Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[C:17](Br)=[C:16]([O:19][CH3:20])[N:15]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([Li])CCC.[CH2:32]([O:34][C:35]([C:37]1[CH:38]=[C:39]([N:43]=[C:44]=[O:45])[CH:40]=[CH:41][CH:42]=1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35](=[O:36])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44]([C:17]2[C:13]([CH2:12][O:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[N:14][N:15]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:16]=2[O:19][CH3:20])=[O:45])[CH:38]=1)[CH3:33]
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: COc1c(Br)c(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Agent: [Li]CCCC
Product: CCOC(=O)c1cccc(NC(=O)c2c(COC34CC5CC(CC(C5)C3)C4)nn(C3CCCCC3)c2OC)c1

Procedure:
The compound was prepared by treating 3-(adamantan-1-yloxymethyl)-4-bromo-1-cyclohexyl-5-methoxy-1H-pyrazole with n-butyl lithium and 3-ethoxycarbonylphenyl isocyanate as outlined in Reaction Scheme 4.
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]1[CH2:30][O:29][CH2:28][CH:27]1[OH:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CN(C=O)C>[O:31]=[C:27]1[CH2:28][O:29][CH2:30][CH:26]1[NH:25][C:11]([CH:10]([NH:9][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:8])[CH2:14][S:15]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:16])=[O:12]
Reactant: NC1COCC1O
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1COCC1NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (100 mg, 0.28 mmol), 4-aminotetrahydrofuran-3-ol (100 mg, 0.96 mmol), EDC (200 mg, 1.04 mmol), and HOBt (200 mg, 1.28 mmol) were combined. DMF (2 mL) was added and then 4-methylmorpholine (0.2 mL). The mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (100 mL) the solution was washed with 1N aqu. HCl (30 mL), sat. aqu. NaHCO3 (30 mL) and brine (30 mL), dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (300 mg, 0.71 mmol) was added, and the reaction mixture was stirred at ambient temperature for 1 h. After dilution with ethyl acetate (100 mL), the solution was washed with 0.26M Na2S2O3 in sat. aqu. NaHCO3 (30 mL), sat. aqu. NaHCO3 and brine, dried with MgSO4, and evaporated under vacuum. Purification by flash-chromatography on silica gel (ethyl acetate) gave morpholine-4-carboxylic acid [1-(4-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide (8.6 mg, 0.020 mmol) as a colorless glass. Mixture of diastereomers: 1H NMR: (DMSO) [8.42 (d, J=6.8 Hz), 7.15 (d, J=7.2 Hz), 1H], 7.40–7.32 (m, 5H), [7.06 (d, J=8 Hz), 7.05 (d, J=8 Hz), 1H], 4.78–4.68 (m, 1H), 4.49 (s), 4.48 (s), 2H], 4.32–3.75 (m, 5H), 3.60–3.23 (m, 10H). MS: (M+H)+ 440.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.O[N:21]1[C:25]2N=CC=C[C:24]=2N=N1.C(N)C.O>O1CCCC1.C(Cl)(Cl)Cl>[CH2:25]([NH:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:4]=1)[CH3:24]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: On1nnc2cccnc21
Agent: CCN
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 24 h
Yield: 831.3 %

Procedure:
4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.3 g) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g) and 3H-[1,2,3] 1-hydroxy-7-azabenzotriazole (0.077 g) was added to a stirred solution of ethylamine in tetrahydrofuran (2M, 5 ml) in chloroform (30 ml) and the mixture was stirred for 24 h. The mixture was poured into water, passed through a hydrophobic filter tube and the organic phase was concentrated under vacuum. The residual solid was purified on an SCX cartridge eluting with methanol to give the title compound as a pale yellow solid (1.36 g)
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O=C1CCC(=O)N1[O:32][C:33]([C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41](=[O:57])[CH2:42][CH2:43][CH:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[CH2:36]1)=O.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH2:18]([O:17][C:15]1[CH:16]=[C:11]([C@@H:2]([NH:1][C:33]([C@@H:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:41](=[O:57])[CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:46][CH2:45]3)[CH2:36]2)=[O:32])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:12]=[N:13][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1cncc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccccc2)c1

