Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]1[CH2:13][CH2:12][CH2:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]1=O.[NH2:15][C:16]([NH2:18])=[S:17]>O>[N:15]1[C:4]2[C:5]3[C:6]([CH2:11][CH2:12][CH2:13][C:3]=2[S:17][C:16]=1[NH2:18])=[N:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=C1c2cccnc2CCCC1Br
Reactant: NC(N)=S
Agent: Br
Solvent: O
Product: Nc1nc2c(s1)CCCc1ncccc1-2
Yield: 92.8 %

Procedure:
A solution of 6.78 g (21.12 mmol) of 6-bromo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one, hydrobromide and 1.93 g (25.35 mmol) of thiourea in 100 ml of water is heated on a steam bath for 2 hours. The mixture is filtered hot through a pad of Celite to remove a small amount of insoluble solid. The filtrate is cooled, basified with ammonium hydroxide, and a precipitate is collected. Recrystallization from acetonitrile affords 4.26 g (92.8%) of the title compound as a tan solid; mp 220°-222° C. (dec.).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-])=O)[CH:9]=[C:8]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)C.C1(C)C=CC=CC=1.C[O-].[Na+]>O1CCCC1.[C].[Pd]>[O:3]=[C:4]1[CH2:6][N:7]2[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9][C:10]3[C:15]2=[C:14]([CH:13]=[CH:12][CH:11]=3)[NH:16]1
Reactant: CCOC(=O)Cn1c(C(=O)OCC)cc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc3c2n1CC(=O)N3
Yield: 85.7 %

Procedure:
Ethyl 1-ethoxycarbonylmethyl-7-nitro-1H-indole-2-carboxylate (2.11 g, 6.59 mmol) was subjected to catalytic reduction in the presence of 10% palladium-carbon (0.20 g) in tetrahydrofuran (70 ml) at ordinary temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. Toluene (100 ml) and sodium methoxide (0.35 g, 6.48 mmol) were added to the residue, and the resulting mixture was heated under reflux for 2 hours. Then, the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/8) to obtain ethyl 2,3-dihydro-2-oxo-1H-pyrrolo [1,2,3-de]quinoxaline-5-carboxylate (1.38 g).
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[N:10]=[CH:9][NH:8][N:7]=2)[CH2:3][CH2:2]1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].O>N1C=CC=CC=1>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:7]1)=[O:15])[CH3:12]
Reactant: CCN(CC)C(=O)Cl
Reactant: c1nc(SCC2CC2)n[nH]1
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)C(=O)n1cnc(SCC2CC2)n1
Reaction time: 10 h
Yield: 83.5 %

Procedure:
To a solution of 3-cyclopropylmethylthio-1,2,4-triazole (3.8 g) in pyridine (30 ml), diethylcarbamoyl chloride (3.4 g) was added, and the resultant mixture was allowed to stand at room temperature for 10 hours. Water (250 ml) was added to the reaction mixture, which was then extracted with chloroform (150 ml) two times. The chloroform extract was washed with 1N hydrochloric acid (150 ml) two times and water (200 ml) one time, dried over magnesium sulfate, and concentrated under reduced pressure to give 5.2 g of 1-diethylcarbamoyl-3-cyclopropylmethylthio-1,2,4-triazole (Compound No. 1). Yield, 84%. M.P. 51°-52° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[F:14][C:15]([F:20])([F:19])[CH:16]1[O:18][CH2:17]1>>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][CH2:17][CH:16]([OH:18])[C:15]([F:20])([F:19])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: FC(F)(F)C1CO1
Product: OC(CNCc1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 36.8 %

