Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([CH3:16])=[O:15])=[C:10]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([CH3:16])=[O:15])=[C:10]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC(C)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.870 g (2.60 mmol) of methyl 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonyl-benzoate was dissolved in a mixture of 10 ml of THF and 10 ml of water, and 0.114 g (2.90 mmol) of NaOH was added. The mixture was stirred at RT for 12 h and then evaporated to dryness. The residue was taken up in water, 6 N HCl was added and the mixture was extracted with CH2Cl2. Drying with Na2SO4 and concentration of the organic phase gave 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonylbenzoic acid in the form of a colorless viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([O:43][C:44](=[O:52])[NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]1)([CH3:42])([CH3:41])[CH3:40].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:39]([O:43][C:44](=[O:52])[NH:45][C@@H:46]1[CH2:51][CH2:50][CH2:49][N:48]([C:22]([C:21]2[N:20]=[C:19]([C:25]([F:28])([F:27])[F:26])[N:16]3[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=4[F:38])[CH2:14][C:15]=23)=[O:24])[CH2:47]1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 62.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.12 g, 0.218 mmol), piperidin-3-yl-carbamic acid tert-butyl ester 11b (0.173 g, 0.545 mmol) and triethylamine (0.275 g, 2.18 mmol) were dissolved in 12 mL of dichloromethane under stirring, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.138 g, 0.545 mmol) was then added to the mixture. The reaction mixture was reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-(1-{7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperidin-3-yl)-carbamic acid tert-butyl ester 11c (0.1 g, yield 63%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][N:11]([CH2:19][C@H:20]([OH:32])[C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].FC(F)(F)C(O)=O.[F:40][C:41]([F:56])([F:55])[C:42]([N:44]1[CH2:49][C:48]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[O:47][CH2:46][CH2:45]1)=[O:43].C(N(CC)CC)C>C(#N)C>[OH:32][C@H:20]([C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[CH2:19][N:11]([CH2:10][CH2:9][S:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:52]1[CH2:53][CH2:54][C:48]2([O:47][CH2:46][CH2:45][N:44]([C:42](=[O:43])[C:41]([F:40])([F:55])[F:56])[CH2:49]2)[CH2:50][CH2:51]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(CCSCCCCCCBr)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N(CCSCCCCCCN1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C

Procedure:
(R)-tert-Butyl 2-(6-bromohexylthio)ethyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate (example 101, step c) (0.55 g) was combined with 2,2,2-trifluoro-1-(1-oxa-4,9-diaza-spiro[5.5]undec-4-yl)-ethanone trifluoroacetic acid salt (example 101, step e) (0.25 g) and triethylamine (0.26 mL) in acetonitrile (20 mL) and heated at 80° C. for 48 h. The volatiles were evaporated in vacuo. Purification was achieved by silica gel chromatography eluting with 10% MeOH in DCM to give the subtitled compound as a yellow gum. Yield 0.10 g and 0.074 g (less pure).
Reaction SMILES: [CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N)CC1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(Cl)Cl>[CH:1]1([C@H:7]2[C@@H:16]3[CH2:17][CH2:18][CH2:19][O:20][C@@H:15]3[C:14]3[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(O)c1ccc2c(c1)[C@H]1OCCC[C@H]1[C@H](C1CCCCC1)N2
Reaction time: 8 h
Yield: 19.8 %

