Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:8]([CH:10]=O)[O:9][C:5]=2[CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:10]/[C:8]1[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:18]=[CH:17][C:6]=2[C:7]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCc1c(C=O)oc2cc(OC)ccc12
Solvent: ClCCl
Product: CCCCCc1c(/C=C/C(=O)OC)oc2cc(OC)ccc12
Yield: 76.9 %

Procedure:
As in Example 111, 6-methoxy-3-pentyl-2-benzofurancarboxaldehyde (4.82 g) and (carbomethoxymethylene)triphenylphosphorane (6.7 g) in dichloromethane (75 mL) was stirred at room temperature for 42 hours. Purification of the crude reaction product by HPLC (diethyl ether-hexane; 1:12) gave 4.55 g of (E)-3-(6-methoxy-3-pentylbenzofuran-2-yl)-2-propenoic acid methyl ester as an oil.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:6][CH:5]([NH2:7])[CH2:4]1.C(Cl)Cl.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[F:2][C:3]1([F:8])[CH2:6][CH:5]([NH:7][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:4]1
Reactant: NC1CC(F)(F)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CC(F)(F)C1
Reaction time: 16 h

Procedure:
0.60 g 3,3-Difluoro-cyclobutylamine hydrochloride were suspended using 40 ml CH2Cl2 and 2.9 ml of triethylamine added at ambient temperature while receiving a clear solution. Thereafter, 1.0 ml of methanesulfonylchloride were added dropwise at ambient temperature and the mixture left at that temperature for 16 h. The volatiles were removed in vacuo, the residue was redissolved using 200 ml of EE and 100 ml of a saturated aqueous Na2CO3-solution and the layers separated. The organic layer was washed twice using 20 ml of a saturated aqueous NaHSO4-solution each time and washed twice using 30 ml of a saturated aqueous Na2CO3-solution each time. The organic layer was dried over MgSO4 and the solvent removed in vacuo. Yield: 700 mg of a colorless resin.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][C:33]5[CH:34]=C(C=CC=5)C(OC)=O)[C:28](=[O:43])C4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1.N1(C2N=CC(NC(C3OC(N4CCCC(C)C4)=NC=3C(F)(F)F)=O)=CC=2)CCCNCC1.ClC([O:79][CH:80]1[CH2:84][CH2:83][CH2:82][CH2:81]1)=O>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:34][CH2:33][CH2:32][N:29]([C:28]([O:79][CH:80]5[CH2:84][CH2:83][CH2:82][CH2:81]5)=[O:43])[CH2:30][CH2:31]4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1cccc(CN2CCN(c3ccc(NC(=O)c4oc(N5CCCC(C)C5)nc4C(F)(F)F)cn3)CC2=O)c1
Agent: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCCNCC4)nc3)o2)C1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc(N4CCCN(C(=O)OC5CCCC5)CC4)nc3)o2)C1

Procedure:
Compound 43 was prepared by the general procedure for compound 8, by using compound 39 and cyclopentyl chloroformate as starting materials. 1H NMR (500 MHz, CDCl3) δ 8.10 (br s, 1H), 7.90 (d, 1H, J=9 Hz), 7.50 (s, 1H), 6.50 (d, 1H, J=9 Hz), 5.10 (br s, 1H), 4.10 (t, 2H, J=14.5 Hz), 3.80 (m, 2H), 3.60 (m, 3H), 3.40 (t, 1H, J=6 Hz), 3.25 (t, 1H, J=6 Hz), 3.05 (t, 1H, J=13 Hz), 2.70 (t, 1H, J=13 Hz), 1.55-2.00 (m, 16H), 1.20 (q, 1H, J=12.5 Hz), 1.00 (d, 3H, J=7 Hz). MS (M+1): 565.
Reaction SMILES: Br[CH2:2][C:3](=[O:19])[C:4]([OH:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[OH:18][C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:3](=[O:19])[CH2:2][N:30]1[CH2:31][CH2:32][N:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][CH2:29]1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CBr)C(O)(CN1CCCCC1)c1ccccc1
Solvent: CCOCC
Product: O=C(CN1CCN(Cc2ccccc2)CC1)C(O)(CN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1 63 g (5 mmole) of 4-bromo-2-hydroxy-2-phenyl-1-piperidino-3-butanone in 35 mL of ether is added 1.76 g (5 mmole) of 4-benzylpiperazine. The solution is stirred at room temperature for 18 hours and then washed twice with brine dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. Purification by flash column chromatography gives 2-hydroxy-2-phenyl-1-piperidino-4-(4-benzyl-1-piperazinyl)-3-butanone. This was converted into its hydrochloride salt in the usual manner.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].O1CCCC1.C(N(CC)CC)C.[CH2:40]([NH:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>>[CH2:59]([N:58]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 93.8 %

