Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][CH2:8][C:7](=O)[CH2:6]2.[CH2:14]([NH:17][CH2:18][CH2:19][C:20](OC)=[O:21])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[S:9][CH2:8][C:7]3[N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20](=[O:21])[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CS2
Reactant: CCCNCCC(=O)OC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCN1CCC(=O)C2=C1CSc1ccc(OC)cc12

Procedure:
The starting material is prepared as follows: A mixture of 7.5 g 6-methoxythiochroman-3-one [J. Org. Chem. 34, 1566 (1969)], 5.8 g of methyl 3-(propylamino)-propionate and 0.8 ml of trifluoroacetic acid in 80 ml of toluene is heated under reflux for 22 hours in a Dean Stark apparatus. Additional 0.8 ml portions of trifluoroacetic acid are added after 2, 5, and 16 hours. The solvent is removed, the residue is taken up in ether and the product is extracted with 3N hydrochlorid acid. After neutralization the aqueous layers are extracted with ethyl acetate, the organic layer is dried and the solvent is removed. The product is crystallized from a small volume of methanol to afford 9-methoxy-4-propyl-1,2,3,5-tetrahydro-4H-[1]-benzothiopyrano[3,4-b]pyridin-1-one, m.p. 108°-110°.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14].[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][C@H:28]([NH2:30])[CH3:29].C(N(CC)CC)C>C(O)C>[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][C@H:28]([NH:30][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14])[CH3:29]
Reactant: C[C@@H](N)Cc1sccc1Cl
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H](C)Cc3sccc3Cl)ncnc21

Procedure:
A solution of 6-chloro-9-(2'-O-methyl-β-D-ribofuranosyl)-9H-purine (prepared as in EP Publication No. 0378518) (0.28 g), 2-(3-chloro-2-thienyl)-(1R)-1-methylethylamine (0.163 g), and triethylamine (0.5 ml) in ethanol (30 ml) is refluxed for about 18 hours, cooled and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 10% methanol in methylene chloride, followed by crystallization from hexane/ethyl acetate, to give the desired product, m.p. 75°-76° C.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[NH:12][C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:25]=3[CH3:34])[C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: CC(C)c1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(C(C)C)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.8 %

Procedure:
To a 100 mL round bottomed flask containing DMF (50 mL) was added 4-bromo-2-isopropyl-6-nitro-1H-benzo[d]imidazole (4.1 g, 14.43 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (3.6 mL, 21.34 mmol) and potassium carbonate (5.98 g, 43.3 mmol). The resultant suspension was heated to 50° C. and after stirring for 30 minutes the mixture was allowed to cool to rt and diluted with 100 mL H2O. The mixture was stirred overnight and the next day a black filterable solid was isolated by filtration providing crude 4-bromo-2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (7.1 g, 15.56 mmol, 108% yield). MS (ES+) m/e: 455.1, 455.9 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:30])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15](Cl)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>>[NH2:1][C:2]1[C:3](=[O:30])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][N:34]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2[nH]c1=O
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc(Oc2cccc3[nH]c(=O)c(N)nc23)cc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
The reaction of 3-amino-5-(2-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (433 mg, 1.0 mmol, Example 106(a)) with tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (428 mg, 2 mmol, Fluorochem) under the conditions of Example 34 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 612 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C-:16]#[N:17].[Na+]>O>[C:16]([CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)#[N:17]
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(CC#N)C2
Temperature: 80 °C
Yield: 102.4 %

Procedure:
2-Bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (6.5 g, 18.6 mmol) was dissolved in dimethylsufoxide (30 ml). Sodium cyanide (1.43 g, 88 mmol ) was added and the resulting mixture was stirred at 80° C. for hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 2:.i). The crude crystals obtained were recrystallized from methanol to obtain the desired compound (4.1 g, yield: 79.7%), m.p. 58°-59° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:11]([O:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC=CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2CC1
Temperature: 25 °C

Procedure:
According to scheme 10, to a stirred solution of 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester (XXX) in dichloromethane was added at −60° C. m-chloroperbenzoic acid (MCPBA). The mixture was allowed to slowly warm to room temperature overnight and 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester (XXXI) was obtained. To a solution of 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in ethanol was added water, ammonium chloride and sodium azide. The mixture was stirred at 75° C. over night, to give 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXII). 4-Azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester in methanol was hydrogenated in the presence of palladium on charcoal (10%) to yield 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXIII). 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1,1′-carbonyl-diimidazole in dimethylformamide are stirred at room temperature for about 16 hours. 4-Amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester was added and stirring was continued for 16 hours at room temperature. It was obtained 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester (XXXIV). To a solution of 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester in dimethylsulfoxide was added triethylamine, dichloromethane and a solution of sulfur trioxide pyridine complex in dimethylsulfoxide. The mixture was stirred for 18 hours at room temperature. After purification 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester (VIII) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Nc1nc(Cl)c([N+](=O)[O-])cc1C(=O)O

