Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[N:5][N:4]=[N:3]1.OS([O-])(=O)=O.[K+]>>[C:16]1([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1nnnc1CC(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: Cn1nnnc1C=C(c1ccccc1)c1ccccc1
Temperature: 200 °C
Yield: 84.4 %

Procedure:
A mixture of 2(1-methyltetrazol-5-yl)-1,1-diphenylethanol (2.15 g; 7.68 mmole) and KHSO4 (300 mg) was heated at 200° C. for 20 minutes. The cooled mixture (50° C.) was triturated with CHCl3 (50 mL) and the organic solvent was decanted from the inorganic residue. Evaporation afforded the title compound as a cream solid (1.7 g; 85%); m.p.=147°-148° C. (crystallized from EtOAc-hexane). MS (CI): m/e=263 for (M+H)+ ;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=2[CH:36]([CH3:38])[CH3:37])=[O:25])[C:6]1=[O:39].[C:40](OC(=O)C)(=[O:42])[CH3:41]>N1C=CC=CC=1>[C:40]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=2[CH:36]([CH3:38])[CH3:37])=[O:25])[C:6]1=[O:39])(=[O:42])[CH3:41]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCN)c3ncccc23)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCNC(C)=O)c3ncccc23)c1
Reaction time: 0.67 h

Procedure:
N-[1-(3-Aminopropyl)-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (50 mg, 0.1 mmol) was dissolved in pyridine (1 ml), and thereto was added acetic anhydride (0.5 ml). The mixture was stirred for 40 minutes, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the title compound (49 mg, 0.09 mmol).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[NH:23][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:24]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1ccccc1N
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccccc4[nH]3)cc2)S1

Procedure:
2-[4-[(2,4-Dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:44][C:45]([F:50])([F:49])[C@@H:46]([NH2:48])[CH3:47].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:48][C@@H:46]([CH3:47])[C:45]([F:50])([F:49])[F:44])=[O:19])=[N:15][CH:16]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cnc(Cl)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
N,N-Diisopropylethylamine (1.3 mL, 7.5 mmol) was added to a mixture of 5-chloropyrazine-2-carboxylic acid (0.40 g, 2.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.0 g, 2.8 mmol) and (2S)-1,1,1-trifluoropropan-2-amine (0.28 g, 2.5 mmol) (Oakwood: Cat. #44272) in methylene chloride (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-15%) to afford the desired product (0.64 g, 73%). LCMS (M+H)+: m/z=253.9/255.9.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O1CCCC1.[Si:28]([O:35][CH:36]([C:38]1[CH:39]=[CH:40][C:41]([CH:44]=[O:45])=[N:42][CH:43]=1)[CH3:37])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Si:28]([O:35][CH:36]([C:38]1[CH:39]=[CH:40][C:41]([C:44](=[O:45])[CH2:10][CH2:9][C:8](=[O:11])[CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:42][CH:43]=1)[CH3:37])([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ccc(C=O)nc1
Reactant: C=CC(=O)C(CC1CCCC1)c1ccc(SC)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2ccc(C(C)O[Si](C)(C)C(C)(C)C)cn2)nc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of 5-cyclopentyl-4-[5-(methylsulfanyl)pyridin-2-yl]pent-1-en-3-one (455 mg) in a mixed solvent of ethanol (8 mL) and tetrahydrofuran (8 mL) were added 5-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridine-2-carbaldehyde (878% mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (44.5 mg) and triethylamine (92.0 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (848 mg, yield 95%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-benzyloxy-5-((S)-2-methoxy-1-methylethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:20])(=[O:19])[NH:4][CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O>CC(C)=O.O>[CH3:18][C:15]([NH:14][S:11]([C:9]1[S:10][C:6]2[S:5](=[O:20])(=[O:19])[NH:4][CH2:3][C:2](=[O:1])[C:7]=2[CH:8]=1)(=[O:13])=[O:12])([CH3:16])[CH3:17]