Procedure:
Lithocholic acid (81) (7.1 g, 18.8 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) Isobutylchloroformate (2.6 g, 2.6 mL, 18.8 mmol) was added followed by the addition of triethylamine (3.84 g, 5.3 mL, 38 mmol) and dioctadecylamine (9.8 g, 18.77 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL) The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 82 (15.5 g) in 93% yield. This was used as such for the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.Cl.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(N(CC)CC)C>CCO>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][C:2]1[N:7]=[C:6]([S:8][C:9]#[N:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: NCc1ccccc1Br
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CSc1nc(NCc2ccccc2Br)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
2-Chloro-5-nitro-4-thiocyanatopyrimidine (100 mg, 0.46 mmol) was suspended in 1 mL absolute EtOH. o-Bromobenzylamine hydrochloride (103 mg, 0.46 mmol) was dissolved in 1 mL absolute EtOH and added to the reaction quickly at ambient temperature. Then triethylamine (129 μL, 0.92 mmol) was added dropwise via syringe. The reaction was stirred 16 h at ambient temperature. The resulting precipitate was filtered providing 136 mg of the desired (2-bromo-benzyl)-(5-nitro-4-thiocyanato-pyrimidin-2-yl)-amine as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[CH2:25][CH2:24]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)c1ccc(-c2ccc(CC(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2ccc(CC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)cc2)cc1
Reaction time: 12 h
Yield: 67 %

Procedure:
[4-(4-Acetylphenyl)phenyl]acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (2.5 g) were suspended in DMF (50 mL), and triethylamine (2.1 mL), EDC hydrochloride (1.6 g) and HOBt (1.3 g) were added-to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (2.5 g) as a white solid. melting point: 184° C.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(Cl)Cl>[CH3:30][NH:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)=[N:24][CH:25]=1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Oc2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)nc1
Temperature: 100 °C

Procedure:
A mixture of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-ol (Example 47, 20 mg, 0.066 mmol), 6-chloro-N-methylnicotinamide (Example 71A, 11 mg, 0.066 mmol) and K2CO3 (27 mg, 0.20 mmol) in N,N-dimethylformamide (0.25 mL) was heated to 100° C. for 1 hour, cooled, diluted with CH2Cl2, filtered, and concentrated. The residue was purified by HPLC as described in Example 66. The product was further purified by chromatography on silica gel eluting with a gradient of 2 to 10% (9:1 methanol:ammonium hydroxide) in CH2Cl2 to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.44-1.53 (m, 2H), 1.59-1.67 (m, 4H), 1.94-2.10 (m, 1H), 2.24-2.34 (m, 1H), 2.39-2.57 (m, 4H), 2.95-3.06 (m, 1H), 3.01 (d, J=4.7 Hz, 3H), 3.43 (t, J=9.3 Hz, 1H), 3.48-3.60 (m, 1H), 3.70-3.89 (m, 2H), 6.09-6.18 (m, 1H), 6.92 (dd, J=8.5, 0.7 Hz, 1H), 7.07 (dd, J=8.5, 2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 8.12 (dd, J=8.6, 2.5 Hz, 1H), 8.53 (dd, J=2.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 438 (M+H)+.
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[C:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([F:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[C:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:21]([NH:20][C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:22])=[C:40]([F:45])[CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenylethanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19]([NH2:21])=[S:20])=[N:2]1.C(O)C.Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29].N>>[CH2:31]([O:30][C:28]([C:27]1[N:21]=[C:19]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)[S:20][CH:26]=1)=[O:29])[CH3:32]
Reactant: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Agent: N
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)n1
Yield: 13.1 %

