Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1.[C:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>C1COCC1>[CH3:27][C:24]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:21]([C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH:9]=[CH:8][NH:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])=[CH:33][CH:34]=1)([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2cccc3cc(Oc4ncnc5[nH]ccc45)ccc23)cc1
Reaction time: 14 h

Procedure:
THF (1.3 mL) was added to 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-1-naphthoyl chloride (84.0 mg, 0.259 mmol) in a 10 mL round bottom flask, followed by 4-t-butyl aniline (62.4 μL, 0.389 mmol) and Hunig's base (45.1 μL, 0.259 mmol). The resulting solution was stirred for 14 h and then transferred to a 50 mL flask. To this solution was added ˜5 g of silica gel. The resulting slurry was concentrated by reduced pressure. The impregnated silica gel was loaded into a dry pack column cartridge and the crude mixture was purified through Biotage chromatography (Hex:EtOAc). The collected product was repurified through trituration with DCM. MS (ESI, pos. ion) m/z: 437.1 (M+1). Mass Calc'd for C18H15NO3: 436.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:17]2[CH2:18][O:15][CH2:16]2)[CH2:10][CH2:9]1
Reactant: O=C1COC1
Reactant: Fc1cncc(Cl)c1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1cncc(Cl)c1N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-(3-chloro-5-fluoropyridin-4-yl)piperazine (900 mg, 4.173 mmol) in THF (9.000 mL) was added 3-oxetanone (601.4 mg, 8.346 mmol). To this mixture, under N2, was added sodium triacetoxyborohydride (2.034 g, 9.598 mmol) portionwise over 5 min and the reaction mixture was stirred at RT overnight. MeOH (2 ml) was added to the flask before the mixture was concentrated in vacuo. The residue was partitioned between water (50 ml) and EtAOc (50 ml). The aqueous phase was basified to pH 7-8 with NH4OH. Combined organics washed with brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(3-chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine as a cream solid that was used in next step without further purification. MS (ES+) 272.1.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+]>Cl.O>[N:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.2 %

