Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.O[CH2:14][CH2:15][C@@H:16]1[CH2:18][C@@H:17]1[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]2([CH3:31])[CH2:30][CH2:29]2)=[O:26])[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C.O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3([CH3:31])[CH2:30][CH2:29]3)=[O:26])[CH2:21][CH2:20]2)=[CH:7][CH:6]=1
Reactant: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCO)CC2)CC1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl (4-hydroxyphenyl)acetate (37 mg, 0.22 mmol), 1-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (60 mg, 0.22 mmol), and triphenylphosphine (88 mg, 0.34 mmol) were dissolved in tetrahydrofuran (1 mL) under an atmosphere of nitrogen and cooled at 0° C. DIAD (68 mg, 0.34 mmol) was added and the resulting mixture was warmed to RT and stirred overnight. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL), and the layers were separated. The organic layer was washed with brine (2×10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (24 g of silica gel, ISCO, eluted with a gradient 0-100% ethyl acetate in Hexane) to afford the title compound. HPLC/MS; 1.27 min, 438 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2O[C:10](=[O:18])[C:11]3[CH:17]=[N:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[C:4]([CH3:19])[C:3]=1[O:20][C:21](=[O:23])[CH3:22].[CH:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH2:26][CH3:27])[CH3:25]>C(O)(=O)C>[CH:24]([C:28]1[CH:29]=[CH:30][C:31]([N:32]2[C:10](=[O:18])[C:11]3[CH:17]=[N:16][CH:15]=[CH:14][C:12]=3[N:13]=[C:8]2[C:6]2[CH:5]=[C:4]([CH3:19])[C:3]([O:20][C:21](=[O:23])[CH3:22])=[C:2]([CH3:1])[CH:7]=2)=[CH:33][CH:34]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CC(=O)Oc1c(C)cc(-c2nc3ccncc3c(=O)o2)cc1C
Solvent: CC(=O)O
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OC(C)=O)c(C)c3)nc3ccncc3c2=O)cc1
Temperature: 120 °C
Reaction time: 60 h

Procedure:
To a solution of acetic acid 2,6-dimethyl-4-(4-oxo-4H-pyrido[4,3-d][1,3]oxazin-2-yl)-phenyl ester (1.04 g, 3.35 mmol) in glacial acetic acid (20 mL) was added 4-(sec-butyl)-aniline (B) (0.750 g, 5.02 mmol). The reaction mixture was stirred at 120° C. for 60 hours under nitrogen and cooled to room temperature. Acetic acid was removed under reduced pressure. The residue was diluted with water (100 mL), neutralized to pH 7 with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate (200 mL). The organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Solvent was evaporated and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 20-30% ethyl acetate in hexanes as eluent) to give acetic acid 4-[3-(4-sec-butyl-phenyl)-4-oxo-3,4-dihydro-pyrido[4,3,d]pyrimidin-2-yl]-2,6-dimethyl-phenyl ester (7) as a white solid. Yield: 0.580 g (39%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN>CN(C=O)C.C1COCC1>[CH3:33][NH:34][C:6]([CH:4]1[CH2:5][C:2]([OH:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:22])([F:23])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8]
Reactant: O=C(O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
To a stirred solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 4, 0.060 g, 0.118 mmol) in dry DMF (1 mL) was added HATU (0.067 g, 0.177 mmol), HOBt (0.0175 g, 0.129 mmol), DIPEA (0.03 g, 0.236 mmol) and saturated solution of methyl amine in THF (2 mL) at 0° C. Resulting reaction mixture was stirred 0° C. for 2 hours and at room temperature for 18 hours. After complete consumption of starting material, reaction mixture was quenched with water (5 mL), extracted with EtOAc (10 mL). Organic layer was washed with saturated solution of lithium chloride (2×20 mL), water (2×20 mL), dried over sodium sulphate and evaporated in vacuo to get brown crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1.2% methanol in DCM to afford sticky mass, which was crystallized by chloroform:pentane (1:9) to afford white solid (0.018 g, 29%). 1H-NMR (400 MHz, CDCl3) δ: 2.49-2.52 (m, 2H), 2.81-2.83 (m, 2H), 2.84-2.86 (m, 1H), 2.88 (d, 3H, J=4.88 Hz), 3.67 (d, 1H, J=17.08 Hz), 4.07 (d, 1H, J=17.16 Hz), 5.67 (bs, 1H), 5.81 (s, 1H), 7.55 (d, 2H, J=8.4 Hz), 7.62-7.64 (m, 4H). LC-MS (m/z): [M−H] 518.80. HPLC purity: 98.48%.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].[C:8](OC)(=O)[CH:9]=[CH2:10].[C:14](#[N:17])[CH:15]=[CH2:16].[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:14](#[N:17])[CH:15]=[CH2:16].[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OC
Reactant: C=C(C)C(=O)OC
Solvent: C=Cc1ccccc1
Solvent: C=CC#N
Product: C=CC(=O)OCCCC

Procedure:
