Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: C1CCNC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-pyrrolidin-1- ylisonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and pyrrolidine using method A. NMR; δH [2H6]—DMSO 10.28,(1H. s), 8.62,(1H, t), 8.19,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.66,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 6.97,(1H, d), 6.86,(1H, s), 3.43,(4H, m), 3.16,(2H, t), 2.20,(3H, s), 1.95,(4H, m), 1.04,(1H, b), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.85 min, M+455.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=1)=[CH:8][CH:7]=2.C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:29][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=1)=[CH:8][CH:7]=2
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCO)cc4c3)nc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCBr)cc4c3)nc2c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[2-(2-hydroxy-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one (6.20 g, 16.9 mmol) in anhydrous DMF (25 mL) was added carbon tetrabromide (6.47 g, 19.5 mmol) and triphenylphosphine (5.11 g, 19.5 mmol). The reaction mixture was stirred at 40° C. for 16 hours. DMF was removed under vacuum and water (150 mL) was added. The separated solid was filtered and mixed with ether (150 mL) and heated for 10 minutes. The solid was filtered and dried under vacuum to give 2-[2-(2-bromo-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 6.1 g (84%).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:10]=[C:11]3[CH:17]=[N:16][N:15]([CH3:18])[C:12]3=[N:13][CH:14]=2)C=CC=CC=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:18][N:15]1[C:12]2=[N:13][CH:14]=[C:9]([NH2:8])[CH:10]=[C:11]2[CH:17]=[N:16]1
Reactant: Cn1ncc2cc(N=C(c3ccccc3)c3ccccc3)cnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2cc(N)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
1-Methyl-1H-pyrazolo[3,4-b]pyridin-5-amine. A degassed mixture of 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (880 mg, 4 mmol), diphenylmethanimine (1.08 g, 6 mmol), tris(dibenzylideneacetone)palladium (0) (734 mg, 0.8 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.24 g, 2 mmol), and sodium tert-butoxide (576 mg, 6 mmol) in toluene (18 mL) was heated at 115° C. under nitrogen overnight. The reaction mixture was purified by column chromatography on silica gel (eluting with 4% ethyl acetate in petroleum ether) to give N-(diphenylmethylene)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (1.2 g, crude). The crude N-(diphenylmethylene)-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine was dissolved in tetrahydrofuran (10 mL), and hydrochloric acid (2 N, 5 mL) was added. The mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH=8 with saturated sodium carbonate solution, and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography on silica gel (eluting with 33% ethyl acetate in petroleum ether) to give 1-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (420 mg, 68.4% yield) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-chloro-phenylboronic acid to give [1-(4-chloro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 39 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (76 mg, 0.14 mmol), 3-tributylstannanyl-pyridine (0.070 mL, 0.21 mmol) and PdCl2(PPh3)2 (20 mg, 0.029 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-95% EtOAc/hexanes+1% AcOH) to give 29 mg of the title compound. MS: (+) m/z 532.30 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([OH:14])=[O:13].[CH3:15]O>>[CH3:15][O:13][C:12]([C@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C@H:6]1[NH2:5])=[O:14]
Reactant: N[C@@H]1CCCC[C@@H]1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (4.73 mL, 64.8 mmol) was slowly added to a chilled (ice-water bath) suspension of (1S,2R)-2-aminocyclohexanecarboxylic acid (16.2 mmol) in anhydrous methanol (200 mL). After complete addition, the cold bath was removed and the resulting mixture warmed to room temperature. After 24 h, the reaction mixture was evaporated to dryness under a stream of dry nitrogen. The crude product, (1S,2R)-2-aminocyclohexanecarboxylic acid methyl ester, was obtained as a white solid and used in the next step without purification or characterization.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3]#[C:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O.Cl>C(Cl)Cl>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3]#[C:4][C:5]([Cl:12])=[O:6]
Reactant: CC(C)(C)C#CC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)C#CC(=O)Cl

Procedure:
466 g of 4,4-dimethyl-2-pentynoic acid was blended with 3.5 liters of methylene chloride and stirred. 483 g of thionyl chloride was added thereto and reacted for 1 hour and then heated under reflux, whereby a hydrogen chloride gas was vigorously generated. After the reaction system was heated under reflux for 2 hours, the solvent was distilled away under reduced pressure. The product was a colorless liquid having a boiling point of about 70° C. at 20 mm Hg. Yield: 290 g, 54.3%.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12].C([O-])(=O)C.[NH4+]>CC(O)C>[C:11]([C:10](=[CH:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:14])[CH3:8])(=[O:13])[CH3:12]
Reactant: O=Cc1ccco1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccco1)C(C)=O
Yield: 61 %