Procedure:
EX-632A) 3-Trifluoromethoxybenzenemethanamine (1.15g, 6 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (0.67 g, 6 mmol) were combined and stirred at 80° C. for 1.5 h. The mixture was cooled to room temperature, and the resulting solid was recrystallized from hot hexanes. The white solid was isolated by vacuum filtration and washed with cold hexanes to give 0.67 g (37%) of pure 3-[[[3-(trifluoromethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol. 1H NMR (CDCl3) δ7.37 (t, 1H), 7.24 (d, 1H), 7.15 (m, 2H), 3.99 (m, 1H), 3.85 (d, 2H), 2.98 (dd, 1H), 2.88 (dd, 1H), 2.79 (s, 1H). 19F NMR (CDCl3) δ−58.19 (s, 3F), −78.88 (s, 3F). HRMS calcd. for C11H11F6NO2: 304.0772 [M+H]+, found: 304.0794.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:31]([N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[CH:42]=[C:41]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:40]=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cnn(Cc2ccccc2)c1
Yield: 43 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a brown solid (43% yield); 1H-NMR (d6-DMSO) 1.12 (9H, s), 3.61 (2H, t), 4.02 (2H, t), 5.24 (2H, s), 6.31 (1H, s), 7.27-7.33 (6H, m), 7.64 (1H, s); 13C-NMR (CDCl3) 27.8, 41.9, 56.2, 66.5, 125.5, 128.1, 128.2, 128.8, 130.9, 136.9; MS ES(+) 342.0 (M++1); HRMS m/z calcd for C19H23N3O3+H+ 342.1818 [M+H+]. Found 342.1826. IR λmax=1697 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15].I[CH2:19][CH3:20].C(N(CC)C(C)C)(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:19][CH3:20])[CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCI
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN1C[C@@H](C(=O)OC)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a stirred solution of methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate, from preparation 19 (10.5 g, 43 mmol) in tetrahydrofuran (215 mL) at room temperature under dry nitrogen was added iodoethane (3.8 mL, 48 mmol) and N,N-diisopropylethylamine (8.3 mL, 48 mmol) in single portions. The resulting mixture was stirred at room temperature under dry nitrogen for 72 hours, then quenched by the addition of water (200 mL) and extracted with ethyl acetate (2×250 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a 2:1 pentane:ethyl acetate mixture increasing polarity to 1:1. This afforded the title compound as a clear oil (7.9 g, 68%).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:57])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:46][C:47]=3[CH3:48])=[C:37]([O:55][CH3:56])[CH:36]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:56][O:55][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[O:41][CH2:42][C:43]1[N:44]=[C:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:46][C:47]=1[CH3:48])[C:34]([NH:33][C:23]1[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:24]=1)=[O:57]
Reactant: COc1cc(C(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (215 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 38 mg), and the mixture was stirred at room temperature for 20 min. A solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzamide (433 mg) in N,N-dimethylformamide (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless amorphous form (205 mg, yield 38%) from a fraction eluted with ethyl acetate-hexane (1:1 to 1:0, v/v).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]([F:31])([F:30])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:27][C:26]1[CH:25]=[CH:24][C:23]([CH:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C:7]([F:31])([F:30])[F:6])=[N:9][N:10]=4)[N:13]=3)[CH2:22][CH2:21]2)=[CH:29][CH:28]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of chloroacetyl chloride (140 mg, 1.24 mmol) in DCM (2 mL) was added dropwise to a stirred suspension of 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]aniline (obtained as described in Example 615) (375 mg, 1.03 mmol) and pyridine (164 mg, 2.07 mmol) in DCM (3 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 2 hours. The resulting precipitate was collected by filtration, washed with DCM (2 mL) and dried under vacuum to give 2-chloro-N-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (418 mg, 92%) as a solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[N:12]=[CH:11][N:10]=1>C1COCC1>[F:30][C:29]1[C:24]([C:20]2[N:19]([CH2:18][C:13]3[C:14]([CH2:15][CH2:16][CH3:17])=[C:9]([N:3]4[CH:7]=[CH:6][CH:5]=[N:4]4)[N:10]=[CH:11][N:12]=3)[CH:23]=[CH:22][N:21]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (15 mg, 60% in mineral oil, 0.37 mmol) in anhydrous THF (4 mL), a solution of pyrazole (20 mg, 0.3 mmol) in THF (3 mL) is added dropwise. The mixture is stirred at room temperature for 20 minutes. To the mixture, a solution of 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (100 mg, 0.3 mmol) in THF (3 mL) is added. The mixture is stirred at room temperature overnight. The solvent is removed in vacuo. The residue is dissolved in DCM, and the mixture is washed with brine, dried over (MgSO4), filtered, and the solvent is evaporated. The residue is purified by preparative TLC with 10% MeOH/DCM to give the title compound. 1H-NMR (CDCl3) δ: 0.95 (t, 3H), 1.55-1.61 (m, 2H), 3.11 (t, 2H), 5.94 (s, 2H), 6.46-6.47 (m, 1H), 7.16 (s, 1H), 7.22 (s, 1H), 7.34 (s, 1H), 7.51 (t, 1H), 7.77 (d, 1H), 8.26 (s, 1H), 8.45 (d, 1H), 8.71 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)[CH2:23][CH2:22]1
Reactant: OB(O)C1CC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C2CC2)c2ccc(C=O)cc21
Temperature: 97.5 °C
Reaction time: 24 h
Yield: 105.3 %

