Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:6]([S:21][CH2:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4].[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.N1C=CC=CC=1.O>[C:31]([O:1][CH:2]([CH:6]([S:21][CH2:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4])(=[O:33])[CH3:32]
Reactant: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(O)C(N)=O)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(OC(C)=O)C(N)=O)cc1
Reaction time: 1 h

Procedure:
To a solution of 3.5 g (0.01 mol) of rac.-(R,*S*)α-(hydroxy)-4-methoxyphenyl-β-[(2-oxo -2-phenYlethYl)thio]benzenepropanamide in 130 mL of methylene chloride and 4.4 mL of pyridine was added dropwise at ice-bath temperature a solution of 1.1 g (0.014 mol) of acetyl chloride in 25 mL of methylene chloride. The mixture was stirred at this temperature for one hour then at room temperature for 17 hrs and diluted with water. The aqueous suspension was extracted with methylene chloride and the combined organic solutions were washed with water and dried (MgSO4). Removal of the solvent gave the crude ester, which after crystallization from ethyl acetate afforded 2.9 g (74%) of rac.-(S,*R*)-α-(acetyloxy)-4-methoxyphenyl -β-[(2-oxo-2-phenylethyl) thio]benzenepropanamide, mp 122°-123°.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(=O)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccccc1CBr
Temperature: 0 °C
Yield: 43.2 %

Procedure:
To a solution of ethyl 2-methylbenzoylformate (10 g) in carbon tetrachloride (200 ml) were added N-bromosuccinimide (10 g) and 25%-hydrous benzoyl peroxide (1 g) and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled with ice-water and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give a yellow oil. The oil was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give the desired ethyl 2-(bromomethyl)benzoylformate (6.1 g, yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)[C:17](Cl)=[O:18].[NH2:22][C@H:23]([CH3:40])[C@:24]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])([OH:31])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(N(CC)CC)C>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:13][C:11]([C:17]([NH:22][C@H:23]([CH3:40])[C@:24]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[F:39])([OH:31])[CH2:25][N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[O:18])=[C:9]([CH3:10])[N:8]=2)=[CH:14][CH:15]=1
Reactant: C[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(Cl)cc2)oc1C(=O)N[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(4-chlorobenzoyl)-L-alanine (1.46 g, 6.41 mmol) in benzene (35 mL) was treated with oxalyl chloride (0.55 mL, 6.41 mmol) at 45° C. for 3 h. Next, a solution of (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1.72 g, 6.41 mmol) and triethylamine (2.2 mL) in CHCl2 (20 mL) was slowly added and the reaction mixture was stirred at 0° C. for 0.5 h. The crude product was then poured into cold water and extracted with CHCl3. The organic solution was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a mixture of several products (TLC) from which the title compound was isolated by flash chromatography as a white solid (140 mg): mp 89°-93° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.04 (d, J=8.5, 2H, arom), 7.79 (s, 1H, triazole), 7.78 (s, 1H, triazole), 7.49 (d, J=8.5, 2H, arom), 7.37 (dt, Jd =6.5, Jt =8.8, 1H, arom), 6.8-6.6 (m, 3H, arom, NH), 5.38 (d, J=1.1, 1H, OH), 5.04 (d, J=14.3, 1H, TrCH(H)), 4.96 (br quint, J=7, 1H, CHMe), 4.53 (d, J=14.3, 1H, TrCH(H)), 2.60 (s, 3H, Me-oxazole), 1.04 (d, J=6.8, 3H, MeCH); HPLC-MS 263 and 265 (ethylaminoacyl group, C13H12ClN2O2), 220 and 222 (acyl group, C11H7ClNO2), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =-141° (c 0.5, CHCl3). Analysis calculated for C23H20ClF2N5O3 : C 56.62; H 4.13; N 14.35. Found: C 56.41; H 4.19; N 14.50.
Reaction SMILES: [C:1]([NH2:11])(=[S:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:12][CH2:13][C:14]1[N:11]=[C:1](/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:10][CH:16]=1
Reactant: NC(=S)C=Cc1ccccc1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClCc1csc(/C=C/c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
A mixture of thiocinnamamide (11.7 g), 1,3-dichloro-acetone (9.1 g) and ethanol (145 ml) was stirred for one hour under reflux. The reaction mixture was poured into ice-water, which was neutralized with potassium carbonate, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The concentrate was purified by means of column chromatography on silica gel. From the fraction eluted with ether-hexane (1:6, v/v), was obtained 4-chloromethyl-2-[(E)-styryl]thiazole (9.4 g, 56%), which was recrystallized from ether-hexane to yield colorless plates, m.p.88-89° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH:40][C:41]2[CH:46]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:44]=[C:43]([O:56][CH3:57])[CH:42]=2)(=[O:39])=[O:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)(=[O:38])=[O:39])[CH:42]=[C:43]([O:56][CH3:57])[CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)Cc2ccc(F)cc2)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added 1-(4-fluorophenyl)-N-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (138 mg, 0.33 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 273 μl of a 2M aqueous solution of cesium carbonate in dioxane (5 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0 to 80%, hexane-ethyl acetate) to give 155 mg (85% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].C(NC(C)C)(C)C.[Li].Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]1)=[O:4]
Reactant: CCCCC1CC(C(=O)OC)C1
Reactant: COC(=O)Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC1CC(C(=O)OC)(C(=O)OC)C1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of 3-butyl-cyclobutanecarboxylic acid methyl ester (7.75 g, 45.6 mmol) in THF (30 mL) was added dropwise to a solution of lithium diisopropylamine (7.26 g, 68.4 mmol) in THF (70 mL) at −78° C. After stirring for 1.5 h at the same temperature, methyl chloroformate (6.46 g, 68.4 mmol) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (200 mL) and the aqueous residue was extracted with EtOAc (75 mL×5). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a clear yellow oil (8.37 g, 81%). MH+229.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CC(C)=O.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reaction time: 2.5 h
Yield: 93.5 %