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 3,4-dihydro-4-hydroxy-N-(1,1-dimethylethyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide (3.36 g, 9.87 mmol) in acetone (15 mL) at room temperature was added Jones reagent [2 mL (prepared by dissolving CrO3 (7 g) in H2O (50 mL) and adding H2SO4 (6.1 mL)]. The mixture was stirred at room temperature for one hour, solvent was evaporated and the residue dissolved in ethyl acetate (75 mL). This solution was washed with saturated aqueous sodium bicarbonate until the the organic layer was neutral. The aqueous layer was separated and washed with ethyl acetate (3'25 mL). The combined extracts were dried (NaSO4) and evaporated to provide a residue which was purified by column chromatography (silica, 40% ethyl acetate in hexane) to give an off-white solid (2.74 g, 82%): mp 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N+:23]#[C-:24])=[CH:18][C:17]=1[CH3:25]>C1(C)C=CC=CC=1.[Cu-]=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:9][C:8]([C:6]3[CH:5]=[C:4]([Cl:14])[CH:3]=[C:2]([Cl:1])[CH:7]=3)([C:10]([F:11])([F:13])[F:12])[CH:24]=[N:23]2)=[CH:18][C:17]=1[CH3:25]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: [C-]#[N+]Cc1ccc(Br)c(C)c1
Agent: O=[Cu-]
Solvent: Cc1ccccc1
Product: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)ccc1Br
Temperature: 110 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
A mixture of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation described in, for example, EP 1,731,512) (8.03 g), 1-bromo-4-isocyanomethyl-2-methyl-benzene (Example 10.3) (4.16 g) and copper(I) oxide (0.13 g) in toluene (50 ml) was stirred at 110° C. for 16 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptane) to give 2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrole (2.39 g). 1H-NMR (400 MHz, CDCl3): 7.39-6.86 (m, 7H), 5.39-4.98 (m, 1H), 3.24-2.77 (m, 1H), 2.35 (m, 3H), 2.32-2.09 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[C:24]([F:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)[C:9]2[C:10]([C:16](O)=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:15])[C:13]=3[CH3:14])[C:16](=[O:17])[N:19]2[C:20]2[CH:25]=[C:24]([F:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(Nc2cc(F)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)nn1C
Solvent: ClCCl
Solvent: CO
Product: Cc1c2c(nn1C)C(=O)N(c1cc(F)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(5-fluoro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (Step 31.2). tR: 3.64 min (HPLC 1); tR: 0.80 min (LC-MS 2); ESI-MS: 387 [M+H]+ (LC-MS 2); Rf=0.51 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 (s, 3H) 3.43 (s, 3H) 3.83 (s, 3H) 6.13 (s, 1H) 7.23-7.29 (m, 2H) 7.33-7.40 (m, 2H) 7.57-7.67 (m, 1H) 7.79 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([CH:24]=[C:25]([C:27](OCC)=[O:28])[N:26]=2)[CH:12]=[C:13]([C:15]2[S:19][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:17][CH:16]=2)[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([CH:24]=[C:25]([CH2:27][OH:28])[N:26]=2)[CH:12]=[C:13]([C:15]2[S:19][C:18]([CH2:20][CH:21]([CH3:22])[CH3:23])=[N:17][CH:16]=2)[CH:14]=1