Procedure:
To tert-butyl (3S)-3-amino-3-[5-(benzyloxy)pyridin-3-yl]propanoate (1.15 g, 3.5 mmol) in DMF (13.4 mL) was added tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate and triethylamine (1.46 mL, 10.5 mmol) in dichloromethane (13.5 mL) at 0° C. After 3 hours the mixture was quenched by addition of saturated aqueous ammonium chloride solution, phases were separated and the aqueous phase was extracted with diethyl ether. Combined organic extracts were dried over sodium sulphate, concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 20 to 100% followed by methanol in ethyl acetate 0 to 20%) to yield 1.76 g tert-butyl 4-{3-[(3R)-3-({(1S)-1-[5-(benzyloxy)pyridin-3-yl]-3-tert-butoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=2)[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[C:41]([C:49]([F:51])([F:52])[F:50])[CH:40]=2)[C:36]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (188.7 mg, 1.06 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (237 mg, 0.626 mmol) in methylene chloride (4 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warn to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (188 mg, 1.88 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (83 mg, 29%) as an amorphous solid: EI-HRMS m/e calcd for C20H23F3N2O3S2 (M+) 460.1102, found 460.1100.
Reaction SMILES: [Cl-:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>C1(C)C(C)=CC=CC=1>[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[CH:8][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][Cl:1])=[CH:31][CH:30]=1
Reactant: [Cl-]
Reactant: Cc1ccc(C=O)cc1
Reactant: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(C=CC(=O)CCCCCl)cc1
Temperature: 25 °C

Procedure:
2 parts of [(tetrahydro-2H-pyran-2-ylidene)methyl] triphenylphosphonium chloride and 0.82 part of 4-methylbenzaldehyde were combined in 45 parts of xylene. This suspension was maintained under a nitrogen atmosphere and was refluxed for 4.5 hours to produce a clear solution. After the solution was cooled to room temperature, the xylene was removed at a temperature of about 40° C., under reduced pressure to yield a product mixture. This mixture was separated chromatographically on a silica column using as an elution solvent increasing concentrations of ethyl acetate in toluene, to yield 1-(4-methylphenyl)-7-chloro-1-hepten-3-one in the fraction containing 1.5 percent by volume of ethyl acetate in toluene which, after recrystallization from cyclohexane, melted at about 79°-82° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])CO)[CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>CO.CCOCC.CCCCCC>[F:17][C:14]([F:15])([F:16])[C:10](=[O:13])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a solution of 4.9 g (15.8 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol in 100 mL of MeOH was added 10 g (45.9 mmol) of sodium periodate. The mixture was stirred for 4 hours and was then diluted with 100 mL of ether and 100 mL of hexane, filtered through diatomaceous earth, and concentrated in vacuo. The crude residue was dissolved in hexane and passed through a pad of silica gel, eluting first with hexane then with EtOAc-hexane (2:98, then 4:96) to afford 3.85 g (87%) of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a clear oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[N+]([O-])([O-])=O.[NH4+].[Ce].[Ce].[I:19]I>C(#N)C>[I:19][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([F:1])([F:10])[F:11])[NH:6][CH:7]=1
Reactant: O=C(c1ccc[nH]1)C(F)(F)F
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: O=C(c1cc(I)c[nH]1)C(F)(F)F
Yield: 112.1 %

Procedure:
An acetonitrile solution (20 ml) of 2-(trifluoroacetyl)-1H-pyrrole (0.5 g), dicerium ammonium nitrate (0.84 g) and iodine (0.47 g) was refluxed for 2 hours. After cooling, the reaction solution was washed with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 4-iodo-2-(trifluoroacetyl)-1H-pyrrole (0.6 g).
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=C\C(O)=O.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]2[CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][NH:17][CH2:18][CH2:19][C:13]=2[CH:12]=1.[Cl:28][S:29](O)(=[O:31])=[O:30].S(Cl)(Cl)=O>>[C:1]([N:17]1[CH2:16][CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:26]=[C:27]([S:29]([Cl:28])(=[O:31])=[O:30])[C:11]([O:10][CH3:9])=[CH:12][C:13]=2[CH2:19][CH2:18]1)(=[O:8])[CH3:2]
Reactant: COc1ccc2c(c1)CCNCC2c1ccccc1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)/C=C\C(=O)O
Solvent: O=S(Cl)Cl
Product: COc1cc2c(cc1S(=O)(=O)Cl)C(c1ccccc1)CN(C(C)=O)CC2