Procedure:
A solution of 3-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester (15.0 g, 69.7 mmol) and triethylamine (14.6 mL, 104.5 mmol) in dichloromethane (270 mL) was stirred on a bath of ice and acetone. A solution of methanesulfonyl chloride (5.5 mL, 71.1 mmol) in dichloromethane (25 mL) was added dropwise at a rate which kept the internal temperature remained below 0° C. (the addition required about 20 minutes). The mixture was stirred on an ice bath for 2.5 hours, then was concentrated under vacuum. The residue was dissolved in ethyl acetate, and the mixture was filtered to remove a white crystalline solid. The filtrate was concentrated under vacuum to provide an orange gum. Purification by flash chromatography (50% ethyl acetate in hexane) provided a white solid (19.12 g, 93%). 1H NMR (300 MHz, CDCl3) δ4.10 (m, 2H), 3.95 (bd, J=13 Hz, 1H), 3.81 (dt, J=14, 4 Hz, 1H), 3.03 (s, 3H), 2.92 (ddd, J=14, 10, 3 Hz, 1H), 2.79 (dd, J=13, 10 Hz, 1H), 1.97 (m, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.49 (m, 1H), 1.46 (s, 9H), 1.30 (m, 1H).
Reaction SMILES: [O:1]1[CH:3]([C:4]([F:7])([F:6])[F:5])[CH2:2]1.Cl.[CH3:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][N:30]([CH:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[CH:31]=4)=[CH:23][N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:12]=[N:11]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:5][C:4]([F:7])([F:6])[CH:3]([OH:1])[CH2:2][N:35]1[CH2:34][CH2:33][CH:32]([N:30]2[CH:31]=[C:27]([C:24]3[CH:25]=[N:26][C:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([C:13]5[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=5)[CH:16]=4)=[N:22][CH:23]=3)[CH:28]=[N:29]2)[CH2:37][CH2:36]1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)cn1
Reactant: FC(F)(F)C1CO1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCN(CC(O)C(F)(F)F)CC5)c4)cn3)c2)cn1
Temperature: 50 °C
Yield: 36.3 %

Procedure:
1,2-Epoxy-3,3,3-trifluoropropane(84 mg; 0.72 mmol; 2.4 eq.) was added to a solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidine (example 1, 200 mg; 0.31 mmol; 1.0 eq.) and DIEA (53 μl; 0.31 mmol; 1.0 eq.) in DMF (4 mL). The reaction mixture was stirred at 50° C. O/N. It was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:EtOAc, gradient from 40:60 to 0:100) afforded the title compound as a beige powder (56 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.59-8.49 (m, 2H), 8.27 (s, 1H), 8.25-8.18 (m, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.75-7.67 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 6.24-6.13 (m, 1H), 4.28-4.08 (m, 2H), 3.90 (s, 3H), 3.12-2.97 (m, 2H), 2.66-2.53 (m, 2H), 2.36-2.17 (m, 2H), 2.12-1.86 (m, 4H). HPLC (Condition A): Rt 2.85 min (purity 98.4%). MS (ESI+): 498.4.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:21])[CH2:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:9].[S:22](Cl)([Cl:25])(=[O:24])=[O:23]>C(Cl)Cl>[CH2:14]([N:13]([S:22]([Cl:25])(=[O:24])=[O:23])[CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)Cl
Reaction time: 4 h
Yield: 69 %