Procedure:
A degassed mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (51 mg, 0.12 mmol), cyclopropylboronic acid (21 mg, 0.24 mmol), powdered K3PO4 (103 mg, 0.48 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) in PhMe (2 mL) and H2O (0.1 mL) was heated with stirring in a sealed tube under Ar at 95-100° C. for 1 d. The crude mixture was concentrated and purified by prepTLC (SiO2 5:1 hexanes/EtOAc) to provide the title compound as a clear oil (40 mg, quant): 1H NMR (400 MHz, CDCl3) δ ppm 10.13 (s, 1H), 8.02 (s, 1H), 7.87 (d, J=8.28 Hz, 1H), 7.70 (d, J=8.28 Hz, 1H), 5.71 (s, 2H), 3.54 (d, J=8.53 Hz, 2H), 2.19-2.28 (m, 1H), 1.06-1.12 (m, 4H), 0.89 (d, J=8.28 Hz, 2H), −0.07 (s, 9H); MS ESI 317.1 [M+H]+, calcd for [C17H24N2O2Si+H]+ 317.5.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6](O)=[O:7])=[O:2].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([Cl:15])=[O:7])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 3-formyl-5-methylbenzoic acid (75.0 g, 0.457 moles), thionyl chloride (65 g, 0.0547 moles), and dimethylformamide (1 ml), in toluene (500 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 h. The toluene was eliminated in a rotavap to yield 3-formyl-5-methylbenzoic chloride used in the next step as such.
Reaction SMILES: [C@H:1]1([NH2:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21]>CN(C=O)C>[NH2:10][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][C@H:1]2[NH:11][C:20](=[O:21])[NH:19][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN=C=O
Reactant: Nc1ccc2c(c1)[C@H](N)CC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)N[C@@H]1CCc2ccc(N)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
(R)-2,3-dihydro-1H-indene-1,6-diamine (1 eq, 100 mg, 0.46 mmol) and triethylamine (2.5 eq, 158 μL, 1.15 mmol) were dissolved in 2 mL of DMF. The reaction mixture was cooled at 0° C. and ethyl isocyanatoacetate (1 eq, 59 mg, 51 μL, 0.46 mmol) was added dropwise and stirred for 2 hours at 0° C. The reaction mixture was concentrated and purified on reverse phase (H2O/MeCN) to afford the compound 46 (26 mg, 21%) as a white solid Rf=0.26. 1H NMR (300 MHz, DMSO): δ 6.91 (d, J=7.8, 1H), 6.47-6.39 (m, 2H), 6.36 (d, J=8.3 Hz, 1H), 6.11 (t, J=5.9 Hz, 1H), 5.02-4.88 (m, 3H), 4.13 (q, J=7.1 Hz, 2H), 3.83 (d, J=6.0, Hz 2H), 2.87-2.57 (m, 2H), 2.40-2.25 (m, 1H), 1.72. 1.56 (m, 1H), 1.31-1.17 (t, J=7.2 Hz, 3H). HPLC method A tr=5.60 nm (93.4%). ESI-MS m/z: 278.2 [M+H]+.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[OH:17])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[OH-].[Na+].[C:20](Cl)(=[O:23])[CH:21]=[CH2:22]>CC(C)=O.CCOCC>[C:20]([O:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)(=[O:23])[CH:21]=[CH2:22]
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=CC(=O)Oc1ccc(C)cc1-n1nc2ccccc2n1
Yield: 67.7 %

