Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.CN(OC)[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16].Br[C:21]1[S:22][C:23]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:24][CH:25]=1.C([Li])CCC>C(OC(=O)C)C.O.CCCCCC>[C:31]([O:30][C:28]([NH:27][CH2:26][C:23]1[S:22][C:21]([C:8]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH2:16])=[O:17])=[CH:25][CH:24]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)s1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)c2cc(Cl)ccc2N)s1
Yield: 7.3 %

Procedure:
A tetrahydrofuran (60 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (4.96 g) and 2-bromo-5-tert-butoxycarbonylaminomethylthiophene (5.45 g) was cooled to −78° C. To the solution was gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (47 ml). To the mixture were further added water (200 ml) and acetic acid ethyl ester (200 ml). The organic layer was washed with water and dried over anhydrous MgSO4, followed by distilling off the solvent. The residual oily compound was purified by means of a silica gel column chromatography to give 2-(2-tert-butoxycarbonylaminomethylthiophen-5-yl)carbonyl-4-chloroaniline (0.5 g) as a yellow oily product. To a methanol (8 ml) solution of this product (0.15 g) was added sodium borohydride (60 mg). The mixture was stirred for 30 minutes at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off. To a methanol (5 ml) solution of the residue were added 4-biphenylcarbaldehyde (100 mg) and acetic acid (40 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano borohydride (40 mg). The mixture was stirred for 30 minutes at 60° C., to which was added acetic acid ethyl ester (50 ml). The mixture was washed with water and dried over anhydrous MgSO4. The solvent was then distilled off to leave 0.2 g of a residual compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([C:14](OC)=[O:15])=[N:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccn(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccn(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round-bottomed flask was charged with methyl 1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate 63 (0.800 g, 2.96 mmol) and 10 mL of THF. After being cooled to 0° C., lithium aluminum hydride (1.0 M solution in THF, 2.96 mL, 2.96 mmol) was added dropwise. After 1 h, the reaction was quenched with 0.5 mL of water, 0.5 mL of 1 M NaOH, and 1.5 mL of water (added in that order). The resulting precipitate was filtered and the filtrate concentrated to give (1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methanol 64.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:5]([CH3:16])[CH:4]=1.[Li]CCCC.[CH2:22]1[O:25][C@@H:23]1[CH3:24]>C1COCC1>[OH:25][CH:23]([CH3:24])[CH2:22][CH2:16][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@@H]1CO1
Reactant: COc1ccc(NC(=O)C(C)(C)C)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)C(C)(C)C)c(CCC(C)O)c1
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To a stirred solution of the the product from Step A (3.00 g, 13.6 mmol) at 0° C. in anhydrous THF (50 mL) was added a solution of 2.5 M n-BuLi in hexanes (13.6 mL, 2.5 equiv.) over about 2 min under a nitrogen atmosphere. After 10 minutes a solution of (R)-propylene oxide (1.18 g, 1.5 eq) in anhydrous THF (5 mL) was added and the mixture was stirred for about 30 min. The reaction was quenched by the addition of ice-water. The THF was evaporated and the residue was extracted with ethyl acetate to give a viscous oil (4.03 g), which was used in next reaction without further purification: LC/MS (+APCI) m/z 280 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[S:15][CH:16]=[CH:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:20]([S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].O.CN(C=O)C>[CH:20]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:3]=[C:4]([C:9]3[O:10][C:11]([C:14]4[S:15][CH:16]=[CH:17][C:18]=4[CH3:19])=[N:12][N:13]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:28][CH:27]=1)(=[O:24])=[O:25])([CH3:22])[CH3:21]
Reactant: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2N)o1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccsc1-c1nnc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N)o1
Temperature: 150 °C
Yield: 19.6 %

Procedure:
A microwave vial was charged with 5-bromo-3-[5-(3-methyl-2-thienyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (75 mg, 0.2218 mmol), (4-isopropylsulfonylphenyl)boronic acid (50.59 mg, 0.2218 mmol), palladium; triphenylphosphane (12.82 mg, 0.01109 mmol) and an aqueous sodium carbonate (332.7 μL of 2 M, 0.6654 mmol) solution was then added followed by DMF (1 mL) and the vial sealed. The reaction mixture was heated in the microwave at 150° C. for 30 min. After this time water was added and the resulting precipitate collected by filtration. The precipitate was passed through a palladium scavenging column eluting with MeCN and MeOH. The solvent was removed to give the product as a yellow solid (19.2 mg, 19% yield); 1H NMR (400 MHz, DMSO) d 1.20 (d, 6H), 2.69 (s, 3H), 3.48 (t, 1H), 7.23 (d, 1H), 7.92 (d, 2H), 7.98 (d, 2H), 8.36-8.34 (m, 2H) and 9.06 (s, 1H) ppm; MS (ES+) 442.0
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:12](=[O:13])[C:11](=[O:17])[NH:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
A mixture of 4,5-dichlorophenylenediamine (54 g, 305 mmol) and diethyl oxalate (124 mL, 146.1 g, 920 mmol) was refluxed overnight, cooled to room temperature, and filtered. The residue was washed with ethanol and dried in vacuo to give the title product as a gray solid powder (67.5 g, 96%); mp>320° C.; IR (KBr, cm−1) 3188, 3156, 3057, 2918, 1724, 1693, 1613, 1497, 1452, 1340, 1338, 1250, 1131, 877, 811, 676, 669, 565; 1H NMR (DMSO) δ 12.00 (s, 2H), 7.18 (s, 2H); 13C NMR (DMSO) δ 154.8, 126.0, 124.4, 116.0; MS (ACPI), m/z 231.0 (M+); Anal. Calcd for C8H4N2O2Cl2: C, 41.59; H, 1.75; N, 12.12. Found: C, 41.60; H, 1.85; N, 12.05.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][CH:14]([N:17]([CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: CC(C)NCCNC(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NCCN(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-Nitrobenzenesulfonyl chloride (22.1 g, 0.1 mole) in methylene chloride (150 ml) was added dropwise with stirring to N,N'-diisopropyl ethylene diamine (14.4 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (400 ml). The reaction was stirred one hour at room temperature, washed with water and the solvent removed. The residue dissolved in diethyl ether precipitated the unwanted "bis" byproduct which was filtered and discarded. Chromatography of the filtrate on Dry Column Silica Gel (500 g) with ethyl acetate provided pure product free base as a gum (14.31 g). Conversion, using isopropanol/HCl, to the hydrochloride salt provided the title compound as the hydrochloride salt (14.85 g) m.r. 219°-222° C.
