Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:31]2[CH:32]=[CH:33][S:34][C:30]=2[CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:31]5[CH:32]=[CH:33][S:34][C:30]=5[CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nccc2sccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nccc5sccc45)cc3CC[C@@H]12
Yield: 24.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 4-chlorothieno[3,2-c]pyridine (78 mg, 0.46 mmol) and 1 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 37 mg (25%) of the title compound as a white solid. mp 196°-197°. FDMS: m/e=394. α[D]589 =+75.17 (c=0.57, chloroform).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:30][CH:29]=3)=[CH:19][CH:18]=2)[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:32][CH:33]=3)=[CH:19][CH:18]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(CCCc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 49.7 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(3-phenylpropyl)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (767 mg), which is the product of Example 3, was reacted with an aqueous sodium hydroxide solution (1N, 2.86 ml) and the reaction mixture was treated. The residue was crystallized from a mixture of diisopropyl ether and ethyl acetate to give the title compound (361 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=O)=[CH:15][CH:16]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:35][C:36]([NH2:38])=[NH:37]>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:21])[NH:37][C:36]([NH2:38])=[NH:35])=[CH:15][CH:16]=1)=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: N=C(N)N
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)s1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC(=N)N)s1)NC(=O)OCc1ccccc1
Yield: 10.5 %

Procedure:
0.272 g (0.55 mmol) of the product obtained in step c) were suspended in 30 ml of dry tetrahydrofuran. 0.168 g (2.75 mmol) of guanidine (free base) were added. The resulting suspension was heated under reflux for 2.5 hours. The solvents were removed in vacuo and the residue was dissolved in 200 ml dichloromethane. The resulting solution was washed four times with 30 ml each of water. The organic phase was then dried with dry magnesium sulfate, filtered off and evaporated. 30 mg of a resinous material were obtained which was sufficiently pure for use in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18]([OH:20])=O)[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:58]1([CH2:64][CH2:65][CH2:66][CH2:67][NH2:68])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][CH:17]([NH:21][S:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])[C:18]([NH:68][CH2:67][CH2:66][CH2:65][CH2:64][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1
Reactant: NCCCCc1ccccc1
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Cl)S(=O)(=O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC(c2ccc(CC(NS(=O)(=O)c3ccccc3)C(=O)NCCCCc3ccccc3)cc2Cl)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.4 %

Procedure:
(2S)-3-[3-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-2-[(phenylsulfonyl)-amino]propanoic acid (15.0 mg, 0.0317 mmol) in DMF (1 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.8 mg, 0.0381 mmol) and stirred at rt for 5 minutes. A solution of 4-phenylbutan-1-amine (10 μL, 0.0634 mmol) and N,N-diisopropylethylamine (28 μL, 0.16 mmol) in DMF (1 mL) was added and the reaction stirred at rt for 1 h. Purification by preparative LCMS afforded product as a white solid (12.9 mg, 67%). 1H NMR (400 MHz, CD3OD): δ 7.68–7.64 (m, 2H), 7.54–7.34 (m, 4H), 7.27–7.11 (m, 7H), 5.59–5.57 (m, 1H), 3.92–3.87 (m, 1H), 3.42–3.35 (m, 1H), 3.35–3.28 (m, 1H), 2.99–2.84 (m, 3H), 2.79–2.74 (m, 1H), 2.56 (t, J=7.5 Hz, 2H), 1.53–1.47 (m, 2H), 1.33–1.29 (m, 2H); LCMS found for C28H31ClN3O6S2 (M+H)+: m/z=604.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[CH2:9]O)=[CH:4][CH:3]=1.CC(C)(C)[O-].[K+]>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@H:8]2[CH2:9][O:11]2)=[CH:4][CH:3]=1
Reactant: OC[C@H](O)COc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(OC[C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a stirred mixture of 13.4 parts of (+)-(S)-3-(4-fluorophenoxy)-1,2-propanediol, O1 -4-methylbenzenesulfonate and 45 parts of tetrahydrofuran were added 4.9 parts of kalium 1,1-dimethyl ethoxide. The whole was stirred for 30 minutes at room temperature. It was filtered over Hyflo, washed with tetrahydrofuran and the filtrate was evaporated. The residue was distilled, yielding 3.8 parts (57.3%) of (-)-(R)-[(4-fluorophenoxy)methyl]oxirane; bp. 54° C. at 66.5 Pa; [α]D =4.08 (c=0.5% in trichloromethane) (148).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1
Reactant: NC(=O)C1CCNCC1
Reactant: FC(F)(F)c1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(c2ccnc(C(F)(F)F)n2)CC1
Yield: 69.6 %

