Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CC1C(C)=C(O)C2C(=CC(F)=C(F)C=2)N=1.[CH2:18]([C:20]1[C:29]([CH3:30])=[C:28]([O:31][C:32]([CH:34]2[CH2:36][CH2:35]2)=[O:33])[C:27]2[C:22](=[CH:23][C:24]([F:38])=[C:25]([F:37])[CH:26]=2)[N:21]=1)C.[CH2:39]([C:41]1[C:50]([CH3:51])=[C:49]([O:52][C:53]([CH:55]2[CH2:57][CH2:56]2)=[O:54])[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:59])[C:47]=2[F:58])[N:42]=1)C>O1CCCC1.O>[CH3:18][C:20]1[C:29]([CH3:30])=[C:28]([O:31][C:32]([CH:34]2[CH2:35][CH2:36]2)=[O:33])[C:27]2[C:22](=[CH:23][C:24]([F:38])=[C:25]([F:37])[CH:26]=2)[N:21]=1.[CH3:39][C:41]1[C:50]([CH3:51])=[C:49]([O:52][C:53]([CH:55]2[CH2:56][CH2:57]2)=[O:54])[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:59])[C:47]=2[F:58])[N:42]=1
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: Cc1nc2cc(F)c(F)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Product: Cc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Reaction time: 1 h

Procedure:
3,4-Difluoroaniline (5.16 g) and 5.76 g of ethyl-2-methyl acetoacetate were refluxed in toluene (80 ml) in the presence of 0.3 ml of boron trifluoride etherate for 3 hr. The reaction mixture was washed with a saturated sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation. The resultant intermediate was refluxed in diphenyl ether for 30 min. The reaction solution was allowed to stand for cooling, and the precipitate was then collected by filtration under the reduced pressure to give 4.0 g of a mixture of 2,3-dimethyl-4-hydroxy-6,7-difluoroquinoline with 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline. In 10 ml of tetrahydrofuran was suspended 230 mg of 60% sodium hydride. The mixture of 2,3-dimethyl-4-hydroxy-6,7-difluoroquinoline with 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) (1 g) was suspended in 20 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The reaction mixture was stirred for one hr. Cyclopropanecarbonyl chloride (starting material 2) (600 mg) was then added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (200 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 890 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (compound 15) and 90.6 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (compound 16). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[C:3](=[O:13])[NH:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]=1[CH3:23].O>CN(C)C=O>[CH3:23][C:22]1[N:21]([C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:20]=[N:19][C:18]=1[CH2:17][N:2]1[CH2:1][C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[C:3]1=[O:13]
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NCc2cc3ccccc3n21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN2Cc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,2-dihydro-imidazo[1,5-a]indol-3-one (3 g; 0.0174 moles) in 50 ml of anhydrous dimethylformamide kept under nitrogen atmosphere, 50% NaH (0.84 g; 0.0174 moles) is added. The solution is stirred for 1 hour at 60° C.; then, at room temperature, 4-chloromethyl-5-methyl-1-triphenylmethyl-1H-imidazole (6.5 g; 0.0174 moles) is added. The reaction mixture is stirred for 6 hours at 70° C., then cooled, poured into water and extracted with methylene chloride.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([F:45])[CH:34]=1.COCCS(N)(=O)=O.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1>>[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:43][CH2:44]2)=[CH:40][C:36]([C:37]([NH:60][S:57]([CH:54]2[CH2:56][CH2:55]2)(=[O:59])=[O:58])=[O:39])=[C:35]([F:45])[CH:34]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Agent: COCCS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 67 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with cyclopropanesulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.090 g, 67%): 1H NMR (300 MHz, DMSO-d6) δ 11.54 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.84 (d, J=13.1 Hz, 1H), 4.82-4.73 (m, 1H), 3.08-2.98 (m, 1H), 2.60-2.53 (m, 1H), 2.26-1.18 (m, 1H), 2.18-2.05 (m, 1H), 2.03-1.93 (m, 1H), 1.91-1.79 (m, 1H), 1.62-1.48 (m, 1H), 1.47-1.18 (m, 4H), 1.12-1.03 (m, 4H), 0.97-0.79 (m, 3H), 0.68-0.59 (m, 2H); MS (ES+) m/z 394.1 (M+1).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](O)=[O:11])(=[O:4])[CH3:3].[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:2]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([N:23]1[CH2:24][C@H:20]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][C@H:22]1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:30][CH:29]=1)=[O:26])=[O:11])(=[O:4])[CH3:3]
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Product: CC(=O)N1CCC[C@H]1C(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 36.2 %

