentration 1 mg/ml; flow rate 1.3 mL/min; detector UV 254 nm). Anal. Calcd for C20H20F3N3O4S, %: C, 52.74; H, 4.43; N, 9.23; S, 7.04. Found, %: C, 52.04; H, 4.29, N, 8.86; S, 7.20.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.CO.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCOc2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(CCOc2ccc(N)cc2)n1
Yield: 90.5 %

Procedure:
To a solution of 2.8 g of 4-[2-(6-methyl-2-pyridyl)ethoxy]nitrobenzene in the mixture consisting of 30 ml of methanol and 20 ml of ethyl acetate is added 0.5 g of 10% palladium carbon, and then the mixture is shaken in a stream of hydrogen. After absorption of hydrogen ceased, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 2.24 g of 4-[2-(6-methyl-2-pyridyl)ethoxy]aniline as yellowish brown powder.
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][OH:10])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>>[CH3:1][N:2]([CH2:8][CH2:9][O:10][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1
Reactant: CN(CCO)c1nccs1
Reactant: O=Cc1ccc(F)cc1
Product: CN(CCOc1ccc(C=O)cc1)c1nccs1

Procedure:
The title compound was prepared from 2-[N-methyl-N-(2-thiazolyl)amino]ethanol (10.7 g) and 4-fluoro-benzaldehyde (15.9 g) by an analogous procedure to that described in Preparation 5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COc1ccc(S)cc1
Reactant: COC(=O)C=CC=CCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C=CC=CCSc1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.50 g, 7.3 mmol) and 4-methoxythiophenol (0.93 mL, 7.3 mmol) in tetrahydrofuran (40 mL) was added dropwise triethylamine (1.1 mL, 8.0 mmol) under an atmosphere of argon. The mixture was stirred at 20° C. for one hour, then filtered. The filtrate was concentrated under reduced to pressure and the residue was dissolved in ethyl acetate (50 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (25 mL), demineralised water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography ((9:1 to 8:2 40-60° C. petroleum ether:diethyl ether) to give the title compound as a colourless oil (1.6 g, 86%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[I-].[Na+].Cl.[OH-:26].[Na+]>CS(C)=O.O>[CH3:16][C:15]1[C:3]2[C:2](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[NH:5][C:4]=2[N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:14]=1
Reactant: Cc1cccc2nc3c(c(C)nn3-c3ccccn3)c(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc2[nH]c3c(c(C)nn3-c3ccccn3)c(=O)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 4-chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.65 g, 5.34 mmol), sodium iodide (0.96 g, 6.41 mmol) and conc. hydrochloric acid (1 mL) in dimethylsulfoxide (20 mL) was heated and stirred at 100° C. for 2 hours. The solution was cooled to room temperature, and the residue was poured into water. The mixture was made basic by the addition of a sodium hydroxide solution, and organic matter was extracted with 10% methanol/chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:hexane=90:10) to give the title compound (1.13 g, 73% yield).
Reaction SMILES: [OH:1]CC1NC(=O)CC1.[CH:9]1([C@H:15]2[CH2:19][NH:18][C@H:17]([CH2:20][OH:21])[CH2:16]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1([C@@H]2N3C(=O)CCC3CO2)C=CC=CC=1>>[CH:9]1([C@H:15]2[CH2:19][NH:18][C@H:17]([C:20]([OH:1])=[O:21])[CH2:16]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: OC[C@@H]1C[C@@H](C2CCCCC2)CN1
Reactant: O=C1CCC(CO)N1
Agent: O=C1CCC2CO[C@H](c3ccccc3)N12
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1

Procedure:
(trans)-4-Cyclohexyl-L-proline was prepared from 5-hydroxymethyl-2-pyrrolidone using the procedure described in Example 1, but substituting the following methodology for preparing (2-S-trans)-4-cyclohexyl-2-pyrrolidinemethanol from (R)-tetrahydro-3-phenyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[S:21])[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: S=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Yield: 98.8 %

Procedure:
A suspension of 7-benzyloxy-3,4-dihydroquinazolin-4-one (7 g, 28 mmol), (prepared as described for the starting material in Example 6), in pyridine (350 ml) containing phosphorus pentasulphide (12.5 g, 33 mmol) was heated at reflux for 8 hours. After cooling, the mixture was poured into water (1 liter). The precipitate was collected by filtration, and washed with water. The solid was dissolved in 6M sodium hydroxide and the solution was filtered. The filtrate was acidified to pH2 with 6M hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum at 60° C. to give 7-benzyloxy-3,4-dihydroquinazolin-4-thione (7.42 g, 99%).
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([Cl:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([Cl:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2Cl)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Reaction time: 4.5 h
Yield: 92.2 %

Procedure:
To a mixed solution (1:1) of 2.5 ml of 4N hydrochloric acid and acetic acid was added 600 mg of ethyl 1-[6-(t-butylamino)-3-chloro-5-fluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 4.5 hours. After adding 2 ml of distilled water, the solution was allowed to cool and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 458 mg of the title compound as a pale yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[C:16](=O)([O:22]C(C)(C)C)[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.2 %