Procedure:
A solution containing 2.9g of furfural, 5.0 g of 2,4-pentanedione and 1 g of ammonium acetate in 25ml of 2-propanol was refluxed for 3 h. The solvent was evaporated in vacuo and the residue was purified by using column chromatography. Yellowish oil, yield 61%.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:15](=[O:31])[C:14]=2[C:32]#[N:33])[CH2:9]1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH:8]1[CH2:11][CH:10]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[C:15](=[O:31])[C:14]=2[C:32]#[N:33])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2c(C#N)c(=O)n(Cc3ccc(F)cc3)c3ccccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(NC2CNC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reaction time: 24 h

Procedure:
To a solution of 3-[3-Cyano-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinolin-4-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.250 g, 0.56 mmole) in 1,4-dioxane (2 mL) was treated with 4N HCl in dioxane (5.0 ml). Reaction stirred for 24 h before concentrating to residue and triturating with diethyl ether to afford 4-(Azetidin-3-ylamino)-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt as a yellow solid (0.194 g, quantitative yield, calc M+H 349, obs M+H 349).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2].B(Br)(Br)Br.O.C(OCC)(=O)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CCC2
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCC1CCCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 52 %

Procedure:
To a solution of 1-[2-(acetylamino)ethyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene (3.14 g, 12.7 mmol) in dichloromethane (70 ml) was added dropwise, under ice-cooling, boron tribromide (6.4 g, 25.4 mmol). The reaction mixture was stirred for 50 minutes at room temperature, which was poured into water. The organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (chloroform:methanol=9:1) to give the above-titled compound (1.54 g, yield 52%), m.p.153-155° C. (recrystallized from ethyl acetate).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[N:24][CH:25]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: Fc1ccc(Br)nc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2ccc(F)cn2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-5-fluoro-pyridine.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Oc1cccc(F)c1-n1cccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc2c1-n1cccc1C1(CCNCC1)O2
Reaction time: 12 h
Yield: 79.3 %

Procedure:
3-Fluoro-2-(1H-pyrrol-1-yl)phenol (2.7 g, 16.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.3 g, 16.6 mmol) were dissolved in dry dichloromethane (53.6 mL). TFA (2.3 mL, 30.3 mmol) was added over 15 min and stirring was continued for 12 hours. Additional TFA (2.3 mL, 30.3 mmol) was added at 25° C. The reaction mixture was concentrated under vacuum and the residue diluted with dichloromethane (350 mL) then washed with 1M NaOH (2×50 ml), dried, filtered and evaporated to dryness. The resulting material was purified by silica gel chromatography eluting with 0.5-40% MeOH in dichloromethane to yield 9-fluorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (3.4 g, 86%). ESI-MS m/z calc. 258.1, found 259.1 (M+1)+; Retention time 0.90 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[N:7][C:6]([C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(C(F)(F)F)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A solution of ethyl 6-(trifluoromethyl)-3-pyridazinecarboxylate (73 mg, 0.332 mmol) in ethanol (1 ml) was treated with 2M sodium hydroxide (2 ml, 4.00 mmol) and stirred overnight at room temperature. The suspension was then acidified by addition of dilute hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a pale solid (60 mg);
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-].[Na+].B(F)(F)F>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CO)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of 2-fluoro-5-methoxy-4-nitrobenzoic acid (Compound 130E, 1.60 g, 7.44 mmol) in THF (23.6 mL) is slowly charged with sodium borohydride (0.633 g, 16.8 mmol) and stirred for 5 minutes. A solution of boron trifluoride, ethyl ether complex (0.895 mL, 7.26 mmol) in THF (7.85 mL) is added to the reaction mixture. The resulting solution is heated at reflux for 4 h. The reaction mixture was cooled to 0° C., then quenched with ice (15 mL) and diluted with ether (25 mL) and 2 N NaOH (10 mL). The ether layer was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an off-white solid, 1.45 g (97% yield). This material was used without any further purification. 1H NMR (CDCl3, 400 MHz): δ=3.99 (s, 3H), 4.86 (s, 2H), 7.29 (d, J=5.81 Hz, 1H), 7.64 (d, J=9.09 Hz, 1H). MS (ES+): m/z 202.05 [MH+] (TOF, polar).
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]\[C:13]2[N:14]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[S:16][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]1[N:36]([CH2:37][C:38]([OH:40])=O)[N:35]=[C:34]([C:41]([F:44])([F:43])[F:42])[CH:33]=1>>[CH3:31][C:32]1[N:36]([CH2:37][C:38]([N:21]2[CH2:22][CH2:23][CH:18]([C:15]3[S:16][CH:17]=[C:13](/[CH:12]=[CH:11]\[C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[N:14]=3)[CH2:19][CH2:20]2)=[O:40])[N:35]=[C:34]([C:41]([F:44])([F:43])[F:42])[CH:33]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(/C=C\c3cccc4ccccc34)cs2)CC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(/C=C\c3cccc4ccccc34)cs2)CC1

Procedure:
tert-Butyl 4-{4-[(Z)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-3, 171 mg) is deprotected analogously to Example II-2 and then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (100 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[(E)-2-(naphthalen-1-yl)ethenyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (200 mg).
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:10][C:9]1[C:8]([O:11][CH3:12])=[CH:7][CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[F:1])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C#N)c(F)c1O
Solvent: c1ccncc1
Product: COc1ccc(C#N)c(F)c1OC(C)=O