Procedure:
To a stirred solution of (4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline-9-carboxylic acid (50 mg, 0.16 mmol, 1 equiv.) in dry CH2Cl2 (1.6 mL) under argon atmosphere at 0° C. was added cyclopropanamine (12.1 μL, 0.17 mmol, 1.1 equiv.) followed by DIPEA (41 μL, 0.24 mmol, 1.5 equiv.) and EDC (33.5 mg, 0.17 mmol, 1.1 equiv). The reaction mixture was allowed to reach r.t. and stirred overnight. The solvent was removed under reduced pressure and the residue directly purified by Combiflash chromatography (SiO2, c-Hexane/AcOEt) to afford (4aS,5S,10bS)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline-9-carboxylic acid (10 mg, 17%). The compound was prepared as hydrochloride salt following the method described in example 1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:5][CH2:6]1
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a solution of 1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (540 mg, 2.01 mmol) (obtained as described in Reference Example 11(2)) in methylene chloride (27 ml) were added methanesulfonyl chloride (0.467 ml, 6.03 mmol) and triethylamine (0.845 ml, 6.03 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate as the eluant to afford 1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (688 mg, yield 99%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26].[CH3:28][C:29]([CH3:31])=O>>[CH:25]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH:29]([CH3:31])[CH3:28])[N:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:27])[CH3:26]
Reactant: CC(C)=O
Reactant: CC(C)I
Reactant: CCOC(=O)c1c(O)cc(O)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c(OC(C)C)cc(OC(C)C)nc1C(F)(F)F
Yield: 98 %

Procedure:
A mixture of 37.3 g of product of Example 1, 41 g of potassium carbonate, 99 g of 2-iodopropane and 300 ml of acetone was held at reflux for 21 hours. The reaction mixture was filtered. The acetone filtrate was concentrated. The residue was taken into ether and the ether solution was washed with 10% sodium hydroxide, dried, and concentrated. The residue was kugelrohr distilled to give 48.8 g (98%) of product, nD25 1.4491.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][S:9][C:5]2=[C:6](Cl)[N:7]=1.CC(O)=O.Cl.[Sn]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][S:9][C:5]2=[CH:6][N:7]=1
Reactant: Clc1cc2ccsc2c(Cl)n1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: Clc1cc2ccsc2cn1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 5,7-dichlorothieno[2,3-c]pyridine (1.86 g, 8.20 mmol), AcOH (9.42 mL, 164 mmol), and concentrated HCl (3.16 mL, 38.4 mmol) was treated with tin powder (3.04 g, 24.6 mmol) at 60° C. After 3 h heating, another portion of concentrated HCl (3.16 mL) was added followed by another portion of tin powder (3.04 g). After 2 h heating, another portion of concentrated HCl (3.16 mL) was added followed by tin powder (1.03 g). After 2 h, the heating was stopped, and the reaction mixture was cooled and diluted with water (50 mL). After filtration, the residue was washed with water. The combined filtrates were extracted with EtOAc (4×100 mL). The combined extracts were washed with aqueous 1 N NaOH until the pH was >9, followed by brine (100 mL), dried over MgSO4, and concentrated in vacuo. Purification by ISCO chromatography (0 to 30% EtOAc:heptane) afforded 980 mg (70%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.93 (d, J=0.4 Hz, 1 H), 7.79 (d, J=6.4 Hz, 1 H), 7.75 (d, J=1.2 Hz, 1 H), 7.33 (dd, J=5.6, 0.8 Hz, 1 H); MS (ESI): 169.98, 171.98 [M+H]+; HPLC tR=1.29 min (TOF: polar—3 min).
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.[Cl:19][C:20]1[CH:49]=[CH:48][C:23]([C:24]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:31](=[O:40])[CH:30]=[C:29]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[C:1]([Si:5]([CH3:13])([CH3:12])[C:6]1[N:7]([CH3:11])[C:8]([C:24]([C:23]2[CH:48]=[CH:49][C:20]([Cl:19])=[CH:21][CH:22]=2)([OH:25])[C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH2:36][CH:37]2[CH2:38][CH2:39]2)[C:31](=[O:40])[CH:30]=[C:29]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[CH:42]=2)=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Reactant: Cn1ccnc1[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)cnc1[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
A solution of 2-(tert-Butyl-dimethyl-silanyl)-1-methyl-1H-imidazole (1.61 g, 8.2 mmol) in THF (40 mL) at −78° C. was treated with sec-butyllithium (1.3 M in cyclohexane, 7.9 mL, 10.3 mmol). The reaction mixture was warmed to 0° C., stirred for 3 hours, and cooled to −78° C. A solution of 6-(4-Chloro-benzoyl)-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (2.87 g, 6.4 mmol) in THF (20 mL) was cannulated into the reaction mixture, slowly warmed to room temperature, and stirred overnight. The reaction mixture was quenched with ammonium chloride (12 mL), diluted with ether (200 mL), and washed with H2O (200 mL) and brine (200 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to give 6-[[2-(tert-butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (4.35 g) as a yellow foam. The crude material was used in the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)C=1.[CH3:22][OH:23].C[O-].[Na+]>CO>[CH3:22][O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Br)c2)CC1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COCCCCCOC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of tert-butyl 4-(5-bromophenyloxy)-1-piperidinecarboxylate (12.98 g) in methanol (70 ml) was added 28% sodium methoxide methanol solution (37.8 ml) and the mixture was stirred under refluxing for 4 hours. After cooling, the reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give tert-butyl 4-(5-methoxypentyloxy)-1-piperidinecarboxylate (16.31 g). This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1(O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:26])[CH:23](Br)[CH3:24]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:23]([CH3:24])[C:22]([O:21][CH3:20])=[O:26])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
Using 4-hydroxy-3-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a light yellow solid (1.55 g, 61% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (d, J=6.82 Hz, 3H) 3.70 (s, 3H) 5.46 (q, J=6.65 Hz, 1H) 7.45 (d, J=8.84 Hz, 1H) 8.13 (d, J=8.84 Hz, 1H) 8.43 (s, 1H) 9.94 (s, 1 H). ESI-MS: m/z 254.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:15]([CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)([O-])=O.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]N>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][N:15]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Reactant: NCc1ccccc1Cl
Product: Clc1ccc(-c2cn(Cc3ccccc3Cl)c3c2CNCC3)cc1