Procedure:
Proceeding as in Example 1, but substituting (S)-1-acetylpyrrolidine-2-carboxylic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 93, (2S,4R)-1-((S)-1-acetylpyrrolidine-2-carbonyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (11.5 mg, 36.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.54 (m, 2H), 7.29-7.24 (m, 4H), 7.20-7.14 (m, 5H), 6.93 (m, 2H), 4.46 (m, 2H), 3.47-3.37 (m, 4H), 2.66 (m, 2H), 1.95-1.83 (m, 8H), 1.76-1.69 (m, 2H). MS (EI) for C31H32FN3O4. found 530.6 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+]>C1COCC1.CO>[CH:23]1([NH:22][C@H:19]2[CH2:20][CH2:21][C@H:16]([CH2:15][O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:17][CH2:18]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N[C@H]1CC[C@H](COc2ccccc2)CC1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(OC[C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Trans-4-phenoxymethylcyclohexylamine trifluoroacetate (1.2 mmol) is dissolved in a mixture of 4 ml of THF and 4 mL of MeOH in a 20 ml glass vial equipped with a magnetic stirrer and a screw cap. 117 mg of cyclohexanone and 3 g of 3 Å molecular sieves are added. The mixture is stirred for 10 min. after which 2.4 mL of 1N sodiumcyanoborohydride in tetrahydrofuran is added. The reaction stirred 4 days at room temperature then filtered through celite washing through with 30 mL of dichloromethane. The organic phase is washed with 10 mL of water, 10 mL of brine, dried (MgSO4), filtered and concentrated in vacuo to give 300 mg of cyclohexyl-(trans-4-phenoxymethyl-cyclohexyl)-amine.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1.FC1C=CC(S(N)(=O)=O)=CC=1.Cl[CH2:47][CH2:48][CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52](C)[CH2:51][O:50]1.C[C@H]1CNC[C@@H](C)N1>>[C@H:49]1([CH2:48][CH2:47][N:7]2[C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]3[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:13][CH:14]=3)[CH2:3][C@H:2]2[CH3:1])[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][O:50]1
Reactant: CC1COC(CCCl)c2ccccc21
Reactant: CC1CN(c2ccc(S(N)(=O)=O)cc2)CC(C)N1
Agent: C[C@@H]1CNC[C@H](C)N1
Agent: NS(=O)(=O)c1ccc(F)cc1
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: C[C@@H]1CN(c2ccc(S(N)(=O)=O)cc2)C[C@H](C)N1CC[C@@H]1OCCc2ccccc21

Procedure:
Following the general procedure of EXAMPLE 49 and making non-critical variations 2-(isochroman-1-yl)ethanol-O-methanesulfonate (LXXX, 0.412 g) and 4-(3,5-dimethylpiperazin-1-yl)benzenesulfonamide [(IV), 0.433 g; prepared from 4-fluorobenzenesulfonamide, III, and cis-2,6-dimethylpiperazine, II (Aldrich), by the method of EXAMPLE 47] gives the title compound; mp 170°-175°(decomp)°; MS (m/z) 429; IR (mineral oil) 1153, 1596, 1325, 1162 and 1096 cm-1.
Reaction SMILES: [C:1]([C:3]1[C:8]2[NH:9][C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[C:35](=[O:36])[C:34]4[C:29](=[C:30]([F:37])[CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27]3)[C:21]=2[CH3:38])=[N:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:40]>>[CH3:19][O:18][C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:7]3[C:6]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[C:35](=[O:36])[C:34]6[C:29](=[C:30]([F:37])[CH:31]=[CH:32][CH:33]=6)[N:28]=[CH:27]5)[C:21]=4[CH3:38])=[N:5][CH:4]=[C:3]([C:1](=[O:40])[NH2:2])[C:8]=3[NH:9][C:10]=2[CH:11]=1)=[O:17]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(-c3cccc(-n4cnc5c(F)cccc5c4=O)c3C)c12
Reactant: O=S(=O)(O)O
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cnc(-c3cccc(-n4cnc5c(F)cccc5c4=O)c3C)c12
Temperature: 60 °C

Procedure:
A stirred mixture of methyl 4-cyano-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate (0.172 g, 0.342 mmol) and 90% aqueous Sulfuric acid (2.000 ml, 36.8 mmol) was heated at 60° C. for 15-30 minutes. LC-MS showed complete conversion to the desired product plus the corresponding carboxylic acid as a minor product. The reaction mixture was cooled to 0° C. and carefully neutralized to approx. pH=5-6 with 50% NaOH solution then stirred overnight. The reaction mixture was filtered and the residue dried under vacuum overnight to give methyl-4-carbamoyl-1-(3-(8-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-5H-pyrido[4,3-b]indole-7-carboxylate as a tan solid. [0.143 g, 0.274 mmol, 80% yield] The product had an HPLC Retention Time=2.798 minutes[mixture of isomers] [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 522.4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[NH:16][C:15](=[O:17])[O:14][C:8]4([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:6]=3[CH:7]=2)[CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1
Product: O=C1Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc2C2(CCCCC2)O1