Procedure:
1,2,3,4-Tetrahydroquinoline (10 g, 75 mmol) was dissolved in 3N HCl (50 mL) at 0° C. The reaction mixture was stirred for 5 min. at 0° C., then a solution of sodium nitrite (6.22 g, 90 mmol) in water was added at 0° C., and the mixture stirred for 2 h at RT. After completion of reaction, water was added and the mixture extracted with EtOAc (2×200 mL). The combined organic layers were washed with water, dried over sodium sulfate and concentrated under vacuum to obtain 10 g of product.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]([OH:17])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnccc1NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a stirring suspension of 4-(Boc-amino)pyridine-3-carboxylic acid (1.04 g, 4.37 mmol) in methanol (3.5 mL) was added a 2 M solution of (trimethylsilyl)diazomethane in hexanes (3.5 mL, 7 mmol). After 15 min, acetic acid was added and the solvents were removed in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of 20% ethyl acetate in hexanes through 70% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give the title compound (0.894 g, 81%) as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:16][C:17]1[N:21]2[C:22]3[CH:28]=[C:27]([CH3:29])[NH:26][C:23]=3[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.CN(C=O)C>CC#N>[CH3:16][C:17]1[N:21]2[C:22]3[CH:28]=[C:27]([CH3:29])[N:26]([CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[C:23]=3[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
K2CO3 (44 mg, 0.32 mmol) and 2-(bromomethyl)pyridine hydrobromide (0.027 g, 0.11 mmol, Aldrich) were added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20. mg, 0.11 mmol) in DMF (3.0 mL, 39 mmol). After stirring at room temperature for 2 hours, the reaction was heated to 50° C. for 35 minutes. The reaction mixture was diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (8.9 mg, 30%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:34])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30](Br)[CH2:31][CH3:32])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]([F:51])([F:50])[C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:34])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([O:49][C:46]2[CH:47]=[CH:48][C:43]([C:42]([F:41])([F:50])[F:51])=[CH:44][CH:45]=2)[CH2:31][CH3:32])=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
The bromide 49.1 (90 mg, 0.17 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (220 mg, 0.68 mmol) and 4-trifluoromethylphenol (110 mg, 0.68 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc: hexanes) to obtain 49.2 (23 mg). MS ESI (pos.): m/e 609.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]([N:22]([CH:36]1[CH2:38][CH2:37]1)[C:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[C:6]([C:8]1[CH:9]=[N:10][C:11]([O:14]CC2C=CC=CC=2)=[CH:12][CH:13]=1)=O)[CH3:2].FC(F)(F)C([O-])=O.[NH4+:47]>CCO>[CH2:1]([O:3][C:4]([C:5]1[N:22]([CH:36]2[CH2:38][CH2:37]2)[C:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)=[N:47][C:6]=1[C:8]1[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:39])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C(=O)c1ccc(OCc2ccccc2)nc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(O)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To 1.4 g (3 mmol) of 3-(6-benzyloxy-pyridin-3-yl)-2-[cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-propionic acid ethyl ester in 5 ml of EtOH was added 1.4 g (10 mmol) of ammonium trifluoroacetate. The EtOH was evaporated and the residue heated to 110° C. for 16 h. The cooled residue was partitioned between saturated sodium hydrogen carbonate solution and CH2Cl2. The organic phase was dried with sodium sulfate and concentrated. The crude reside was re-dissolved in 10 ml of EtOH, a generous spatula of 10% palladium on activated charcoal was added, and the mixture stirred under an atmosphere of hydrogen for 1 h. The mixture was then filtered over Hyflo and concentrated. Purification by flash column chromatography [MeOH/EtOAc 4:96 to 1:9] afforded 0.8 g (70%) of the title compound as a colorless solid. MS: 434.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4](O)=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:38][S:39]([CH3:42])(=[NH:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([N:41]=[S:39]([CH3:42])([CH3:38])=[O:40])=[O:5]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CS(C)(=N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CS(C)(=O)=NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
A solution of 2.46 g of 2-chloro-5-(o-chloro-p-trifluoromethyl-phenoxy)-benzoic acid in 20 ml of methylene chloride is added dropwise at room temperature while stirring to a solution of 1.3 g of dicyclohexylcarbodiimide and 0.6 g of dimethyl sulphoximine in 5 ml of methylene chloride, a slight exothermic reaction occurring. After a reaction time of 15 minutes the solvent is removed by evaporation under reduced pressure and the residue is purified by chromatography on silica gel with n-hexane/ethyl acetate (9:1). The white crystalline product is then recrystallized from methylene chloride/n-hexane. There is obtained N-[2-chloro-5-(o-chloro-p-trifluoromethyl-phenoxy)-benzoyl]-S,S-dimethyl-sulphoximine, m.p. 128°-131° C.; mass spectrum: m/e 425/427; 1H-NMR (CDCl3): 7.8-6.9 (m,6H), 3.4 (s,6H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[C:23]([Cu])#[N:24].O>CS(C)=O>[C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([C:23]#[N:24])[CH:11]=[CH:10]3)[CH2:18][CH2:17]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: N#C[Cu]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C#N)ccc3c2)CC1
Temperature: 125 °C
Reaction time: 15 h

Procedure:
Compound 2-bromo-6-((trans)-4-tert-butylcyclohexyloxy)naphthalene (2.0 g, 5.5 mmol, 1.0 eq.) and CuCN (742 mg, 8.34 mmol, 1.5 eq.) was dissolved in DMSO (5 mL). Then the mixture was stirred at 125° C. for 15 h. Water was added and the mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using PE/EA (10/1) to give product as a slight yellow solid (1.423 g, 82%). EDI-MS (M+1)+: 308.0 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.78-7.73 (m, 2H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H), 2.29-2.25 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.26 (m, 2H), 1.25-1.10 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: Br[CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4].[NH3:30].Cl>ClCCCl.C(OCC)(=O)C>[NH2:30][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4]
Reactant: CC(Br)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Reactant: N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(N)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Reaction time: 0.5 h
Yield: 64 %