Procedure:
Into a flask provided with a magnetic stirrer is added 10.0 g of 2-(2H-benzotriazol-2-yl)-4-methylphenol dissolved in 350 ml acetone. Then 10% NaOH is added dropwise until the pH is 9. With stirring, 4.1 g of acryloyl chloride is added dropwise while maintaining the pH between 7 and 9 by addition of dilute base. After the addition is complete, the solvent is evaporated leaving a yellow residue which is dissolved in 80 ml ether and extracted with an equal volume of 5% NaOH solution until the aqueous washings are colorless. After evaporation of the ether, there is left 8.4 g of a yellow residue as the product, whose structure, is confirmed by NMR. The yield is 67.7%.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:27]2[C:28]3[C:33]([NH:34][C:26]=2[CH2:25][NH:24][CH2:23]1)=[CH:32][CH:31]=[CH:30][CH:29]=3>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:24]4[CH2:23][CH2:22][C:27]5[C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[NH:34][C:26]=5[CH2:25]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2c([nH]c3ccccc23)C1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and noreleagnine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=458.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([OH:19])=[C:6]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1.[CH3:20]I>CN(C)C=O>[CH3:3][C:4]1[C:5]([O:19][CH3:20])=[C:6]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(C)c(O)c(C(=O)C2CCCCC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C)cc(C)cc1C(=O)C1CCCCC1
Temperature: 70 °C
Yield: 105 %

Procedure:
53 Grams of 60% sodium hydride was gradually added to a solution prepared by dissolving 256.2 g of cyclohexyl 3,5-dimethyl-2-hydroxyphenyl ketone in 1 liter of dimethylformamide with stirring, generating heat at 70° C. After continuation of stirring for 30 minutes, the reaction mixture was cooled to room temperature and thereto was added dropwise 233 g of methyl iodide. The reaction mixture was further stirred at the same temperature for 2 hours and then added to 1 liter of ice water and stirred. The organic layer was extracted with 3 liters of ethyl acetate. The extract was washed with water and then with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 285.2 g of cyclohexyl 3,5-dimethyl-2-methoxyphenyl ketone.
Reaction SMILES: CN(C)/[CH:3]=[C:4]1/[C:5](=O)[C:6]2[S:10][C:9]([N:11]=CN(C)C)=[N:8][C:7]=2[CH2:16][CH2:17]/1.[OH-].[Na+].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25]([NH2:27])=[NH:26])[CH3:23]>COCCO>[NH2:11][C:9]1[S:10][C:6]2[C:5]3[N:27]=[C:25]([N:24]([CH2:28][CH3:29])[CH2:22][CH3:23])[N:26]=[CH:3][C:4]=3[CH2:17][CH2:16][C:7]=2[N:8]=1
Reactant: CCN(CC)C(=N)N
Reactant: CN(C)C=Nc1nc2c(s1)C(=O)/C(=C/N(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCN(CC)c1ncc2c(n1)-c1sc(N)nc1CC2
Temperature: 125 °C
Reaction time: 3.5 h