Procedure:
Compound 161 (0.40 g, 1.4 mmol) was added with ethanol (3.0 mL, 1.5 mmol) and ethyl bromopyruvate (0.10 mL, 0.8 mmol) and after heating under reflux for 18 hours, aqueous ammonia was added to stop the reaction. The precipitated crude product was collected by filtration and purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/2). Then, the product was triturated in ethyl acetate to obtain Compound 169 (41 mg, 17%).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(N(CC)CC)C.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][S:1]([CH3:4])(=[O:3])=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Mesyl chloride (25.8 mg) and triethylamine (0.055 ml) were added to a chloroform (0.9 ml) solution of benzyl alcohol (16.2 mg), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was eluted by NH-type silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography using tetrahydrofuran as a solvent to obtain methanesulfonic acid benzyl ester. To a tetrahydrofuran (0.9 ml) solution of the methanesulfonic acid benzyl ester, 4-chloro-N-[(1R)-1-(4-ethyl-5-mercapto-4H-1,2,4-triazol-3-yl)ethyl]benzenesulfonamide (Compound 90) (17.3 mg) obtained by performing the same procedure as in Example 1 using the corresponding raw materials, and potassium t-butoxide (8.4 mg) were added, followed by stirring the mixture for 20 hours at 40° C. PSA (polymer supported amine) (0.15 ml) was added to the reaction mixture, and the resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was eluted with ethyl acetate and tetrahydrofuran, and the solvents were distilled off. The resulting residue was eluted by NH-type silica gel column chromatography using tetrahydrofuran as a solvent, and the eluate was purified by silica gel column chromatography to obtain Compound 5 (2.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2cccc(F)c2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2cccc(F)c2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3.49 g of 5-(4-chlorophenyl)-4-(2,3-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 3.66 g of 3-chloro-5-(4-chlorophenyl)-4-(2,3-difluorophenyl)-6-methyl pyridazine (hereinafter, referred to as compound (xii) of the present invention).
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17]C)=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 ml), and methanol (50 ml) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 ml of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification, 1H NMR (CDCl3): δ 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1.BrC1C=CC([F:31])=CC=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:20][C:21]([OH:23])=[O:22])=[C:7]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([F:31])=[CH:14][CH:13]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: O=C(O)Cc1c(C(=O)c2ccc(F)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 7, step 1) and 4-bromofluorobenzene.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.O.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CO>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[N:3]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: O=C(CC1c2ccccc2C(=O)N1c1ccccc1)N1CCN(Cc2ccccc2)CC1
Yield: 83.5 %

Procedure:
An oily product (4.3 g), which was prepared from 2.67 g of 3-oxo-2-phenylisoindoline-1-acetic acid and 1.94 g of 1-benzylpiperazine in the same manner as Example 3, was dissolved in 4 ml of methanol, and to this solution a solution of 1.5 g of oxalic acid dihydrate in 6 ml of methanol was added, and the crystals precipitated were collected by filtration. Yield, 4.90 g; m.p., 207°-210° C. (recrystallization from methanol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([Cl:20])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
3,5-Di-t-butylbenzoic acid, purchased from Aldrich Chemical Co., (10 g, 0.042 mol) was dissolved in 50 mL thionyl chloride and the light yellow solution was refluxed for 3 h under argon. The reaction was cooled to room temperature and excess SOCl2 was evaporated under vacuum (liq. N2 trap). The resulting oil was dissolved in dry toluene (100 mL) and the resulting solution was evaporated under vacuum to give the 3,5-di-t-butylbenzoyl chloride as a light brown oil (10.5 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])[CH3:5].[CH2:22](I)[CH2:23][CH3:24].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:5])([N:6]([CH2:22][CH2:23][CH3:24])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:17])[F:18])(=[O:8])=[O:9])[CH3:20]
Reactant: COC(=O)C(C)(C)NS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CCCI
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C(C)(C)C(=O)OC)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
Methyl-2-methyl-2-(2-(trifluoromethyl)phenylsulfonamido)propanoate (310 mg, 0.95 mmol) was dissolved in DMF (8 ml), and added with propyl iodide (0.32 ml, 3.34 mmol) at 0° C., followed by stirring at room temperature for 12 hours. The resultant solution was added with H2O and extracted with EA (×2). The organic solution was washed with H2O, dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-methyl-2-(N-propyl-2-(trifluoromethyl)phenylsulfonamido)propanoate (340 mg, 0.93 mmol, 97%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:22][C:23]([F:47])([F:46])[CH2:24][NH:25][C:26]([C:28]1([CH2:41][CH2:42][CH2:43][CH2:44]Br)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27]>>[F:22][C:23]([F:46])([F:47])[CH2:24][NH:25][C:26]([C:28]1([CH2:41][CH2:42][CH2:43][CH2:44][N:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:11][CH:12]=3)[CH2:17][CH2:18]2)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27]
Reactant: c1ccc(COc2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: Cl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(OCc4ccccc4)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-benzyloxy-phenyl)-piperazine hydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:27][O:28][CH2:29][C:30]([Cl:32])=[O:31].CS(C)=O>N1C=CC=CC=1>[ClH:32].[CH3:27][O:28][CH2:29][C:30]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:31]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COCC(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 27.5 mg (0.25 mmol) of methoxyacetyl Chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is mixed with 3 ml of DMSO and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 16 mg (29.4% of theory) of the title compound are obtained.