Procedure:
2-Amino-6-chloronicotinic acid (0.479 g) [Helvetica Chimica Acta (1976), 59(1), 222-9] was dissolved in concentrated sulfuric acid (5 mL) and cooled in an ice-saltwater bath and 2.5 mL of fuming nitric acid was then added dropwise with stirring. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 8 hours. The mixture was then added dropwise to a saturated sodium bicarbonate solution (200 mL). The mixture was acidified with 9M aqueous sulfuric acid to pH 2. The solid that formed was filtered and rinsed with water to obtain the title compound (0.340 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([OH:23])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]1[CH:45]=[C:44]([CH3:46])[O:43][N:42]=1>>[CH3:46][C:44]1[O:43][N:42]=[C:41]([CH2:40][O:22][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:31][CH:32]=4)(=[O:25])=[O:26])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:23])[CH:45]=1
Reactant: O=C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: Cc1cc(CCl)no1
Product: Cc1cc(COC(=O)[C@]23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(S(=O)(=O)c2ccc(N4CCOCC4)nc2)C3)no1

Procedure:
The title compound was prepared by the method of Preparation 54b using (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid and 3-chloromethyl-5-methyl isoxazole. LCMS (Method F): 635 (M+H)+, Retention time 4.90 minutes.
Reaction SMILES: N1(C[N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)CCCC1.C([Li])CCC.[CH3:17][C:18]([C:21]1[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:23]([C:32](N(OC)C)=[O:33])[N:22]=1)([CH3:20])[CH3:19]>O1CCCC1.C1CCCCC1>[CH3:20][C:18]([C:21]1[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:23]([C:32]([C:11]2[CH:10]=[CH:9][NH:8][N:7]=2)=[O:33])[N:22]=1)([CH3:17])[CH3:19]
Reactant: c1cnn(CN2CCCC2)c1
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)c1nc(C(=O)c2cc[nH]n2)nc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1-(1-pyrrolidinomethyl)pyrazole (0.64 g, 4.2 mmol) (See Katritzky, A. R.; Rewcastle, G. W.; Fan, W-Q; J. Org. Chem 1988, 53, 5688) in tetrahydrofuran (10 mL) at -78° C. under nitrogen atmosphere is added a 2.1M solution of n-butyllithium (2.0 mL, 4.20 mmol) in cyclohexane. The resulting mixture is stirred 1 hour at -78° C. and warmed to ~0° C. After stirring 0.5 hours at 0° C., this mixture is cannula transferred to a solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide in tetrahydrofuran (10 mL) at ~0° C. This reaction mixture is warmed to room temperature and stirred 16 hours. After quenching with aqueous saturated ammonium chloride solution, the mixture is extracted with ethyl acetate and the combined extracts washed with brine. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The organic residue is purified by flash chromatography (SiO2, 10% methanol/hexane) followed by recrystallization from isopropanol and water to give 0.22 g (43%) of title compound as a mixture of tautomers, mp 156°-161° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Yield: 98 %

Procedure:
2-Chloro-5-nitropyridine (1.58 g, 10 mM) was treated with a 33% w/w solution of dimethylamine in methylated spirit (18 ml, 100 mM). An exothermic reaction ensued, with formation of a yellow solid. After 0.5 h the solid was filtered off. The filtrate was evaporated and the residue was combined with the yellow solid, and all material was dissolved in dichloromethane. This solution was washed with water and brine, dried and evaporated, to give the title compound (1.64 g; 98%), m.p. 146°-149° C.
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[O:4]1[CH2:9][CH2:8][CH2:7][O:6][CH:5]1[CH2:10][CH2:11][Mg]Br>C1COCC1>[O:4]1[CH2:9][CH2:8][CH2:7][O:6][CH:5]1[CH2:10][CH2:11][Zn:2][CH2:11][CH2:10][CH:5]1[O:6][CH2:7][CH2:8][CH2:9][O:4]1
Reactant: [Zn+2]
Reactant: Br[Mg]CCC1OCCCO1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C1COC(CC[Zn]CCC2OCCCO2)OC1