Reactant: CCOC(=O)c1cn2cc(-c3cnc(CC(C)C)s3)cc(-c3ccc(F)cc3F)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1ncc(-c2cc(-c3ccc(F)cc3F)c3nc(CO)cn3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a solution of ethyl 8-(2,4-difluorophenyl)-6-(2-isobutylthiazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylate (47.2 mg, 0.107 mmol) in THF (2 mL) was added lithium aluminum hydride powder (12.2 mg, 0.321 mmol). The mixture was stirred at room temperature overnight, then added 1N NaOH (12 mL) and water (3 mL), extracted with dichloromethane, concentrated. The residue was subjected to flash column chromatography using 80% ethyl acetate and hexane to give a white solid (3.9 mg, 9% yield). LCMS (Conditions C): Tr 2.83 min; (M+H)+=400.25 (100%), 401.36 (20%), 402.36 (10%). 1H NMR, 400 MHz, CDCl3: 8.22 (d, J=1.5 Hz, 1H), 7.81 (m, 1H), 7.76 (s, 1H), 7.58 (s, 1H), 7.39 (s, 1H), 7.00-6.88 (m, 2H), 4.78 (s, 2H), 2.84 (d, J=7.1 Hz, 2H), 2.08 (m, 1H), 0.97 (d, J=6.6 Hz, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:23]=O>CO>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CO
Product: C[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
Borane-pyridine complex (130 μL, 1.24 mmol) was added to a methanol solution (4 mL) of an amine (3) (107 mg, 0.41 mmol), 3,5-bis(trifluoromethyl)benzaldehyde (90 μL, 0.54 mmol) at 40° C. and the mixture was stirred for 1.5 hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol=10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (5) as a white solid (132 mg, yield: 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[CH:28][C:11]([C:12]([NH:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH:16]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:30]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:12](=[O:13])[C:11]2[CH:28]=[CH:29][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)[CH:16]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:17]1)(=[O:32])[CH3:31]
Reactant: O=C(NC1CCNCC1c1ccc(F)cc1)c1ccc(-c2cccc(F)c2)nc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(NC(=O)c2ccc(-c3cccc(F)c3)nc2)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of 6-(3-fluorophenyl)-N-[3-(4-fluorophenyl)piperidin-4-yl]nicotinamide (250 mg, 0.64 mmol) in DCM (5 mL) at 0° C. was added TEA (0.11 mL, 0.76 mmol ), DMAP (7.76 mg, 0.064 mmol ) and acetic anhydride (97.3 mg, 0.95 mmol ). After stirring at rt for 1 hr the reaction was diluted with water and then extracted with dcm. The organic extracts were combined, dried (Na2SO4) and solvent removed to give an oil, which after chromatography gave the desired product, N-[1-acetyl-3-(4-fluorophenyl)piperidin-4-yl]-6-(3-fluorophenyl)nicotinamide (235 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6) □ ppm 8.76-8.89 (1 H, m), 8.27-8.51 (1H, m), 8.03-8.17 (2H, m), 7.87-8.02 (2H, m), 7.50-7.62 (1H, m), 7.22-7.46 (3 H, m), 7.03-7.17 (2H, m), 4.33-4.62 (1H, m), 3.89-4.12 (1H, m), 3.54-3.86 (2H, m), 3.34-3.44 (1 H, m), 2.63-2.92 (1H, m), 2.05-2.14 (3H, m), 1.94-2.04 (1H, m), 1.71-1.92 (1H, m). LC/MS (M+H)=436.0 observed, 436.18 expected.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([F:48])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>CO>[F:48][C:43]1[CH:42]=[C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH:46]=[CH:45][C:44]=1[CH3:47]
Reactant: Cc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1F
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(CCc2cc(O)c(=O)[nH]n2)cc1F

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3-fluoro-4-methylphenyl)ethynyl]pyridazine (Intermediate 28) except that the solvent mixture used for the hydrogenation was ethyl acetate and methanol (1:1) and the final product was recrystallised from ethyl acetate.
