Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:45]2[N:50]=[CH:49][CH:48]=[CH:47][N:46]=2)=[C:40]([CH:44]=1)[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:45]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)=[C:40]([C:41]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:7]3)[CH2:2]2)=[O:42])[CH:44]=1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1cc(F)ccc1-c1ncccn1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-pyrimidin-2-yl-benzoic acid for 2-thiophen-2-yl-benzoic acid Additionally, the reaction time was shortened to 30 minutes. MS (ESI) mass calcd. for C25H21FN6O, 440.48; m/z found 441.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][Na].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9]>CO>[F:4][C:5]1[CH:6]=[C:7]([C:8](=[NH:9])[O:2][CH3:1])[CH:10]=[CH:11][CH:12]=1
Reactant: CO[Na]
Reactant: N#Cc1cccc(F)c1
Solvent: CO
Product: COC(=N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 1000.1 %

Procedure:
MeONa (2.35 g, 41 mmol) was added to a stirred solution of 3-fluorobenzonitrile (50.0 g, 413 mmol) in methanol (300 mL). The mixture was stirred at room temperature for 3 days and concentrated in vacuo. The residue was dissolved in ether (300 mL), washed with water (2×150 mL), brine (150 mL), dried with Na2SO4, and concentrated in vacuo to afford 62.8 g (99%) of methyl 3-fluorobenzenecarboximidoate. Methylhydrazine (21.8 mL, 410n mmol) was added to a stirred solution of methyl 3-fluorobenzenecarboximidoate (62.8 g, 410 mmol) in THF (350 mL). The mixture was stirred at room temperature for 3 days, then. Then methyl 2,2-diethoxyethanimidoate (66.1 g, 410 mmol) and acetic acid (37.5 mL, 656 mmol) were added. The mixture was stirred for 24 h. The reaction was diluted with CH2Cl2 (500 mL), and the formed precipitate was filtered off. The filtrate was washed with 10% citric acid (2×200 mL), water (300 mL), brine (200 mL), dried with Na2SO4, and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel using 1% MeOH/CHCl3 as eluent to give 24.0 g (21%) of the title product.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[O:9]([C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH:22]=O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C(O)C>[O:9]([C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH:22]=[N:2][OH:3])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NO
Reactant: O=CCOc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=CCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 25 g of hydroxylamine hydrochloride and 29.4 g of anhydrous sodium acetate in 100 ml of water is added dropwise at room temperature to a solution of 68.5 g of 4-phenoxyphenoxyacetaldehyde in 300 ml ethanol. After the slightly exothermic reaction has subsided, the mixture is stirred for 2 hours at reflux temperature. The mixture is then cooled to 0° C. and stirred for 3 hours at this temperature, whereupon the resultant oxime crystallises. The crystallised 4-phenoxyphenoxyacetaldehyde oxime is isolated by suction filtration, repeatedly washed thoroughly with water and dried in a vacuum cabinet at 40° C. Melting point: 102°-105° C.
Reaction SMILES: C1(S([N:10]2[CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=[C:11]2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31](S(C3C=CC=CC=3)(=O)=O)[CH:30]=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([C:11]2[NH:10][CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=2)=[CH:30]1
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)n2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)c2c[nH]c(-c3c[nH]c4ccccc34)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa) (1 mmol) in ethanol (40 mL) and water (4 mL) was added sodium hydroxide (10 equiv, 10 mmol) and stirred overnight under refluxing condition in darkness. The reaction mixture was diluted by 50 mL of water and extracted by ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 1:1) to give a yellow solid. Yield: 60%. 1H NMR (500 MHz, CD3OD) δ 8.31 (d, J=6.5 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48-7.52 (m, 3H), 7.24-7.28 (m, 2H), 4.00 (s, 6H), 3.93 (s, 3H). MS (ESI) calcd for C21H19N3O4 377.1. found 400.1 [M+Na]+. Mp 208-210° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])[CH3:2].Cl.[F:24][C:25]([F:37])([F:36])[C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][NH:31][CH2:32]2)=[O:27].N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:31]3[CH2:32][CH:33]4[N:28]([C:26](=[O:27])[C:25]([F:36])([F:37])[F:24])[CH:29]([CH2:35][CH2:34]4)[CH2:30]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(N1C2CCC1CNC2)C(F)(F)F
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CC4CCC(C3)N4C(=O)C(F)(F)F)c(F)cc2c1=O
Temperature: 60 °C
Yield: 22.1 %