Procedure:
To a solution of zinc chloride (274 mg, 2.0 mmol) in THF (4 mL) was added (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide (8.8 mL, 4.4 mmol, 0.5M THF) to provide bis(2-(1,3 dioxan-2-yl)ethyl)zinc. In a separate reaction vessel, a mixture of compound 1C (348.6 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMF (5 mL) was stirred at rt for 3 h. After this time, argon was bubbled through the mixture for 5 minutes and then the bis(2-(1,3 dioxan-2-yl)ethyl)zinc and Pd(dppf)Cl2[CH2Cl2] (81.7 mg, 0.10 mmol) were added. Upon completion of addition, the reaction vessel was flushed with argon, capped, and then heated at 90° C. for 16 h. After this time, the reaction mixture was partitioned between diethyl ether and water and stirred vigorously for 15 minutes. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo to yield a residue. The residue was purified via flash chromatography (SiO2, 0-100% ethyl acetate/hexanes) followed by purification via preparative HPLC (Phenomenex Axia Luna column (30×100 mm); 0-100% B over 15 min, then 3 min B hold @40 mL/min; Solvent A=10% MeCN, 90% H2O; Solvent B=90% MeCN, 10% H2O) to afford compound 4A (289 mg, 75%) as a pale-yellow foam. LC/MS (m/z)=384 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:19]([NH:21][NH:22][C:23](=[O:43])[CH2:24][NH:25]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>ClCCl>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:19]([NH:21][NH:22][C:23](=[O:43])[CH2:24][NH2:25])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)C[C@@H](C(=O)NNC(=O)CN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
A solution of 1.54 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-[N-(9-fluorenylmethyloxycarbonyl)-glycinyl]-4-methylvalerohydrazide in 20 ml of dichloromethane was treated with 1.0 ml of piperidine. The mixture was stirred for 1.5 hours at room temperature and evaporated. The residue was purified by flash column chromatography on silica gel using methanol/dichloromethane (1:9) for the elution to give 0.83 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-glycinyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:13]=[C:14]([C:18](=[O:20])[CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)C(C)=O.C(O)(=O)C>CO.[OH-].[Na+]>[NH2:1][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:13]=[C:14]([C:18](=[O:20])[CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
In a mixed solvent of 3 ml of methanol and 3 ml of 10% by weight aqueous sodium hydroxide solution was dissolved 0.5 g of 6-(4-acetaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid, and the resulting solution was subjected to reaction at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and adjusted to a pH of 6.0 with acetic acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 0.36 g of 6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 262°-266° C.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[N:18]1[CH2:24][CH2:25][NH:26][C:27]1[N:28]=[N+:29]([O-:40])[C:30]2[CH:39]=[C:38]3[C:34]([CH2:35][CH2:36][CH2:37]3)=[CH:33][C:31]=2[N:32]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[N:18]1[CH2:24][CH2:25][NH:26][C:27]1[N:28]=[N+:29]([O-:40])[C:30]2[CH:39]=[C:38]3[C:34]([CH2:35][CH2:36][CH2:37]3)=[CH:33][C:31]=2[N+:32]=1[O-:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1CCCC(C)N1CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCCC(C)N1CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
H2O2 (70%, 0.46 mL, ca. 9.2 mmol) was added dropwise to a stirred solution of TFAA (1.3 mL, 9.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 38 (314 mg, 0.9 mmol) and TFA (0.35 mL, 4.6 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 39 (118 mg, 36%) as a red solid: mp (MeOH) 170-172° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.21 (br s, 1H, NH), 3.56-3.63 (m, 2H, CH2N), 3.12 (br dd, J=7.6, 7.3 Hz, 2H, CH2), 3.07 (br dd, J=7.5, 7.4 Hz, 2H, CH2N), 2.95 (br dd, J=7.5, 7.1 Hz, 2H, CH2N), 2.49-2.57 (m, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, CH2), 1.65-1.70 (m, 1H, CH2), 1.53-1.59 (m, 2H, CH2), 1.25-1.40 (m, 3H, CH2), 1.18 (d, J=6.3 Hz, 6H, 2×CH3); 13C NMR δ 155.7, 149.4, 145.7, 137.9, 129.7, 115.8, 111.5, 57.1 (2), 47.2, 39.3, 34.2, 33.4 (2), 32.4, 25.6, 24.4, 21.7 (2). Anal. calcd for C19H27N5O2: C, 63.8; H, 7.6; N, 19.6. Found: C, 64.0; H, 7.6; N, 19.8%.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CC(C)([O-])C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1.O>CS(C)=O>[NH2:4][CH2:3][CH2:1][O:2][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: O=C1CCC(c2ccc(F)cc2)=NN1
Reactant: NCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 65 °C
Yield: 34.4 %