Procedure:
The title compound (149.9 mg) was prepared from 0.50 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 304 μL of 2-chlorobenzylamine, and 0.46 g of (2-nitro-vinyl)-4-chlorobenzene, replacing SiO2 with crushed 4 Å molecular sieves. MS (ESI): exact mass calculated for C20H18Cl2N2, 356.08. found, m/z 357.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.58-7.56 (m, 1H), 7.47-7.45 (m, 1H), 7.37-7.26 (m, 5H), 7.10 (s, 1H), 6.85-6.82 (m, 1H), 5.25 (s, 2H), 4.38 (s, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.88 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(Cl)nn1-c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)nn1-c1cccnc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 210.9 %

Procedure:
A 3-neck round bottomed flask (100 mL) was charged with ethyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (0.200 g, 0.795 mmol) and hydrochloric acid (37%, 4 mL). The reaction was heated at 90° C. for 18 hours and allowed to cool to 20° C. Dioxane (5 mL) was added to the resulting suspension and was concentrated to dryness. Dioxane (5 mL) was added and the suspension was concentrated again to afford a white solid. Dioxane (5 mL) was added and the resulting suspension was stirred for 1 hour at 20° C. The solid was filtered and the solid was rinsed with dioxane (2 mL). The filter cake was dried under vacuum at 20° C. to afford the title compound as a white solid (0.218 g, 100%): 1H NMR (400 MHz, DMSO-d6) δ 9.05 (dd, J=2.5, 0.7 Hz, 1H), 8.84 (dd, J=5.3, 1.4 Hz, 1H), 8.41 (ddd, J=8.3, 2.5, 1.4 Hz, 1H), 7.88 (ddd, J=8.3, 5.2, 0.7 Hz, 1H), 7.26 (s, 1H); 13C NMR (101 MHz, DMSO-d6) δ 158.71, 146.00, 143.44, 140.36, 137.76, 137.00, 136.83, 125.19, 111.71.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[K]>CN(C=O)C>[CH2:21]([O:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(CCCc2ncccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCc2ncccc2OCc2ccccc2)cc1

Procedure:
Methyl 4-[3-(3-hydroxy-2-pyridyl)propyl]benzoate (0.87 g, 3.2 mmol) was dissolved in DMF (5 ml) and treated with benzyl bromide (0.66 g, 3.9 mmol) and potassium carbonate (0.53 g, 3.8 mmol). The reaction was stirred at ambient temperature potassium overnight and then partitioned between EtOAc/water. The organic phase was washed well with water, dried (MgSO4) and evaporated. The residue was purified (SiO2, CH2Cl2 /EtOAc) to give methyl 4-[3-(3-benzyloxy-2-pyridyl)propyl]benzoate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[N:20][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 180 °C