Procedure:
A mixture of 653 mg (2 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-7-chloro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and 732 mg (3 mmoles) 8-trifluoroacetyl-3,8-diazabicyclo[3.2.1]octan,hydrochloride and 985 mg (6.48 mmoles) 1,8-diazabicyclo[5.4.0] undec-7-ene in 30 mL acetonitrile was heated at 60° C. for 72 hours. The solution was cooled and evaporated to dryness. The residue was worked up with dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated to give an oil. Purification was achieved by silicagel column chromatography to obtain 220 mg of 7-(8-trifluoroacetyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester. MP 205° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:9][C:10]([Si:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:12])[CH3:11]>O>[Si:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:10]([CH3:12])([CH3:11])[CH3:9])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-butanediol was added sodium hydride (1.0 g of a 60% dispersion in mineral oil). This mixture was allowed to stir at an ambient temperature for 1 h, before TBDPSCl (5.0 mL, 18.2 mmol) was added. The mixture was stirred overnight at an ambient temperature. The reaction mixture was poured into water and extracted with ether (3×100 mL). The combined extract was washed with water and brine and dried over sodium sulfate. Filtration and concentration gave an oily residue, which was purified via radial chromatography on a 4 mm plate eluting with 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexane. This gave 3.36 g (56%) of desired product as clear oil. 1H NMR (CDCl3); δ1.24 (s, 9H), 1.65 (m, 4 h), 3.65 (m, 4H), 7.40 (m, 6H), 7.64 (d, 2H, J=1.5 Hz).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1C=CCCCCCCCCCCO
Reactant: CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOCCCCCCCCCCC=CN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
0.14 mole of butyl bromide and 0.14 mole of N-hydroxy dodecenylsuccinimide are dissolved in 100 milliliters of dimethylformamide. 50 milliliters of triethylamine are added and the mixture is stirred overnight at room temperature. The solvent is then removed under vacuum and the reaction product is water washed until salt free and then dried. A yield of 85% of N-butoxy dodecenylsuccinimide is recovered.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:20][OH:21]>C(O)C.[Cl-].[Na+].O>[OH:21][N:20]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:14][CH2:15][CH2:16][O:17]2)=[O:8])=[CH:18][CH:19]=1)[NH2:2]
Reactant: N#Cc1ccc(C(=O)OCCCC2OCCO2)cc1
Reactant: NO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(C(=O)OCCCC2OCCO2)cc1
Temperature: 80 °C

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)propyl 4-cyanobenzoate (1.00 g, 4.38 mmol) in ethanol (5 mL), was added hydroxylamine (50% aqueous solution, 5 mL), and the mixture heated at 80° C. for 4 hours. The reaction was diluted with saturated brine and extracted with ethyl acetate (×3). The combined organic fractions were dried with magnesium sulphate, and the solvent evaporated at reduced pressure. The material was used directly in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16](=[O:29])[C:17]3[C:22]([N:23]4[N:27]=[CH:26][CH:25]=[N:24]4)=[CH:21][CH:20]=[CH:19][C:18]=3[F:28])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)[C:17]=1[C:16]([N:12]1[CH2:13][CH:14]2[CH:10]([CH2:9][NH:8][CH2:15]2)[CH2:11]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3c(F)cccc3-n3nccn3)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(2-Fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (1.3 g, 3.21 mmol) was taken up in DCM (6.0 mL) and TFA (3.0 mL) was added. The mixture was allowed to stir at rt for 1 hr. Solvent was removed and then taken back up in DCM and basified with 1N aq. NaOH. The layers were separated. The aqueous was extracted 2 more time with DCM (and a small amount of MeOH). The organics were combined, dried (Na2SO4), filtered, and concentrated to provide the desired free base product, (2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone, as a viscous/foamy residue that was found to be very hydroscopic (950.6 mg, 93.3%). MS (ESI): mass calculated for C15H16FN5O, 301.32, m/z found 302.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.90-7.73 (m, 3H), 7.54-7.42 (m, 1H), 7.19-7.10 (m, 1H), 3.85-2.65 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1.BrC1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:13])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nccs2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
160 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 60 mg of 2-aminothiazole were added to 1.5 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, hexane was added to this and the resultant mixture was allowed to stand still. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 136 mg of 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-N-(2-thiazolyl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 30) represented by the formula:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:12](S(C)(=O)=O)=[CH:11][N:10]=1.[CH3:29][O-:30].[Na+].CO>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:12]([O:30][CH3:29])=[CH:11][N:10]=1
Reactant: CS(=O)(=O)c1cnc(-c2ccc(F)cc2F)nc1-c1cccc(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1cnc(-c2ccc(F)cc2F)nc1-c1cccc(C(F)(F)F)c1
Yield: 83.5 %

Procedure:
2.1 g of 2-(2,4-difluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine, 0.3 g of sodium methoxide and 20 ml of methanol were added to 120 ml of ethylene glycol dimethyl ether and the resulting mixture was heated under reflux for 5 hours. The solvent was distilled away under reduced pressure. The residue was washed with water and then dried to obtain 1.55 g of 2-(2,4-difluorophenyl)-4-(3-trifluoromethylphenyl)-5-methoxypyrimidine (Compound 77).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:11]1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccccn2)=CC1=O
Temperature: 80 °C
Yield: 59.4 %