Procedure:
A solution of triethylamine (2.0 ml, 14.4 mmol) and N-benzylglycine ethyl ester (2.25 ml, 12.0 mmol) in methylene chloride (5 ml) was added to a solution of sulfuryl chloride (0.96 ml, 12.0 mmol) in methylene chloride (30 ml) at −78° C. The reaction mixture was stilted at −78° C. for 4 h and then concentrated. Ether (75 ml) was added and the resulting precipitate was filtered. The organic layer was washed with 1M HCl and brine, dried over MgSO4 and concentrated in vacuo to give ethyl 2-[benzyl-(chlorosulfonyl)amino]acetate as a colorless oil (69%).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccc2c(=O)cc[nH]c12
Product: N#Cc1cccc2c(Cl)ccnc12

Procedure:
4-Oxo-1,4-dihydroquinoline-8-carbonitrile (0.40 g, 0.24 mmol, WO2004/113303) and phosphorous oxychloride (10 mL) were heated to 100° C. for 1.5 h. Solvent removed in vacuo. EtOAc (50 mL) was added and organic phase washed with sat. aqueous Na2CO3 solution, brine (20 mL) and dried (MgSO4). Solvent removed in vacuo to give the title compound: RT=3.09 min; m/z (ES+)=189.0 [M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.Cl[C:11]([O:13]C(Cl)(Cl)Cl)=[O:12].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:29])[CH3:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].[CH3:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:32].[BH4-].[Na+]>C(O)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]([O:29][C:11]([O:13][CH:1]=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:12])[CH3:28])=[CH:25][CH:26]=1)([O-:20])=[O:19].[N+:39]([C:36]1[CH:35]=[CH:34][C:33]([CH:31]([OH:32])[CH3:30])=[CH:38][CH:37]=1)([O-:41])=[O:40]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C=Cc1ccc(O)cc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(O)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(OC(=O)OC=Cc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Poly(4-(1-(4-nitrophenyl)ethyloxycarbonyloxystyrene (FIG. 7A) was prepared from poly(4-hydroxystyrene), available from the Maruzen Oil Company, by treatment with trichloromethyl chloroformate and 1-(4-nitrophenyl)ethanol. Specifically, a solution of 4-nitroacetophenone in ethanol was treated with sodium borohydride at about 0° C. for about 4 hours, then quenched by the addition of water. Extraction with ethyl acetate followed by drying and concentration provided crude 1-(4-nitrophenyl)ethanol, which was purified by recrystallization. A solution of 1-(4-nitrophenyl)ethanol in tetrahydrofuran (THF) was added to a solution of excess trichloromethyl chloroformate and triethylamine in THF, stirred at reflux for about 2 hours, filtered to remove the solids, and concentrated under vacuum. The resulting oil was dissolved in THF and added to a solution of poly(4-hydroxystyrene), 4-dimethylaminopyridine, and triethylamine in THF. This mixture was stirred for about 18 hours at about 20° C., filtered, then concentrated. The residue was dissolved in methylene chloride, treated with aqueous sodium bicarbonate solution, and the polymer was precipitated by addition into methanol.
Reaction SMILES: [O:1]=[C:2]=[N:3]C1CC(C)(C)CC(C)(CN=C=O)C1.C1(C=[CH:23][C:21]([OH:22])=CC=1)O.[C:25]([O:29]CCO)(=[O:28])[CH:26]=[CH2:27]>C(OCCCC)(=O)C>[C:25]([OH:29])(=[O:28])[CH:26]=[CH2:27].[NH2:3][C:2]([O:22][CH2:21][CH3:23])=[O:1]
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(=O)OCCO
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Solvent: CCCCOC(C)=O
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 1 h

Procedure:
This polyester was cooled to 50° C. and 444 g (2 mols) of isophorone diisocyanate, 672 g of butyl acetate and 0.81 g of hydroquinone were added. The mixture was reacted at 80° C. with constant stirring for 1 hour. Thereafter, a solution consisting of 252.2 g (2.2 mols) of 2-hydroxyethyl acrylate and 0.81 g of hydroquinone was added dropwise at 80° C. with stirring over a period of 1 hour. The reaction was further continued for 3 hours, at the end of which time the absorption of the NCO group was no longer observed in the infrared absorption spectrum. The procedure gave a urethane acrylate resin solution A (nonvolatile matter 70%).
Reaction SMILES: [SH:1][CH:2]([OH:4])[CH3:3].[OH-].[K+].[CH3:7][C:8](C)=[O:9].[O:11]=[C:12]1[N:16](CC(Cl)=O)[C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[S:13]1>C(OCC)C.O>[O:11]=[C:12]1[N:16]([CH2:3][C:2](=[O:4])[S:1][CH2:7][CH2:8][OH:9])[C:15]2[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=2[S:13]1
Reactant: CC(C)=O
Reactant: CC(O)S
Reactant: O=C(Cl)Cn1c(=O)sc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(Cn1c(=O)sc2ccccc21)SCCO
Reaction time: 0.17 h