Procedure:
Prepared from 6-bromo-spiro[4H-3,1-benzoxazine-4,1′-cyclohexane]-2(1H)-one and 3-nitrophenyl boronic acid according to Procedure A. Off-white solid: mp 245-246° C. 1H-NMR (CDCl3) δ 8.39 (t, 1H, J=1.9 Hz), 8.20 (dd, 1H, J=8.2, 1.4 Hz), 8.11 (s, 1H, D2O exchangeable), 7.86 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=8.1 Hz), 7.50 (dd, 1H, J=8.2, 1.9 Hz), 7.39 (d, 1H, J=1.8 Hz), 6.93 (d, 1H, J=8.2 Hz), 2.25 (d, 2H, J=12.7 Hz), 1.60-1.99 (m, 7H), 1.31-1.42 (m, 1H); MS (EI) m/z 337 ([M−H]−, 100%). Anal. Calc. For C19H18N2O4.0.35H2O: C, 66.21; H, 5.47, N, 8.13. Found: C, 66.22; H, 5.43; N, 7.86.
Reaction SMILES: [F:1][C:2]1([CH2:18][CH2:19][N:20]2[C:24](=[O:25])[CH2:23][O:22][C:21]2=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:4][CH2:3]1.[CH3:27][NH2:28]>O1CCCC1>[F:1][C:2]1([CH2:18][CH2:19][NH:20][C:21](=[O:26])[O:22][CH2:23][C:24]([NH:28][CH3:27])=[O:25])[CH2:3][CH2:4][N:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:7]1
Reactant: CN
Reactant: O=C1COC(=O)N1CCC1(F)CCN(c2ccc3ccccc3n2)CC1
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1(F)CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 0.52 g (1.46 mmol) of 3-{2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 12.8, and 3.6 ml (7.28 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 99/1 mixture of ethyl acetate and methanol, followed by crystallization from diethyl ether, 0.390 g of pure product is obtained in the form of a 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]=[CH:4][N:3]=1.[NH3:14]>C(O)CO.CO.[Cu-]=O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH2:14])=[N:3][CH:4]=[CH:5]2
Reactant: COc1ccc2c(Cl)nccc2c1
Reactant: N
Agent: O=[Cu-]
Solvent: OCCO
Solvent: CO
Product: COc1ccc2c(N)nccc2c1
Temperature: 120 °C
Yield: 72 %

Procedure:
A sealable tube was charged with 1J (770 mg, 3.98 mmol), copper (I) oxide (30 mg) and ˜12M ammonia in ethylene glycol (5 mL). The tube was sealed and the reaction was heated to 120° C. for 72 h. After cooling to rt, the reaction was diluted with methanol and was purified via preparative HPLC (MeOH/water/TFA) to provide 1K (832 mg, 72%). LC-MS: 175.23 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[N:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])(=[O:16])=[O:15]>C(#N)C>[CH3:10][N:8]([CH3:9])[C:6]1[N:5]=[C:4]([O:11][CH3:12])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:14]([CH3:13])(=[O:16])=[O:15])(=[O:25])=[O:24])=[O:28])[N:7]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(N(C)C)n1
Solvent: CC#N
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2S(C)(=O)=O)nc(N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-4-dimethylamino-6-methoxy-1,3,5-triazine (1.02 g, 6.00 mmol) in dry acetonitrile (30 ml) was added 2-methylsulfonylbenzenesulfonyl isocyanate (1.50 g, 6.00 mmol). After stirring at room temperature overnight, the reaction mixture was filtered and the solid washed with acetonitrile to give the product as a white powder with a melting point of 192°-195° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[NH:31]1[CH2:35][CH:34]=[CH:33][C@H:32]1[C:36]([NH2:38])=[O:37]>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:31]5[CH2:35][CH:34]=[CH:33][C@H:32]5[C:36]([NH2:38])=[O:37])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:25])[CH3:26]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Reactant: NC(=O)[C@@H]1C=CCN1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CC=C[C@H]3C(N)=O)cc1OCC2