Procedure:
To a solution of 2-pyridinecarboxaldehyde (1.26 g, 10.2 mM) and 2,5-dimethyl-2-(4-fluorophenyl)-3(2H)-furanone (2.0 g, 9.8 mM) in ethanol (100 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.2 mL, 1.3 mM). The reaction solution was heated at 80° C. for 4 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to yield a yellow solid (1.7 g, 59% yield), m.p. 70°-72° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]Cl.[Na].[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20]
Reactant: [O-][n+]1ccccc1S
Reactant: ClCc1c(Cl)ccc(Cl)c1Cl
Agent: [Na]
Product: [O-][n+]1ccccc1SCc1c(Cl)ccc(Cl)c1Cl

Procedure:
The compound 2-(2,3,6-trichlorophenylmethylthio)-pyridine N-oxide is prepared from 2,3,6-trichlorobenzylchloride and 2-mercaptopyridine N-oxide sodium salt by the procedure employed in Example 1. Melting point 232° - 234°C. Yield quantative. Structure confirmed by IR and NMR.
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:29])[CH3:28]
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 18 h
Yield: 86 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (0.4 g, 1.5 mmoles) was dissolved in methylene chloride (10 ml) and pyridine (0.4 ml) and acetic anhydride (0.2 ml) were added to the solution. The mixture was allowed to stand at room temperature for 18 hours and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as the developing solvent to give 1-acetoxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (0.4 g, 86%) (Compound I-19) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C1C=CC=CC=1>CO>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: O=C(c1ccc(F)cc1)N1CC1
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNC(=O)c2ccc(F)cc2)C[C@H]1OC

Procedure:
A mixture of 11 parts of 1-(4-fluorobenzoyl)aziridine, 6.28 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 45 parts of benzene and 20 parts of methanol was stirred and refluxed for 6 hours. The reaction mixture was evaporated and the residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 5.09 parts of cis-4-amino-5-chloro-N-[1-[2-[(4-fluorobenzoyl)amino]ethyl]-3-methoxy-4-piperidinyl]-2-methyoxybenzamide; mp. 208.7° C. (compound 131).
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[C:1]1([C:7]2([C:13]([Cl:19])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccccc2)CCCCC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a solution of 1-phenylcyclohexanecarboxylic acid (E7) (0.095 g, 0.46 mmol) in dry dichloromethane (3 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.468 g, 3.68 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at room temperature for 15 minutes and at 40° C. for one hour, then concentrated under reduced pressure to give crude title compound (0.105 g, ca. 100%). The crude product was immediately utilized in the next step of the synthesis without further purification.
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.Cl.CON.N1C=CC=CC=1>C(O)C>[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1
Reactant: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(F)cn4)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(F)cn4)c3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 65 °C
Yield: 83.7 %

Procedure:
A mixture of N-[3-[(4aR,7aS)-2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-fluoro-pyridine-2-carboxamide (320 mg, 560 μmol), O-methylhydroxylamine hydrochloride (485 mg, 5.60 mmol) and pyridine (453 μL, 5.60 mmol) in ethanol (15 mL) is heated at 65° C. in a capped vial for five hours. The reaction is cooled and the solvent removed in vacuo. The crude product is purified over silica gel with a 30 minute 0.5% to 10% gradient of 7 N ammonia in methanol dichloromethane gradient to give N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-fluoro-pyridine-2-carboxamide (219 mg, 84%). This material is dissolved in dichloromethane (1 mL) and methanol (0.5 mL) and 1 M hydrogen chloride in diethyl ether (0.47 mL, 470 μmol) is added. The solvent is removed in vacuo to give the title compound (228 mg, 81%). ES/MS (m/e): 468 (M+H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])=[CH:5][CH:4]=1.[NH:20]([C:22]([C:24]1[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:25]=1)=[O:23])[NH2:21].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:21][NH:20][C:22]([C:24]3[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:25]=3)=[O:23])[CH3:17])[C:13]=2[OH:14])=[CH:5][CH:4]=1
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(F)(F)F)cc3)c2O)s1
Yield: 72.6 %

Procedure:
From 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonylthiophene (57.3 mg, 0.2 mmol), methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (40.0 mg, 0.2 mmol) and tosylic acid monohydrate (11.4 mg, 0.06 mmol), 68.0 mg of the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (yield 73%).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]([N+:33]([O-:35])=[O:34])=[CH:26][CH:25]=1.[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[C:49]([C:50]2[NH:51][CH:52]=[CH:53][N:54]=2)=[CH:48][N:47]=[C:46]([NH:55][CH2:56][CH2:57][NH:58]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:45]=1>>[Cl:36][C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[C:44]1[C:49]([C:50]2[NH:54][CH:53]=[CH:52][N:51]=2)=[CH:48][N:47]=[C:46]([NH:55][CH2:56][CH2:57][NH:58][C:24]2[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]([N+:33]([O-:35])=[O:34])=[CH:26][CH:25]=2)[N:45]=1
Reactant: CN(C)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(C)c1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-3-nitro(2-pyridyl)}dimethylamine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-dimethylamino-3-nitro pyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.