Procedure:
0.9 g of 2-fluoro-3-hydroxy-p-anisonitrile are dissolved in 10 ml of acetic anhydride and 0.5 ml of pyridine, whereupon the mixture is stirred at 120° for 2 hours. The reaction mixture is subsequently evaporated and the residue is partitioned between ice-water and methylene chloride. The organic phase is dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride/hexane. There is obtained 3-cyano-2-fluoro-6-methoxyphenyl acetate of m.p. 90°-91°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:10][S:11](O)(=[O:13])=[O:12].S(Cl)(Cl)=O>>[N+:1]([C:4]1[CH:9]=[C:8]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 107.2 %

Procedure:
123.1 g (1.0 mol) of nitrobenzene was added dropwise at 112° C. to 521.0 g (4.4 mol) of chlorosulfonic acid over the course of 4 hours. The mixture was then stirred at this temperature for 4 hours. After it had been cooled to 70° C., 110.0 g (0.92 mol) of thionyl chloride were added dropwise over the course of 2 hours. The reaction mixture was then stirred at this temperature until evolution of gas had ended. It was then cooled and discharged at 5° C. into ice-water. The precipitated 3-nitrobenzenesulfonyl chloride was then filtered off with suction and washed with water and with sodium hydrogen carbonate. 237.5 g of moist 3-nitrobenzenesulfonyl chloride having a purity of 89.9% were obtained in this manner. The dry content was 213.5 g, which corresponds to a yield of 96.3%.
Reaction SMILES: Cl.C([NH:5][C:6]1[C:7](=[O:17])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([NH2:16])=[CH:11][CH:10]=2)(=O)C>C(O)C>[NH2:5][C:6]1[C:7](=[O:17])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([NH2:16])=[CH:11][CH:10]=2
Reactant: CC(=O)Nc1cc2cc(N)ccc2oc1=O
Agent: Cl
Solvent: CCO
Product: Nc1ccc2oc(=O)c(N)cc2c1
Temperature: 4 °C
Yield: 64.3 %

Procedure:
To a solution composed of 12.63 mL of 12 M hydrochloric acid in 6.32 mL ethanol was added 0.919 g (4.2 mmol) of compound 2. The solution was heated to reflux for 30 min and then cooled to 4° C. overnight. The resulting precipitate was removed by filtration and dissolved in a minimal volume of distilled water. The solution was neutralized by addition of 25% ammonium hydroxide and cooled at 4° C. for three hours. The resulting precipitate was removed by filtration and recrystallized from water to give a yellow compound (3) (0.484 g, 2.7 mmol) in 65% yield. mp 183-186° C. (lit: 183-184° C.). FTIR (KBr) (cm−1): 3420, 3340, 1690, 1635. 1H-NMR (DMSO-d6): δ (ppm) 6.95 (d, J=8.5 Hz, 1H), 6.56 (s, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.46 (dd, J=10.0 Hz, J=2.6 Hz, 1H), 5.48 (bs, 2H), 5.00 (bs, 2H). 13C-NMR (DMSO-d6): δ (ppm) 159.95, 146.50, 141.19, 134.13, 123.04, 116.75, 113.70, 109.30, 108.42. HRMS expected: 177.05920; found: 177.05979.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:30])=[C:20]([CH:29]=1)[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22].C(N(CC)CC)C>C(Cl)Cl.C(O)C>[Cl:30][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:29][C:20]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22]
Reactant: CCCCCOC(=O)c1cc(N)ccc1Cl
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)c1cc(NC(=O)C2=C(C)OCCS2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Thionyl chloride (3.9 g, 0.033 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (5.2 g, 0.032 mole) and methylene chloride (100 ml). The mixture was stirred overnight at room temperature, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (100 ml), and the ice-chilled solution treated dropwise with a solution of pentyl 5-amino-2-chlorobenzoate (7.9 g, 0.033 mole) and triethylamine (3.3 g, 0.033 mole) in methylene chloride (100 ml). The reaction mixture was stirred at room temperature for 4 hours, then worked up by washing in sequence with water, dilute hydrochloric acid, water, 2% sodium hydroxide and water. Evaporation of the solvent left an oil, which solidified very slowly. After recrystallization from ethanol (30 ml) the product (5.9 g, 47% yield) melted at 65°-68° C. A second recrystallization raised the melting point to 70°-71° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccccc1C=Cc1ccccn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCc1ccccn1

Procedure:
A solution of 2-(o-nitrostyryl)pyridine (94.3 g., 0.42 mole) in 400 ml. of ethanol is reduced on a Parr hydrogenation apparatus employing 2 mg. of 10% palladium on carbon catalyst to provide 2-(o-aminophenethyl)pyridine, m.p. 59°-61° C. The isolation of the pyridine product is carried out in the usual manner by collecting the catalyst and evaporating the ethanolic solvent.