Procedure:
A charge containing 0.1 moles of mercaptoethanol, 0.1 moles of 85% potassium hydroxide and 250 ml of acetone is stirred for 10 minutes. To this stirred mixture is added 0.1 moles of 2-oxo-3-benzothiazolineacetyl chloride in one portion. An exothermic reaction set in causing a temperature rise from 30° to about 40° C. After stirring for about 24 hours at room temperature, 500 ml of water and 500 ml of ethyl ether are added and stirring continued at 25°-30° C. for 15 minutes. The separated ether layer is washed with water until neutral to litmus and dried over sodium sulfate. The ether is removed in vacuo at a maximum temperature of 80°-90° C. at 1-2 minutes. Analytical data is summarized in Table I, below.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][N:7]([CH3:11])[C:8]=1[CH2:9][OH:10].I[CH3:13]>C1COCC1.CN(C=O)C.C1COCC1.[Cl-].[Na+].O>[Br:3][C:4]1[CH:5]=[N:6][N:7]([CH3:11])[C:8]=1[CH2:9][O:10][CH3:13]
Reactant: Cn1ncc(Br)c1CO
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COCc1c(Br)cnn1C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
NaH (60%, 58 mg) was added to a solution of (4-bromo-1-methyl-1H-pyrazol-5-yl)methanol (Preparation 149, 97 mg, 1.03 mmol) in THF/DMF (8/4 mL). After stirring for 15 minutes, iodomethane (439 mg, 3.09 mmol) in THF (1 mL) was added. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulphate and concentrated in vacuo to afford the title compound (142 mg, 67%).
Reaction SMILES: COC([C:5]1[C:9](=[O:10])[O:8][CH2:7][C:6]=1O)=O.[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][CH:22]([F:24])[F:23])=[CH:15][CH:14]=1.S([O-])(O)(=O)=O.[K+].O>C(#N)CCC.ClCCl>[Cl:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][CH:22]([F:24])[F:23])[C:6]2[CH2:7][O:8][C:9](=[O:10])[CH:5]=2)=[CH:15][CH:14]=1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Reactant: COC(=O)C1=C(O)COC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCCC#N
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 120 °C
Reaction time: 3 h
Yield: 108.8 %

Procedure:
To a suspension of 5.2 g of 4-(methoxycarbonyl)-5-oxo-2,5-dihydrofuran-3-ol and 5 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethylamine in 70 ml of butyronitrile are added, at room temperature. 4.5 g of potassium hydrogensulphate. The mixture is stirred at a temperature of 120° C. for 3 hours. Subsequently, the mixture is cooled to room temperature and admixed with 60 ml of water and 60 ml of dichloromethane. The organic phase is removed and the aqueous phase is extracted twice with 30 ml each time of methylene chloride. The combined organic phases are concentrated to dryness. 7.6 g of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one are obtained in a purity of 85% (this corresponds to 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=[O:14]>CC(C)=O>[ClH:1].[Cl:11][CH2:12][C:13](=[O:14])[CH2:15][S:7][C:6](=[NH:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: Cl
Product: N=C(SCC(=O)CCl)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
8.58 g (50 mmol) of the 4-chlorothiobenzamide obtained in (a) were dissolved in 35 ml acetone, 6.35 g (50 mmol) of 1,3 dichloroacetone were added and left to stand for 1 day at room temperature. The crystallate was drawn off, washed with acetone and dried.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCS(=O)(=O)c1ccc(CO)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(CCl)cc1

Procedure:
A mixture of (4-(ethylsulfonyl)phenyl)methanol (200 mg, 1 mmol) and thionyl chloride (3 mL) was stirred at reflux for 4 h. The solvent was removed under reduced pressure to obtain a gum. Dichloromethane (10 mL) was added, and the mixture was stirred for 5 min and then concentrated under vacuum. This process was repeated two more times to ensure complete removal of thionyl chloride. After residual solvent removal under vacuum, 205 mg of the title compound was obtained as a white solid. HPLC/MS: retention time=2.308 min, [M+H]+=219.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][F:49])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:49][CH2:48][CH2:47][N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[C:34](=[O:35])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:39]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(CCF)c2ccccc12)C(=O)O
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(CCF)c2ccccc12)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 107.7 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (350 mg) and (R)-2-(tert-butoxycarbonylamino)-3-[1-(2-fluoroethyl)-1H-indol-3-yl]propanoic acid (431 mg) synthesized in Referential Example 1(c) were used, whereby the title compound (744 mg) was yielded.