Procedure:
Following the general procedure of Example 2, 7-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate is acetylated and treated with chlorosulfonic acid followed by thionyl chloride to give 3-acetyl-8-chlorosulfonyl-7-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:19](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([NH2:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CCc1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (1.08 g), triethylamine (1.1 ml) and tetrahydrofuran (100 ml) was added ethyl chlorocarbonate (0.6 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (20 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-(5-phenyl-4-isoxazolyl)propionamide (0.82 g, yield 78%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 151–152° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH:19]([CH3:21])[CH3:20])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][C:6]([OH:22])=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32].C(Cl)(Cl)Cl>CN(C=O)C.C(Cl)Cl>[CH:19]([C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][C:6]([O:22][CH2:30][C:31]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:32])=[CH:7][CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1)([CH3:20])[CH3:21]
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4cc(O)ccc4c3n21
Reactant: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H]1COCc2nc3c(N)nc4cc(OCC(=O)N5CCOCC5)ccc4c3n21
Temperature: 65 °C
Reaction time: 18 h
Yield: 42.3 %

Procedure:
A solution of (11S)-6-amino-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-3-ol (0.30 g, 1.0 mmol) dissolved in 5 mL of DMF was treated with cesium carbonate (1.0 g, 3.0 mmol) and 4-(bromoacetyl)morpholine (0.23 g, 1.1 mmol). After stirring for 18 hours at 65° C., the reaction mixture was concentrated under reduced pressure to give a solid. The solid was dissolved in CH2Cl2 (100 mL) and washed with H2O (100 mL). The organic layer was concentrated under reduced pressure to give a solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a white solid which was crystallized from acetonitrile to give 0.18 g of the title compound as white crystals, mp 137-139° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([O:21]C)[O:19]C)[CH:10]([CH2:23][OH:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36]N)=[CH:32][CH:31]=2)[CH:29]=1.[C:38]([O-:41])([O-:40])=O.[K+].[K+]>OS(O)(=O)=O>[C:18]([OH:21])(=[O:19])[C:38]([OH:41])=[O:40].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[C:32]3[C:33](=[CH:34][CH:35]=[C:30]([N:28]4[CH:29]=[N:25][N:26]=[CH:27]4)[CH:31]=3)[NH:36][CH:18]=2)[CH:10]([CH2:23][OH:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(-n2cnnc2)cc1
Reactant: O=C([O-])[O-]
Reactant: COC(CCCCN1CCN(Cc2ccccc2)CC1CO)OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)C(=O)O
Product: OCC1CN(Cc2ccccc2)CCN1CCCc1c[nH]c2ccc(-n3cnnc3)cc12
Yield: 23 %