Procedure:
A mixture of 4-chloro-2-(trifluoromethyl)pyrimidine (IV, 23.66 g, 0.130 mol), isonipecotamide (V, 16.66 g, 0.130 mol), and sodium carbonate (27.56 g, 0.260 mol) in acetonitrile (250 mL) was refluxed for 4 hr. The mixture was cooled and a solid mass formed. This mass was dissolved in DMF (300 mL) and filtered to remove the inorganics. The solvent was removed in vacuo and the crude product was recrystallized from isopropanol and then from 90% ethanol to give colorless needles (24.8 g, 70%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[OH:9][C:10]1[C:20]2[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C:14]=2[NH:13][C:12](=[O:28])[CH:11]=1>C(Cl)Cl>[Br:8][C:11]1[C:12](=[O:28])[NH:13][C:14]2[CH2:15][CH2:16][N:17]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:18][CH2:19][C:20]=2[C:10]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(=O)cc(O)c2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(=O)c(Br)c(O)c2CC1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
NBS (0.668 mmol, 119 mg) was added in one portion to a stirred solution of tert-butyl 4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.607 mmol, 170 mg) in DCM (3 ml) at room temperature. After 3 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified purified by column chromatography to provide 180 mg (83%) of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. Ag2CO3 (0.42 mmol, 116 mg) was added to a solution of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (75.0 mg, 0.21 mmol) in DCM (1.5 ml) at room temperature. After 10 min of stirring, Mel (0.23 mmol, 15 μl) was added. After 5 h of stirring, sat. aq. NH4Cl was added and the mixture was extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 52 mg (67%) of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. The correct regioselectivity was confirmed by NOESY. 1H-NMR (CDCl3) δ 13.21 (1H), 3.85 (3H), 3.65 (2H), 3.55 (2H), 3.05 (2H), 2.85 (2H), 1.49 (9H) ppm. To a solution of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (51 mg, 0.137 mmol) was added HC1 (2 N in Et2O, 3 ml) at room temperature. After 10 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to provide 33 mg (89%) of 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-4-ol. 1H-NMR (CDCl3) δ 12.02 (br s, 1H), 9.21 (br s, 1H), 3.79 (3H), 3.25 (m, 2H), 3.15 (m, 2H), 3.06 (m, 2H), 2.92 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.[BH4-].[Na+].Cl.C(O)(C(F)(F)F)=O>ClCCl.CCO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)=[CH:16][C:13]([CH2:14][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: NCc1ccncc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CNCc3ccncc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 121.4 %

Procedure:
6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (102.5 mg, 0.230 mmol) was suspended in dichloromethane (1.3 mL) and EtOH (1.3 mL), and 4-(aminomethyl)pyridine (0.070 mL, 0.69 mmol) and tetraisopropoxytitanium (0.20 mL, 0.68 mmol) were added. The reaction was stirred under nitrogen at room temperature. After 50 min, sodium borohydride (30.8 mg, 0.814 mmol) and MeOH (1 mL) were added, and stirring was continued at room temperature. After 1 h, more MeOH and 5N aqueous HCl (0.60 mL) were added, and stirring was continued at room temperature over the weekend. Then, the reaction was treated with DCM and MeOH and was filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and treated with DCM and TFA and some DMSO (about 1 mL) and concentrated. The material was dissolved in water and partially concentrated resulting in the formation of a precipitate. The suspension was filtered, and the solid was washed with MeOH. The solid was set aside. The filtrate was concentrated and filtered again. The solid was combined with the solid collected from the first filtration. The filtrate was concentrated and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 minutes with a total flow of 100 mL/min). The fractions with product were combined with the solid that had been collected, concentrated, and dried under high vacuum, first at about 50° C., and then at room temperature overnight to afford N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-4-ylmethylamino)methyl)pyridin-2-amine (126.6 mg, 96.7% purity, 97% yield) as a TFA salt. 1H NMR (D2O, 400 MHz) δ 8.83-8.77 (m, 4H), 8.43 (s, 1H), 8.21 (dd, J=8.41 Hz, 2.35 Hz, 2H), 8.08-8.03 (m, 3H), 7.82 (dd, J=9.00 Hz, 2.74 Hz, 1H), 6.95 (dd, J=9.00 Hz, 1H), 4.63 (s, 2H), 4.51 (s, 2H), 4.42 (s, 2H), 3.91 (s, 3H), 2.69 (s, 3H). m/z (ESI, pos. ion) 454 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH:11]=[CH:12][CH:13]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B (K2CO3) using 1-(3-fluorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C([O-])(=O)C.[NH4+]>CN(C)C=O.O.C(#N)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.00 g, 7.66 mmol) in dimethylformamide (40 mL) was treated with cesium carbonate (3.74 g, 11.49 mmol) and p-fluoronitrobenzene (1.08 g, 7.66 mmol). The reaction mixture stirred at 80° C. for 5 h under a nitrogen atmosphere. The reaction mixture was added to ice. The precipitate was filtered and washed with water. The product, 4-amino-1-[4-nitrophenyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidine, was dried on the lyophilizer overnight to give 2.55 g (87%). 1H NMR (DMSO-d6, 400 MHz) δ 8.4952-8.4720 (m, 2H), 8.4142-8.3654 (m, 3H); LCMS (Perkin Elmer, Pecosphere C18 column, 3 um particle size, 33×4.6 mm; 100% 50 mM ammonium Acetate in Water to 100% Acetonitrile over 5 min, 3.0 to 3.5 mil/min) tR=3.73 min (100%) M+ 380.6.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][O:57][C:58]1[C:63]([C:64](O)=[O:65])=[CH:62][CH:61]=[CH:60][N:59]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:64]([C:63]1[C:58]([O:57][CH3:56])=[N:59][CH:60]=[CH:61][CH:62]=1)=[O:65]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: COc1ncccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Yield: 66.1 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), 2-(methyloxy)-3-pyridinecarboxylic acid (49.7 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was reduced in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with NaHCO3 (5 ml), twice. The organic layer was dried with magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo to yield the title compound (95 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-])=O.[H][H]>[Ni].C(O)C>[F:20][C:19]([F:22])([F:21])[C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:1][C:4]=2[CH:18]=1
Reactant: [H][H]
Reactant: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1)NCc1ccccc1O2