Procedure:
In a flame-dried, round-bottomed flask, ethanolamine (1.7 ml, 28.1 mmol) was dissolved in dimethylsulfoxide (9.5 ml), and potassium tert-butoxide (95%, 3.3 g, 28.1 mmol) was added to the solution. This mixture was stirred at about 65° C. for about ten minutes, and then 6-(4-fluorophenyl)-4,5-dihydro-2H-pyridazine-3-one (3.6 g, 18.7 mmol) was added. This dark-colored solution was heated to about 80° C. for about twelve hours, and was then cooled to room temperature. Water was added, and the resulting tan solid was removed by filtration. This crude solid was then purified by column chromatography (silica gel; 5% methanol/dichloromethane to 15% methanol/dichloromethane) to afford the product as a white solid (1.5 g, 34% yield). LRMS ([M+H]+)=234.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13](=[O:16])[NH:12][C:11]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[NH:10][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([C:29]([N:19]2[CH2:20][CH2:21][C:11]3([NH:10][C:9]4[CH:8]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:15][C:14]=4[C:13](=[O:16])[NH:12]3)[CH2:17][CH2:18]2)=[O:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NC2(CCNCC2)Nc2cc(-c3ccncc3)sc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NC2(CCN(C(=O)c3ccccc3)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
A stirred solution of 6′-(pyridin-4-yl)-1′H-spiro [piperidine-4,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (0.0500 g, 0.170 mmol) and triethylamine (0.070 mL, 0.51 mmol) in tetrahydrofuran (4 mL) was cooled to 0° C. in an ice bath. A solution of benzoyl chloride (0.0260 g, 0.190 mmol) in tetrahydrofuran (0.1 mL) was added, and the reaction was allowed to warm to room temperature overnight. Then, the solvent was removed and the obtained residue was diluted with methanol (25 mL) and the mixture was stirred with solid NaHCO3 (1.5 g) for 20 min. Then, the solids were removed by filtration. The filtrate was concentrated to give a yellow solid, which was triturated with water and collected by filtration. This solid product was recrystallized from hot methanol/hexanes to give the title compound (0.0315 g, 45%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH:11](C=O)[C:10](=[O:17])[C:9]=2[CH:8]=[C:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(NC1C=CC(S([N:45]=[N+:46]=[N-])(=O)=O)=CC=1)(=O)C>C(N(CC)CC)C>[N+:45](=[C:11]1[CH2:12][CH2:13][C:14]2[N:6]([CH2:5][C:4]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:2]([Cl:1])[CH:3]=3)[C:7]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:8][C:9]=2[C:10]1=[O:17])=[N-:46]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=CC1CCc2c(cc(C(=O)OCc3ccccc3)n2Cc2ccc(Cl)c(Cl)c2)C1=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1CCc2c(cc(C(=O)OCc3ccccc3)n2Cc2ccc(Cl)c(Cl)c2)C1=O
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Triethyl amine (0.36 mL) was added dropwise to a solution of benzyl 1-(3,4-dichlorobenzyl)-5-formyl-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylate (0.5 g) and p-acetamidobenzenesulphonyl azide (305 mg) at room temperature, and stirred for 18 hours to give a brown solution. The solvent was removed in vacuo to afford a brown oil. Purification by column chromatography, using iso-hexane : 20% ethyl acetate as eluent afforded the title compound as a pale yellow solid (0.31 g, 62%), NMR d(CDCl3) 2.80 (2H, t), 3.05 (2H, t), 5.13 (2H, s), 5.57 (2H, s), 6.76 (1H, dd), 7.05 (1H, s), 7.20-7.40 (7H, m); M/z (+) 456, 454 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C)C=O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1N
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Yield: 73.8 %

Procedure:
A solution of 3-amino-4-methylbenzoic acid (15.1 g) and n-decanoyl chloride (19.4 g) in dry dimethylformamide (150 ml) was heated on a steam bath for 90 minutes. The solution was poured into water and the solid was collected, and recrystallised from ethanol (600 ml) to give 3-(n-decanamido)-4-methylbenzoic acid (22.5 g), in the form of a white powder, m.p. 246°-250° C.