Reaction SMILES: C(N(CC)C(C1C=CC=CC=1S([C:14]1[C@H:15]([CH3:38])[C@@H:16]2[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([NH:55][C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=3)=[O:57])[CH2:51]2)=[O:49])[CH2:43]1>>[N+:66]([C:63]1[CH:62]=[CH:61][C:60]([CH2:59][O:58][C:56]([NH:55][C@H:52]2[CH2:53][CH2:54][N:50]([C:48]([C@H:44]3[N:45]([CH3:47])[CH2:46][C@@H:42]([S:41][C:14]4[C@H:15]([CH3:38])[C@@H:16]5[C@@H:33]([C@H:34]([OH:36])[CH3:35])[C:32](=[O:37])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=4)=[O:20])[CH2:43]3)=[O:49])[CH2:51]2)=[O:57])=[CH:65][CH:64]=1)([O-:68])=[O:67]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 60 %

Procedure:
Following a procedure similar to that described in Example 27(b), but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate [prepared as described in Example 27(a) ] and (2S,4S)-4-mercapto-2-[3(S)-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-methylpyrrolidine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a powder in a yield of 60%.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[CH:12]([C:18]([CH3:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([C:12]1[O:9][C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[N:10][C:18]=1[CH3:20])=[O:14])[CH3:17]
Reactant: CC1(C(N)=O)CCCCC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc(C2(C)CCCCC2)nc1C
Temperature: 50 °C

Procedure:
25.0 g 1-Methyl-cyclohexanecarboxylic acid amide was suspended in 40 ml ethanol and warmed to 50° C. At this temperature 29.0 ml Ethyl 2-chloroacetoacetate were added and the reaction mixture heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by chromatography with the eluent petroleum ether:ethyl acetate=4:1 to obtain 21.0 g 4-Methyl-2-(1-methyl-cyclohexyl)-oxazole-5-carboxylic acid ethyl ester as an oil which solidifies upon standing.
Reaction SMILES: B.[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]#[N:6].O>O1CCCC1.CCOCC>[F:14][C:13]([F:15])([F:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:3]([NH2:2])[CH2:4][CH2:5][NH2:6]
Reactant: N#CC=C(N)c1ccccc1C(F)(F)F
Agent: B
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NCCC(N)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
Sixty (60) ml of 1 molar borane in tetrahydrofuran is added to a solution of 7.6 g of β-amino-2-trifluoromethylcinnamonitrile (prepared according to Preparation D, Part 1) in 100 ml of ether. The mixture is stirred at room temperature overnight, then treated with 10 ml of water, and stirred for 45 minutes. The resulting mixture is concentrated under reduced pressure and 200 ml of isopropanol and 80 ml of 20% hydrochloric acid are added thereto. This mixture is refluxed for 2 hours, then concentrated to a small volume. The residue is made alkaline by addition of excess of 20% sodium hydroxide and is extracted 3 times with methylene chloride. The extracts are combined, concentrated and distilled to give 1.7 g of 1-(2-trifluoromethylphenyl)-1,3-propanediamine, bp 73°-77° C./0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C>O1CCCC1>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-Fluoroaniline (7 ml) and acryloyl chloride (7.2 ml) were dissolved in tetrahydrofuran (100 ml), then triethylamine (15 ml) was added thereto, and the mixture was stirred overnight at room temperature. The organic layer was partitioned by adding aqueous saturated sodium bicarbonate and ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate anhydrous, and after the drying agent was filtered off, the filtrate was evaporated, whereby the title compound (12.2g, 100%) was obtained as pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[C:5]([C:13]#[C:14][Si](C)(C)C)=[N:6][C:7]=1[C:8](OCC)=[O:9].C[O-].[Na+].[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>C(=O)(O)[O-].[Na+]>[C:13]([C:5]1[C:4]2[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:9])[N:6]=1)#[CH:14]
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2c(-c3ccccc3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3ccccc3)c12
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Ethyl 7-hydroxy-3-phenyl-4-((trimethylsilyl)ethynyl)isoxazolo[4,5-c]pyridine-6-carboxylate (200 mg, 0.53 mmol) was added to sodium methoxide solution (39.5 mL, 19.7 mmol, 0.5 M in MeOH) and the mixture was refluxed for 30 min. After the mixture was cooled to room temperature, glycine (1.98 g, 26.3 mmol) was added, and the mixture was refluxed for 48 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in 100 mL of water and hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 170 mg of crude solid. The solid was dissolved in 100 mL of saturated sodium bicarbonate solution and washed with EtOAc. The aqueous layer was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The solvent was concentrated in vacuo to give 116 mg of the title compound. MS: (−) m/z 336.28 (M−1).