Procedure:
To a mixture of 6-fluoro-1-(piperidin-4-yl)indoline (256 mg, 1 mmol), 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine prepared as in STEP 1 above (194 mg, 1.0 mmol) in DMSO (3 mL) was added DIPEA (0.52 mL, 3 mmol). The resulting mixture was sealed and heated at 180° C. for 1.5 h under microwave irradiation. The resulting mixture was poured into H2O (30 mL) and the aqueous layer was extracted with 30% CH2Cl2/Et2O (30 mL×5). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield the title compound, 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)indoline.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:28]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1)#[CH:27].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12]([C:27]#[C:26][C:28]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(C#Cc2ncc(Br)cc2Cc2ccccc2)CN2CCC1CC2
Reactant: C#CC1(O)CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2cnc(C#CC3(O)CN4CCC3CC4)c(Cc3ccccc3)c2)CCCC1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
100 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol (Example 22-a), 55 mg of 1-ethynylcyclopentanol, 50 mg of tetrakis (triphenylphosphine)palladium(0), 10 mg of cuprous iodide and 1 ml of triethylamine were mixed in 5 ml of N,N-dimethylformamide, followed by stirring in an oil bath kept at 80° C. for one hour. An aqueous sodium carbonate solution was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 10% methanol/ethyl acetate, to give 93 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:29])[C:5](=[O:28])[NH:6]2.[CH3:30]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC.O>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:29])[C:5](=[O:28])[N:6]2[CH3:30]
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(C)c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
300 mg (0.768 mmol) of the compound from example 41 and 211 mg (0.768 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 109 mg (0.768 mmol) of iodomethane in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 3 h. Water was added, which formed a precipitate. The precipitate was filtered off and purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 203 mg of the title compound were obtained (65% of theory).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][CH2:6][C:5]=2[CH:4]=[N:3][CH:2]=1.[CH2:17]([Br:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Br-:24].[CH2:17]([N+:3]1[CH:2]=[CH:1][C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][CH2:6][C:5]=2[CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCc2cnccc2-c2ccccc21
Solvent: CCO
Product: O=C1NCc2c[n+](Cc3ccccc3)ccc2-c2ccccc21
Product: [Br-]

Procedure:
A mixture of Example 180D (24.6 g, 0.117 mol) and benzyl bromide (40.1 g, 0.234 mol) in 200 mL of ethanol was stirred at reflux overnight. After cooling with an ice-water bath, the solid was collected by filtration and washed with ethanol to obtain the title compound.
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.Cl[CH2:21][C:22]1[S:23][C:24]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=2)=[CH:25][CH:26]=1.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49]>CO>[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[S:4][C:3]([CH2:2][N:39]3[CH2:44][CH2:43][N:42]([CH2:21][C:22]4[S:23][C:24]([C:27]5[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=5)=[CH:25][CH:26]=4)[CH2:41][CH2:40]3)=[CH:7][CH:6]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2ccc(CCl)s2)cc(OC)c1OC
Reactant: COc1cc(-c2ccc(CO)s2)cc(OC)c1OC
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: COc1cc(-c2ccc(CN3CCN(Cc4ccc(-c5cc(OC)c(OC)c(OC)c5)s4)CC3)s2)cc(OC)c1OC

Procedure:
2-Hydroxymethyl-5-(3,4,5-trimethoxyphenyl)thiophene (234 mg) was treated in the same manner in Preparation Example 4 to synthesize 2-chloromethyl-5-(3,4,5-trimethoxyphenyl)thiophene. Since this product was unstable, it was immediately reacted with piperazine (36 mg) in the same manner in Example 1 without isolating it to obtain a product as a free base. This product was dissolved in methanol, and maleic acid was added to the solution, thereby converting it into the title compound.