Procedure:
A solution of 55 parts of the ether obtained in the preceding paragraph in 800 parts of ethanol was hydrogenated over Raney nickel catalyst at room temperature and atmospheric pressure. When hydrogen uptake ceased, the catalyst was removed by filtration and the ethanol solvent was evaporated. The residue was then dissolved in 500 parts by volume of hexane, filtered, and then cooled. There was then obtained yellowish-white crystals which were separated by filtration to give 8-(trifluoromethyl)10,11,-dihydrodibenz-[b,f][1,4]oxazepine melting at about 86°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:39]2[CH2:38][CH2:37][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[F:29])[CH2:41][CH2:40]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 82.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (578 mg, 1.51 mmol, 82%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[I:23]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([I:23])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)ccc1O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(I)c1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(3-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (27 mL) and methanol (3 mL), and N-iodosuccinimide (1.79 g) and trifluoromethanesulfonic acid (5 droplets) was added to the solution, and then the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (1.30 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C)[C@@H:28]([O:29]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@H:18]3[O:19]C(=O)C)=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:46]([O:53][CH2:54][CH2:55]Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[OH-].[Na+]>C(#N)C.O.CO>[CH2:46]([O:53][CH2:54][CH2:55][N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[C:11]([O:16][C@@H:17]2[O:34][C@H:33]([CH2:35][OH:36])[C@@H:28]([OH:29])[C@H:23]([OH:24])[C@H:18]2[OH:19])=[N:12]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CCOCc3ccccc3)c2C)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-[(4-ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.030 g) and cesium carbonate (0.091 g) in acetonitrile (0.4 mL) was added benzyl(2-bromoethyl)ether (0.035 mL), and the mixture was stirred at 80° C. for 30 minutes. After cooling to room temperature, the reaction mixture was further stirred overnight. To the reaction mixture were added methanol (0.4 mL) and 2 mol/L aqueous sodium hydroxide solution (0.55 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was purified by CBA solid phase extraction (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give to give 1-(2-benzyloxyethyl)-4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.012 g).
Reaction SMILES: [C:1]([NH:5][CH:6]([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].S(OCC)(O[CH2:13][CH3:14])(=O)=O.[OH-].[K+]>>[C:1]([N:5]([CH:6]([CH3:8])[CH3:7])[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)NC(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: CCN(C(C)C)C(C)(C)C

Procedure:
A mixture of tert-butylisopropylamine (11.5 g, 0.1 mol) and diethyl sulfate (15.42 g, 0.1 mol) was refluxed for 2 h. Aqueous 8 M potassium hydroxide (20 ml, 0.16 mol) was added and the organic layer was separated. The aqueous layer was extracted with n-pentane (20 ml). The organic solutions were combined, dried over magnesium sulfate, and the product was isolated by distillation: 7.16 g, (50%), bp 140-142° C.; 1H NMR (CDCl3) δ0.99 (m, J=6.2 Hz, 9H, CH3), 1.10 (s, 9H, CH3), 2.55 (q, J=6.2 Hz, 2H, CH2, 3.35 (septet, J=6.2, 1H, CH).