Procedure:
23.04 g of 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7-tetrahydrothieno[2,3-C]pyridine was dissolved in 65 ml of 1,2dichloroethane and 65 ml of ethyl acetate, into which ammonia gas was passed at -15° C. for 1 hour. This solution was placed in a sealed tube and reacted at 110° C. for 2 hours. In order to complete the reaction, ammonia was again passed into the solution at -15° C. for 30 minutes in the sealed tube where the reaction was continued at 110° C. for 1.5 hours. After ice-cooling, the reaction solution was charged into ice-cooled 2N hydrochloric acid, to which ethyl acetate was added, from which the resultant aqueous phase was collected. sodium carbonate was added to the aqueous phase under ice-cooling conditions so that the pH was adjusted to 8, followed by extraction with chloroform under salting-out conditions. The extract was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. followed by filtration and concentration to obtain 12.97 g (yield 64%) of the intended compound.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](OCC)=[O:7])C.[C:19]1([C:25]([O:27][Si](C)(C)C)=[CH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N#N>CCCCCC.C(OCC)(=O)C>[OH:7][C:6]1[CH:26]=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:27][C:4](=[O:3])[C:5]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(Oc1ccccc1)C(=O)OCC
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=c1oc(-c2ccccc2)cc(O)c1Oc1ccccc1
Temperature: 100 °C
Yield: 18.3 %

Procedure:
To a is pressure reactor was added 2-phenoxypropanedioicacid diethylester 8.11 g (0.032 moles) and 1-phenyl-1-(trimethylsilyloxy)ethylene 12.35 g (0.064 moles). The vessel was pressurized to 600 psi with N2. The mixture was heated at 100° C. for 8 hours then an additional 63.5 hours at 147-154° C. The vessel was cooled to room temperature and rinsed with ethyl acetate. Crude flash chromatography (hexane/ethyl acetate 1/1) afforded partially purified material which was then flashed on silica gel using hexane/ethyl acetate 95/5-40/60 as eluents. The resulting solid was recrystallized from diethyl ether and ethyl acetate to afford 1.64g (18%) of the title compound (mp=215-219° C.). 1H NMR (400 MHz, DMSO-d6) δ6.90 (s, 1 H), 6.95 (dd, 2 H), 7.02 (t, 1 H), 7.28-7.33 (m, 2 H), 7.52-7.56 (m, 3 H), 7.80-7.856 (m, 2 H), 12.0 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:21]([O-:23])=[O:22])=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1.0 g (3.3 mmol) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 10 ml of concentrated sulfuric acid, and 0.25 g (4.0 mmol) of fuming nitric acid was dropwise added thereto under cooling with ice, followed by stirring for 1 hour. This reaction solution was poured into ice water and extracted with ethyl acetate. After washing with water and a saturated sodium hydrogencarbonate aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 1.1 g (yield: 96%) of the desired product. Melting point: 139-140° C.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:32])[NH2:14])=[CH:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (11.47 g), Lawesson's reagent (15.2 g) and tetrahydrofuran (150 mL) was stirred at 50° C. for 4 hr. The reaction mixture was concentrated, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (11.16 g, yield 93%) as yellow crystals. melting point 239-240° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:24]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc2cc(O)ccc2c1
Product: COc1ccc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2c1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (75 mg) and 6-methoxy-2-naphthol (174 mg) obtained in Example 1 were mixed and stirred at 180° C. for 30 minutes, and the reaction mixture was then purified by thin layer chromatography on silica gel (eluting with hexane/acetone (2/1)) to obtain 71 mg of the title compound (yield: 59%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[NH:9][C:8]1=[O:17])[CH2:4][CH2:5][CH3:6].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CO>[CH2:18]([N:12]1[C:11]2[C:10](=[O:16])[NH:9][C:8](=[O:17])[N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[C:15]=2[N:14]=[CH:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
10 g (0.25 mol) of sodium hydroxide dissolved in 100 ml of water were added to a suspension of 52 g (0.25 mol) of 3-butylxanthine in 300 ml of methanol and the reaction mixture was stirred at 70° C. for one hour, then treated dropwise at the same temperature with 42.8 g (0.25 mol) of benzyl bromide and kept between 70° and 80° C. for 5 hours. 1.0 g (0.025 mol) of sodium hydroxide and 4.28 g (0.025 mol) of benzyl bromide were then added. After a further 2 hours, the mixture was cooled, diluted with 1500 ml of water and filtered cold on a suction filter, the product was washed with water on the suction filter and dissolved in 1000 ml of 1 N sodium hydroxide solution, and the solution was filtered and slowly brought to pH 3 with stirring using concentrated hydrochloric acid. The crystallizate was filtered off from the solution, washed with water until chloride-free and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[F:24][C:25]1[CH:26]=[C:27]([C@@H:32]2[O:36][C:35](=[O:37])[NH:34][C@@H:33]2[CH3:38])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:34]2[C@H:33]([CH3:38])[C@H:32]([C:27]3[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=3)[O:36][C:35]2=[O:37])[CH:6]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1cc(F)cc(F)c1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3cc(F)cc(F)c3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-5-(3,5-difluoro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:21]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([O:14][CH3:13])[CH:22]=3)[C@H:5]2[CH3:9])[CH2:2][CH2:3]1
Reactant: COc1cc(F)ccc1C#N
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1cc(N2CC[C@@](O)(C3CC3)[C@@H]2C)ccc1C#N