Polymerization was conducted in the same manner as in Production Example 16 excepting that 36 parts of methyl methacrylate and 2 parts of methyl acrylate used in graft polymerization was changed to 10 parts of acrylonitrile and 28 parts of styrene, obtaining graft copolymer latex obtained by graft-polymerizing acrylonitrile and styrene to butyl acrylate rubber.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([Cl:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:17]>>[Cl:28][C:23]1[CH:22]=[C:21]([S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:26]=[CH:25][C:24]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 25 step (iv) and the product of example 3 step (i).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][CH3:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:8][O:9][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][CH3:30])[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC)C(C)=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
Triethylamine (0.167 mL, 1.2 mmol) was added to O-methyl-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]hydroxylamine (0.32 g, 1.0 mmol) in dichloromethane (10 mL) and cooled to 0° C. Acetic anhydride (0.103 mL, 1.1 mmol) was added dropwise and the reaction mixture was stirred for 6 hours. The reaction was then diluted with dichloromethane (40 mL) and saturated aqueous sodium bicarbonate (10 mL) and stirred overnight. The phases were separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organics were dried over potassium carbonate, filtered, and concentrated to afford 0.35 g of N-methoxy-N-[4-(2-propy-1H-imidazo[4,5-c]quinolin-1-yl)butyl]acetamide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@H:3]([OH:5])[CH3:4].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]>>[F:1][C:2]([F:7])([F:6])[C@H:3]([O:5][C:9](=[O:10])[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[CH3:4]
Reactant: C[C@@H](O)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-1,1,1-trifluoro-propan-2-ol and 4-nitrophenyl chloroformate following a procedure analogous to that described for Intermediate 20.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([O:29][CH2:30][C:31]=1[CH2:32][CH:33]=[O:34])[CH:27]([NH:35][C:36](=[O:66])[C:37](=[N:63][O:64][CH3:65])[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[S:41][CH:42]=1)[C:26]2=[O:67])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[S:68](Cl)([C:71]1[CH:77]=[CH:76][C:74]([CH3:75])=[CH:73][CH:72]=1)(=[O:70])=[O:69].CCOCC>C(Cl)Cl>[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([O:29][CH2:30][C:31]=1[CH:32]=[CH:33][O:34][S:68]([C:71]1[CH:77]=[CH:76][C:74]([CH3:75])=[CH:73][CH:72]=1)(=[O:70])=[O:69])[CH:27]([NH:35][C:36](=[O:66])[C:37](=[N:63][O:64][CH3:65])[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[S:41][CH:42]=1)[C:26]2=[O:67])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC=O)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
Triethylamine (0.27 cc) is added, in the course of 10 minutes, to a solution, cooled to -5° C., of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-(2-oxoethyl)-5-oxa-1-azabicyclo-[4.2.0]oct-2-ene (1.00 g) and tosyl chloride (0.35 g) in methylene chloride (20 cc). The mixture is stirred at -5° C. for 10 minutes and then left to return to 20° C. The mixture is then stirred for 30 minutes. The solvent is evaporated off under reduced pressure (350 mm Hg; 47 kPa). This yields a chestnut-coloured oil, which solidifies on stirring with ether (100 cc). The solid is filtered off and dried. This yields the E form of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-8-oxo-3-(2-tosyloxyvinyl)-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.38 g) in the form of a cream-coloured powder. The filtrate is concentrated to a residual volume of 5 cc and isopropyl ether (100 cc) is added. A pale yellow solid separates out. It is isolated on a filter and a second fraction of the E form of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-(2-tosyloxyvinyl)-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.11 g) is obtained.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([OH:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)OCC1.O=C(C1CCCC2([O:35][CH2:34][CH2:33][O:32]2)C1)CC(OCC)=O.O=C(C1CCC2(OCCO2)CC1)CC(OCC)=O>>[O:32]1[C:6]2([CH2:5][CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([OH:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7]2)[O:35][CH2:34][CH2:33]1
Reactant: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Reactant: CCOC(=O)CC(=O)C1CCCC2(C1)OCCO2
Agent: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Product: Oc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12

Procedure:
5-(1,4-dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidin-7-ol was synthesized in a manner similar to the synthesis of 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol, but with ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-7-yl)propanoate substituted for ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate.