Procedure:
A mixture of 4-benzyl-2-hydroxymethyl-1-(5,5-dimethoxypentyl)piperazine (245 mg, 0.73 mmol) and 4-(1,2,4-triazol-4-yl)phenylhydrazine (127 mg, 0.73 mmol) in 4% H2SO4 (8 mL) was heated at reflux overnight. The solution was basified using sat. K2CO3 solution and extracted with nBuOH (2×30 mL). The combined organic layers were evaporated and the residue chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (90:10:1). The title compound (73 mg, 23%) was isolated as a pale yellow foam. The free base was converted to the oxalate salt by treatment with oxalic acid in methanol/water. mp 130°-132° C. Found: C, 59.90; H, 6.18; N, 15.35%. C25 H30N6O. 1.3 (C2H2O4). 0.3 (H2O). 0.1 (Et2O) requires C, 60.01; H, 6.15; N, 15.00%. 1H NMR (360 MHz, d6 -DMSO) δ 1.92-2.10 (2H, m), 2.36-2.46 (2H, m), 2.70-3.06 (6H, m), 3.14-3.36 (3H, m), 3.57-3.72 (4H, m), 7.24-7.40 (7H, m), 7.49 (1H, d, J=8.6 Hz), 7.79 (1H, s), 8.99 (2H, s), 11.19 (1H, br s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[OH-].[Na+].[SH:13][CH2:14][CH2:15][OH:16]>COC1C=CC(O)=CC=1.O1CCCC1>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][S:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:5]=1)=[CH2:8]
Reactant: OCCS
Reactant: C=Cc1ccc(CCl)cc1
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1ccc(CSCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
A polymerization inhibitor, p-methoxyphenol (1.24 g; 0.01 mole), was added to a mixture of 152 g (1.0 mole) of p-(chloromethyl)styrene, 60 g (1.5 moles) of sodium hydroxide and 0.5 liter of tetrahydrofuran. The resulting mixture was boiled, and 78 g (1.0 mole) of 2-mercaptoethanol was added dropwise over 0.5 hour. The boiling was continued for 3 hours. After cooling to room temperature, the reaction mixture was filtered by the same operation as in Example 1, and distilled under reduced pressure (140-145 ° C./1-2 mmHg) to give 93 g of 2-(4-vinylbenzylthio)ethanol as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[CH2:31])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]=[CH:12][C:7]=1/[CH:31]=[CH:30]/[C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1
Reactant: O=c1c(Br)c(OS(=O)(=O)C(F)(F)F)ccn1Cc1cccc(F)c1
Reactant: C=Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(Br)c(/C=C/c2ccc(F)cc2)ccn1Cc1cccc(F)c1
Temperature: 65 °C
Yield: 6.5 %

Procedure:
A mixture of 3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g, 0.0023 mol), and 4-fluorostyrene (0.33 mL, 0.0028 mol) in degassed DMF (100 ml) containing diisopropyl ethyl amine (0.37 g, 0.0029 mol) was treated with PdCl2(PPh3)2 (0.32 g, 0.46 mmol) and heated at 65° C. under argon atmosphere for 16 h. DMF was distilled in vacuo, and the residue was purified by flash chromatography (EtOAc/hexane 1:4 v/v) to afford a yellow substance which was further purified by by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min), at flow rate of 100 mL/min. The appropriate fractions were combined, concentrated to a small volume (20 mL), added EtOAc (25 mL) and washed successively with satd. sod. bicarbonate, water, and dried (Na2SO4). EtOAc was removed under reduced pressure and residue was dried in vacuo to afford the title compound (0.06 g, 6%) as yellow powder: 1H NMR (CD3OD/400 MHz) δ 7.68 (m, 3H), 7.39 (m, 3H), 7.2-7.0 (m, 5H), 6.82 (d, 1H, J=7.2 Hz), and 5.22 (s, 2H); 19F NMR (CD3OD/400 MHz) δ−113.9 (m) and −115 (m); ES-HRMS m/z 402.0305 (M+HC20H15NOF2Br, requires 402.0300).
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])[O:6][N:5]=1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[N:8]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-Ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(4-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg; compound B85) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (205 mg; compound C10) and HBTU (215 mg) in DCM (7 ml) in the presence of DIPEA (0.36 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH:14](OC(=O)C)=[O:15]>O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:14]=[O:15])[CH3:2]
Reactant: CC(=O)OC=O
Reactant: CCOC(=O)CNc1ccccc1
Solvent: O
Product: CCOC(=O)CN(C=O)c1ccccc1
Reaction time: 8 h
Yield: 70 %

Procedure:
N-Phenylglycine ethyl ester (100 g; 0-56 mol) was added in small portions to acetic formic anhydride (100 g; 1.14 mol) with vigorous stirring. The mixture was allowed to stir overnight, then it was poured into water, and extracted with ether. The ether solution was washed with sodium bicarbonate solution and then with water. The ether was evaporated in vacuo to give an oil which was distilled to give N-phenyl-N-formylglycine ethyl ester (81 g; 70%) having a bp 115°-117° C.