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2-methoxy-4-fluorobenzonitrile (277 mg) and lithium carbonate (180 mg), the title compound was obtained as a pale-yellow solid (yield: 192 mg, yield: 58%).
Reaction SMILES: [N+](C(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(F)(F)F)CC3)C=2)C=1)(C)CCC(O)=O)([O-])=O.C[O:33][C:34](=[O:67])[CH2:35][CH2:36][C:37]([N+:64]([O-:66])=[O:65])([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:53][C@H:54]3[CH2:59][CH2:58][C@H:57]([C:60]([F:63])([F:62])[F:61])[CH2:56][CH2:55]3)[C:45]=2[C:49]([F:52])([F:51])[F:50])[CH:40]=1)[CH3:38]>>[N+:64]([C:37]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:53][C@H:54]3[CH2:55][CH2:56][C@H:57]([C:60]([F:61])([F:62])[F:63])[CH2:58][CH2:59]3)[C:45]=2[C:49]([F:50])([F:51])[F:52])[CH:40]=1)([CH3:38])[CH2:36][CH2:35][C:34]([OH:67])=[O:33])([O-:66])=[O:65]
Reactant: COC(=O)CCC(C)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Product: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]

Procedure:
4-Nitro-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid was synthesized as per 4-nitro-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (Example 280) in 93% yield, using 4-nitro-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid methyl ester as starting material.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.O.NN>CCO>[NH2:3][CH:12]1[CH2:13][CH2:14][C:15]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C)CCC(N)CC1
Temperature: 80 °C
Yield: 102.3 %

Procedure:
To an ice-cold solution of ethyl 4-(1,3-dioxoisoindolin-2-yl)-1-methylcyclohexanecarboxylate (0.30 g, 0.95 mmol) in EtOH (20 mL) was added hydrazine hydrate (0.115 mL, 2.38 mmol) and the resulting mixture heated up to 80° C. for 2-3 h. After the completion of reaction (by TLC), solvent was evaporated under reduced pressure, water added (20 mL), extracted with EtOAc (3×50 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product as a viscous liquid (0.18 g, crude). MS: 186.20 [M+H]+.