Reaction SMILES: C(S[C:9]1[N:14]=[C:13]2[NH:15][C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)C1C=CC=CC=1.Cl[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](OO)=O)[CH:29]=1.[O-:38][S:39]([O-:42])(=S)=O.[Na+].[Na+]>ClCCl>[CH2:34]([S:39]([C:9]1[N:14]=[C:13]2[NH:15][C:16](=[O:26])[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:18][C:12]2=[CH:11][N:10]=1)(=[O:42])=[O:38])[C:30]1[CH:29]=[CH:28][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1Nc2nc(SCc3ccccc3)ncc2CN1c1ccccc1Cl
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1 g (2.61 mmol) of 7-benzylthio-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 10 mL of dichloromethane was cooled in ice and treated with 1.29 g (5.23 mmol) of 70% 3-chloroperbenzoic acid. The mixture was stirred at room temperature for 2 hours, then treated with 25 mL of 10% aq. Na2S2O3 and left to stir for 30 minutes. The reaction was diluted with 100 mL dichloromethane and the phases were separated. The organic phase was washed with 10% aq. K2CO3, brine, and then dried over magnesium sulfate and filtered. Concentration of the filtrate under reduced pressure gave 0.73 g of 7-benzylsulfonyl-3-(2-chlorophenyl)-3,4-dihydropyrimido[4,5-d]-pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:25]([CH2:24][CH2:23][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:10]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:43]
Reactant: CCOC(=O)CCCCCBr
Reactant: c1ccc(CNCCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCCN(CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)Cc1ccccc1

Procedure:
A suspension of 3,4-bis(phenylmethoxy)-N-phenylmethyl benzeneethanamine (10 g), ethyl 6-bromohexanoate (10.5 g), potassium carbonate (6.34 g) and potassium iodide (1 g) in acetonitrile (250 ml) was heated under reflux for 24 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])(O)=[O:19].[Na+].OOS([O-])=O.[K+].[OH2:29]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)(=[O:19])=[O:29])=[CH:4][CH:3]=1
Reactant: O
Reactant: Fc1ccc(Sc2c[nH]c3ncccc23)cc1
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=S(=O)(c1ccc(F)cc1)c1c[nH]c2ncccc12
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 3-[(4-fluorophenyl)thio]-1H-pyrrolo[2,3-b]pyridine (3.36 g, 13.8 mmol) in acetone is treated with a solution of NaHCO3 (2.90 g, 34.5 mmol) in water. The reaction is then treated with Oxone®1 (25.5 g, 41.4 mmol), stirred for 3 h at 20° C., diluted with water, cooled in an ice-water bath and filtered. The filtercake is washed with water and vacuum dried to afford the title compound as a white solid 1.73 g, mp 212-213° C., characterized by mass spectral and NMR analyses.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:13]/[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])/[CH:3]=1.[CH3:22][N:23]1[C:27]([SH:28])=[N:26][N:25]=[N:24]1>C1COCC1>[CH3:22][N:23]1[C:27]([S:28][C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[N:13][S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH:3]=2)=[N:26][N:25]=[N:24]1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Reactant: Cn1nnnc1S
Solvent: C1CCOC1
Product: Cn1nnnc1SC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
36 mg (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)-thiophene-2-sulfonamide (12a) was dissolved in 3 ml THF, to which was added 11.7 mg 1-methyl-tetrazole-5-thiol. The reaction mixture was stirred at r.t. for 2 hrs and concentrated via rotavap. The residue was dissolved in dichloromethylene and triturated with hexane. The precipitate was filtered and washed with dichloromethylene/hexane (1:1) affording the title compound 28.8 mg (68.9%) as an orange-red solid, m.p.: 172° C. (dec.).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[Cl:20][Si](C)(C)[CH3:22]>CO>[Cl-:20].[CH3:22][O:17][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C@@H:9]([NH3+:8])[CH3:10])=[CH:12][CH:13]=1)=[O:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}benzoic acid from Example 1, Step 8 (48.0 g, 181 mmol) in MeOH (175 mL) at r.t. was added chlorotrimethylsilane (116 mL, 905 mmol) and the suspension was stirred at r.t. for 6 h (became a clear solution). The solution was concentrated in vacuo to give a white solid which was triturated with ether and filtered. The white solid was collected and dried under high vacuum to give the desired product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[CH3:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]1[CH2:31]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:31][C:21]1[N:20]([CH3:19])[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: Cc1cccc(COc2cccc(O)c2)c1CO