Procedure:
To a solution of 4-(4-nitrophenyl)piperidine (412 mg, 2 mmol) in CH2Cl2 (100 mL) was added di-tert-butyl carbonate (480 mg, 2.2 mmol) and N,N-dimethylpyridin-4-amine (50 mg, 0.4 mmol). The mixture was stirred for 20 h at room temperature. The mixture was added saturated NaHCO3 (100 mL). The organic layer was separated and aqueous was extracted with CH2Cl2 (50 mL×2). The combined organic solution was dried and concentrated in vacuo. The residue was dissolved in MeOH and bubbled with Ar for 2 min. before adding 10% Pd—C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (460 mg, 83%) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.1 %

Procedure:
A mixture of 2-bromophenol (10 g, 57.8 mmol), benzyl bromide (27.5 ml, 0.23 mol) and potassium carbonate (64 g, 0.462 mol) in N,N-dimethylformamide (70 ml) was stirred at room temperature for 72 hours. The suspension was poured into water (500 ml) and extracted with ethyl acetate (2×300 ml). The combined organic fractions were washed with water (300 ml), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (98:2) to give the title compound as a colourless oil (2.9 g). 1H NMR (250 MHz, CDCl3) δ 7.58-7.19 (8H, m), 6.95-6.81 (2H, m), and 5.16 (2H, m).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[N:15][CH:16]=2)[CH:2]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[OH:20][C:17]([C:13]1[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]3[C:10](=[N:1][CH:2]=2)[N:9]([C:21]([NH2:29])=[O:28])[CH2:8][CH2:7][CH2:6]3)[CH:16]=[N:15][CH:14]=1)([CH3:18])[CH3:19]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)(O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(O)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 50 °C
Yield: 32 %

Procedure:
2-[5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-2-ol (33 mg, 0.12 mmol) and benzoyl isocyanate (40 mg, 0.25 mmol) are mixed in 1.0 mL of DCM and the mixture is heated at 50° C. for 16 hrs. Then the solvent is removed and the residue is dissolved in 1.0 mL of EtOH. K2CO3 (29 mg, 0.21 mmol) is added and the mixture is heated at 80° C. for 2 hrs, cooled down to room temperature for 16 hrs and heated at 80° C. again for another 3 hrs. Then the solvent is removed and the residue is partitioned between water (15 mL) and EtOAc (25 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is purified by flash column chromatography to give 12 mg of the titled product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[NH:40][C:39]4=[O:47])[CH2:36][CH2:37]3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1,3-dihydro-1-(4-piperidinyl)benzoimidazol-2-one as in General Procedure 10 to give the title compound. LCMS: m/z=647.02 (M+H+); retention time=0.83 minutes.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].FC(F)(F)C(O)=O.C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCC1.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: COc1nc2nc(OC3CCC3)[nH]c(N)c-2n1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC3CCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclobutyloxy)-8-(methyloxy) -1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
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: CCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
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: [Mg+2:1].[Cl-].[Cl-].[CH3:4][N:5]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][K])[CH3:6]>C1COCC1>[CH3:4][N:5]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Mg:1][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[N:5]([CH3:6])[CH3:4])[CH3:6]
Reactant: [Mg+2]
Reactant: CN(C)c1ccccc1C[K]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)c1ccccc1C[Mg]Cc1ccccc1N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Under argon, 0.20 g of MgCl2 (2.1 mmol) and 0.70 g of ortho-N,N-dimethylaminobenzyl potassium (4.0 mmol) are introduced into a Schlenk flask. Around 25 ml of THF are recondensed under vacuum at −78° C. The mixture is stirred at ambient temperature for 30 minutes, then heated at reflux under static vacuum for 5 h, at 50° C. The insoluble MgCl2 crystals have then disappeared. After 1 night at 50° C., the mixture is centrifuged; the white-grey centrifugation pellet of KCl is removed, and the orange solution is concentrated to 1-2 ml, then around 0.5 ml of petroleum ether is added. Colourless crystals appear in the red solution. XRD analysis (Annex 4) of one of the crystals indicates a monomeric structure of the bis(ortho-N,N-dimethylaminobenzyl) magnesium complex (THF). M=0.30 g (yield=42%). 1H NMR (THF-d8, 22° C.): δ=7.00 (d, 2H, CH(6), J(C-H)=7 Hz), 6.90 (d, 2H, CH(3), J(C-H)=7 Hz), 6.75 (t, 2H, CH(4), J(C-H)=7 Hz), 6.55 (t, 2H, CH(5), J(C-H)=7 Hz), 3.65 (t, 4H, free non-deuterated THF), 2.65 (s, 12H, C(8) and C(9), N(CH3)2), 1.80 (m, 4H, free non-deuterated THF), 1.17 (s, 4H, C(1), Mg—CH2—). 13C NMR (THF-d8): δ=152.8 (C(2)), 148.4 (C(7)), 128.9 (C(6)), 125.9 (C(4)), 118.9 (C(5)), 118.4 (C(3)), 45.7 (N(CH3)2), 19.0 (Mg—CH2—).
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].O>C1COCC1>[CH:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[NH:26][C:27]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: Nc1ccccc1NC1CCN(C2CC3CCCc4cccc2c43)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CC3CCCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
N-[1-(1,2,2a,3,4,5-Hexahydroacenaphthylen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.15 g) was dissolved in THF (70 ml), 1,1′-carbonyldiimidazole (0.591 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.76 g) as a white solid.