Procedure:
To N′-{6-[1-dimethylamino-meth-(E)-ylidene]-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl}-N,N-dimethyl-formamidine (Stage A.2, 1 g, 3.59 mmol) in 2-methoxyethanol (10 mL) was added NaOH (0.539 g, 13.47 mmol) and N,N-diethylguanidine (0.454 g, 3.94 mmol) under argon at rt. The RM was stirred for 3.5 h at 125° C. and then cooled to rt. After evaporation in vacuo the residue was dissolved in 0.1 M HCl (50 mL) and washed with EtOAc. The aqueous layer was then basified with 6 N NaOH and extracted 3× with EtOAc. the organic layers were dried over Na2SO4, evaporated and dried under high vacuum at 60° C. to give the title compound as orange crystals. LC: tR 3.60 min (method D). MS: M+H=276. 1H-NMR in DMSO-d6: 7.91 (s, 1H); 7.59 (s, 2H); 3.50 (q, 4H); 2.69 (dd, 4H); 1.07 (t, 6H).
Reaction SMILES: CSC.B.O=[C:6]1[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:8]=2[NH:7]1>C1COCC1>[O:13]=[S:10]1(=[O:12])[CH2:11][CH2:6][NH:7][C:8]2[CH:16]=[C:15]([S:17](=[O:19])(=[O:20])[NH2:18])[S:14][C:9]1=2
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC(=O)N2
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCN2
Temperature: 25 °C
Yield: 15.1 %

Procedure:
Borane dimethylsulfide in THF (4.4 ml, 10M, 44 mmol) was added slowly to a solution of 2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine (2.5 g, 8.9 mmol) in THF (10 ml) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for an addidition hour. Excess borane was destroyed by the addition of 6N HCl and borane adducts were cleaved by heating at reflux for one hr. The solvent was removed and the residue was partitioned between water and ethyl acetate. The organic phase was washed with water and brine then dried over sodium sulfate. After filtration and evaporation of the solvent, the residue was chromatographed over silica gel with CHCl3 /MeOH/NH4OH (80:20:2). Fractions containing the desired product were combined, evaporated and the solid residue was triturated with ethyl acetate to yield 0.36 g 2,3-dihydro-4,4-dioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine, mp 250°-252° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24]Cl>CC#N>[CH3:17][N:18]1[CH2:24][CH2:19][CH2:20][CH2:21][CH:22]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:23]1
Reactant: CN1CCCCC1CCl
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCCCC(Oc2cccc(C=O)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-hydroxybenzaldehyde (3.66 g, 0.03 mol), K2CO3 (12.43 g, 0.09 mol), and CH3CN (100 ml) was stirred at room temperature for 1/2 hour, then N-methyl-2-chloromethylpiperidine hydrochloride (5.49 g, 0.03 mol) was added. The reaction mixture was stirred until the reaction was complete, then the solvent was removed in vacuo and the residue was partitioned between CHCl3 and water. The aqueous layer was extracted with CHCl3 (3×100 ml) and the combined organic layers were concentrated in vacuo to afford 3-(1-methyl-3-hexahydroazepinyloxy)benzaldehyde.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:17])=[C:10]2[O:14][CH:13]([O:15][CH3:16])[CH2:12][C:11]=12)=[O:5])C.[OH-].[Na+]>CO.O>[Cl:17][C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:11]2[C:10]=1[O:14][CH:13]([O:15][CH3:16])[CH2:12]2
Reactant: CCOC(=O)c1ccc(Cl)c2c1CC(OC)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC1Cc2c(C(=O)O)ccc(Cl)c2O1
Temperature: 55 °C

Procedure:
A mixture of 7-chloro-2-methoxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester (1.17 mmol) and NaOH (1.75 mmol) in MeOH (1.3 mL) and water (1.3 mL) is heated to 55° C. for 90 min. The mixture is concentrated in vacuo and made acidic by addition of aq. HCl (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. 1H-NMR (DMSO-d6): δ=13.1 (bs, 1H); 7.45 (d, J=8.3 Hz, 1H); 7.38 (d, J=8.5 Hz, 1H); 5.87 (d, J=6.3 Hz, 1H); 3.67 (dd, J=18.1 Hz, J=6.0 Hz, 1H); 3.47 (s, 3H); 3.30 (d, 1H).