Procedure:
Following the procedures in Example 388, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate and (S)-2,5-dihydro-1H-pyrrole-2-carboxamide were reacted to give 389. M/z 407.2, calc. 406.19. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 6.98 (s, 1H), 6.13 (dd, J=6.2, 1.9, 1H), 6.02-5.88 (m, 3H), 4.97 (s, 1H), 4.52 (dd, J=9.3, 7.1, 4H), 4.39-4.18 (m, 2H), 1.48 (dd, J=6.6, 2.5, 6H)
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[O:26])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:43]([O-:47])([O-])(=[O:45])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:43]([C:15]1[C:16]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[O:26])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)(=[O:47])=[O:45])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cc(C(F)(F)F)cnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)cnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.36 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.20 g of 3-ethylsulfanyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (Compound of Present Invention 1) and 3 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.06 g of 3-ethylsulfonyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 4) and 0.13 g of 3-ethylsulfinyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 5).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10](/[CH:15]=[CH:16]/[C:17]3[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=[N:20][CH:21]=3)=[N:9][C:8]=2[N:7]([CH2:41][CH2:42][CH3:43])[C:5]1=[O:6])[CH2:2][CH3:3].Cl.[CH3:45]O>>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH3:45])[C:10](/[CH:15]=[CH:16]/[C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)=[N:9][C:8]=2[N:7]([CH2:41][CH2:42][CH3:43])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3cncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)nc2n(CCC)c1=O
Reactant: CO
Agent: Cl
Product: CCCn1c(=O)c2c(nc(/C=C/c3c[nH]cn3)n2C)n(CCC)c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
The same procedure as in Example 2 was repeated using 1.96 g (3.44 mmol) of the mixture of Compound l and Compound m to give a crude product. The crude product was dissolved in 50 ml of methanol, and 1.5 ml of 1N hydrochloric acid was added to the solution, followed by stirring at 50° C. for 2 hours. After the solution was concentrated to about a half of its original volume, the concentrate was adjusted to pH 4 and extracted six times with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% methanol/chloroform) to give 640 mg (overall yield: 55%) of Compound 21 as an amorphous substance. The obtained Compound 21 (2.00 g) was treated with a hydrogen chloride/methanol solution and then recrystallized from isopropanol to give 1.04 g of hydrochloride of Compound 21.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:9])[CH:4]=[N:3]1
Reactant: C1COCCN1
Reactant: Cn1cc(C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cn1cc(C(=O)N2CCOCC2)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 15.9 mmol) in DCM (100 ml) and TEA (8.80 ml, 63.5 mmol), EDCHCl (3.65 g, 19.0 mmol) and HOBt (2.57 g, 19.0 mmol) were added under a nitrogen atmosphere at rt and stirred for 30 min. Morpholine (1.68 ml, 19.0 mmol) was then added to the reaction mixture and stirring was continued for 18 h. On completion of reaction (monitored by TLC), the reaction mixture was diluted with water and DCM. The organic layer was separated, dried over Na2SO4 and concentrated to get the crude product. Column chromatography afforded the desired product as off white solid. Yield: 1.20 g (39%); MS: m/z=196.4 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[CH2:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4].Cl.[CH3:24][O:25][NH2:26].N1C=CC=CC=1>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:13](=[N:26]/[O:25][CH3:24])/[CH2:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1[C@@H]1c2ccccc2C(=O)CC1(C)C
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CO/N=C1\CC(C)(C)[C@H](n2cncc2C(=O)OC)c2ccccc21
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)- or (S)-3-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester (0.091 g, 0.299 mmol), which can be prepared as described in Example 13, and methoxyamine hydrochloride (0.076 g, 0.897 mmol) in methanol (2 mL) is added pyridine (0.24 g, 2.99 mmol) and the mixture is heated to 50° C. After 1.5 hours, the mixture is diluted with ethyl acetate and washed twice with aqueous copper sulfate, twice with 1:9 v/v aqueous ammonium hydroxide-saturated aqueous ammonium chloride, water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated to furnish (R)- or (S)-3-{4-[(E)-methoxyimino]-2,2-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl}-3H-imidazole-4-carboxylic acid methyl ester as a 19:1 ratio of geometric isomer without the need for further purification. 1H NMR (400 MHz, MeOD) δ ppm 0.94 (s, 3 H), 1.10 (s, 3 H), 2.52 (d, J=17.9 Hz, 1 H), 2.99 (d, J=17.9 Hz, 1 H), 4.03 (s, 3 H), 4.06 (s, 3 H), 6.65 (s, 1 H), 7.17-7.26 (m, 1 H), 7.41-7.49 (m, 2 H), 8.18-8.22 (m, 2 H), 8.27 (br. s., 1 H).