Reactant: Cn1c(CCl)nc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1CO
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(2-hydroxymethyl-3-methyl-benzyloxy)-phenol (87 mg, 0.38 mmol, example 100) and (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl chloride (94 mg, 0.45 mmol, example 99) in DMF (1 mL) is added powdered K2CO3 (78 mg, 0.5 mmol). The resulting mixture is warmed to 60° C. and stirred at this temperature for 5 h. This mixture is cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 40% ethyl acetate/30% dichloromethane in hexanes) to give the title compound as a foam. MS (ESI) 417 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.S(Cl)([Cl:30])=O>C(Cl)(Cl)Cl.O>[Cl:30][CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1c(-c2ccccc2)oc2c(CO)cccc2c1=O
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)oc2c(CCl)cccc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
53.4 g of Intermediate II and 38.8 ml of anhydrous triethylamine were dissolved in 440 ml of chloroform. Into this solution, maintained at -10° to -20C., there was dropped a solution of 19.8 ml of thionyl chloride in 80 ml of anhydrous chloroform. The reaction mixture was stirred at room temperature for 4 hours, and then diluted with 400 ml of water. The aqueous phase was extracted with chloroform, and the extracts were added to the chloroform phase. The chloroform solution was washed with brine, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. Yield: 56 g of the title compound, which on recrystallization from ethanol was shown to have a melting point of 112°-113° C.
Reaction SMILES: [CH2:1]=O.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[F:12][C:13]1[CH:30]=[CH:29][C:16]([C:17]([NH:19][C:20](=[O:28])[NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:18])=[CH:15][CH:14]=1.N>C(O)(=O)C.O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]([NH:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:1][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:3][CH:4]=3)[CH2:26][CH2:27]2)=[O:28])=[O:18])=[CH:29][CH:30]=1
Reactant: C=O
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(NC(=O)c1ccc(F)cc1)NC1CCNCC1
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: O=C(NC(=O)c1ccc(F)cc1)NC1CCN(Cc2c[nH]c3ccccc23)CC1
Reaction time: 5 h
Yield: 85 %

Procedure:
Formaldehyde (0.4 cm3, 40% aqueous solution) was added to a stirred solution of indole (0.6 g, 0.005 mol) and 4-(4-fluorobenzoylureido)piperidine (1.33 g, 0.005 mol) in acetic acid (3 cm3). The reaction was allowed to stand for 5 hours then diluted with water (50 cm3). The turbid solution was basified by addition of ammonia and the precipitated solid collected by filtration, washed with water and ether to give 1.7 g (85%) of the title compound as the free base. The base was suspended in ethanol (10 cm3) and acidified with ethanolic hydrogen chloride. After stirring at room temperature for 0.5 hours and 0° C. for 0.5 hours the suspension was filtered to remove the hydrochloride. The hydrochloride was then dissolved in hot methanol acidified further with ethanolic hydrogen chloride and cooled to give the crystalline hydrochloride (1.4 g, 65.2%) double m.p. 210° C. and 260° C.
Reaction SMILES: Cl.[F:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][O:10]2)=[C:5]([I:14])[C:4]=1[O:15]COC>C1COCC1.CC(OC)(C)C>[F:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][O:10]2)=[C:5]([I:14])[C:4]=1[OH:15]
Reactant: COCOc1c(F)c(F)c2c(c1I)CCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Oc1c(F)c(F)c2c(c1I)CCCO2
Temperature: 20 °C
Reaction time: 18 h

Procedure:
10.4 ml of conc. HCl are added to a solution of 20.2 g (56.7 mmol) of 7,8-difluoro-5-iodo-6-methoxymethoxychroman in 100 ml of THF, and the mixture is stirred at 20° C. for 18 h. The batch is diluted with MTBE, and the solution is washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:MTBE=1:1), giving 7,8-difluoro-5-iodochroman-6-ol as a pale-brown solid.