Reaction SMILES: [Mg].C[Si](Cl)(C)C.CN1CCN(C)C1=O.II.COC=C(C(=O)C(F)(F)F)C(OC)=O.CNN.[F:34][CH:35]([F:46])[C:36]1[C:40]([C:41]([O:43]C)=[O:42])=[CH:39][N:38]([CH3:45])[N:37]=1.FC(F)N1C(C(OC)=O)C=CN1C>CO>[F:46][CH:35]([F:34])[C:36]1[C:40]([C:41]([OH:43])=[O:42])=[CH:39][N:38]([CH3:45])[N:37]=1
Reactant: COC(=O)c1cn(C)nc1C(F)F
Agent: CNN
Agent: COC(=O)C1C=CN(C)N1C(F)F
Agent: COC=C(C(=O)OC)C(=O)C(F)(F)F
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: Cn1cc(C(=O)O)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium turnings (4.9 g, 0.20 mol), trimethylsilyl chloride (32.6 g, 0.30 mmol) and anhydrous 1,3-dimethyl-2-imidazolidinone (DMI, 160 ml) were initially charged in a 500 ml three-necked flask fitted with magnetic stirrer and thermometer. After activation of the magnesium with iodine, methyl 2-methoxymethylene-4,4,4-trifluoro-3-oxobutyrate (21.3 g, 0.10 mol) was added in an ice-bath over a period of 30 min, the reaction temperature being kept within a range of from 20 to 30° C. After a further 60 min at room temperature, excess trimethylsilyl chloride was removed under reduced pressure. In a second 500 ml three-necked flask, an aqueous methylhydrazine solution (37%, 14.8 g, 0.12 mol) and methanol (320 ml) were initially charged at −50° C. Over a period of 60 min, the cooled reaction solution of the first reaction was added, with cooling being maintained. After a further 2 hours at −50° C., the reaction mixture was allowed to warm to room temperature and stirred for a further 10 hours. According to GC analysis, the reaction mixture contained methyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate (isomer a) as a mixture with methyl 2-difluoromethyl-1-methylpyrazole-3-carboxylate (isomer b) in an a:b isomer ratio of 90:10. The reaction mixture was then concentrated under reduced pressure. 120 g of 10% strength aqueous sodium hydroxide solution were added to the residue, and the mixture was stirred at 100° C. for 4 h. After acidification of the aqueous solution with hydrochloric acid to pH 1 and repeated extraction with MTBE, an organic solution comprising 13.4 g of the title compound (yield isomer a: 71%) was obtained. The title compound was isolated by crystallization as a light-brown solid.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1>[CH2:1]([C:4]1[C:5]([O:13][C:21](=[O:23])[CH3:22])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)[CH:2]=[CH2:3]
Reactant: CC(=O)Cl
Reactant: C=CCc1c(O)ccc2cn[nH]c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCc1c(OC(C)=O)ccc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of the product from Step B (6.35 g, 37 mmol) in THF (100 mL) containing triethylamine (7.6 ml, 55 mmol) was stirred for 5 minutes at ambient temperature, cooled to 0° C. (ice bath), and acetyl chloride (2.63 mL, 37 mmol) was added. The mixture was stirred at 0° C. for 2 hours, additional acetyl chloride (0.26 mL, 3.7 mmol) was added, and the mixture stirred for 10 min at which point another portion of acetyl chloride (0.26 ml, 3.7 mmol) was added and stirring continued for 15 min. The reaction was quenched with triethyl amine (1 mL) and saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The extract was dried (MgSO4) and evaporated to an oil (9.27 g) which was purified by chromatography (silica, 10% to 50% EtOAc/hexane) to give a white solid, (3.50 g, 44%): LC/MS (+APCI) m/z 217 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:4][C:5](O)=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Br:1][C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:4][C:5]([Cl:32])=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCc1nc(O)nc(CCCCCC)c1Br
Solvent: CN(C)c1ccccc1
Product: CCCCCCc1nc(Cl)nc(CCCCCC)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To 19.6 g (57.1 mmol) of 5-bromo-4,6-dihexylpyrimidin-2-ol was added 2.8 g (23 mmol) of N,N-dimethylaniline, and 40.8 g (266 mmol) of phosphoryl chloride was added under a nitrogen atmosphere, and the mixture was stirred at 100° C. for 2 hours. The resultant mixed liquid was cooled down to room temperature, then, 200 g of ice water was added, and the mixture was extracted with MTBE, washed with water and saturated saline in this order, dried over magnesium sulfate and concentrated. The resultant concentrate was purified by a silica gel column (hexane•ethyl acetate) to obtain 20.5 g (56.7 mmol) of 5-bromo-2-chloro-4,6-dihexylpyrimidine represented by the following formula:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]([S:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([S:20][CH3:21])[NH:9][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:7]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccccc1
Reactant: CSc1nc(-c2ccc(F)cc2)c(-c2ccnc(F)c2)[nH]1
Product: CSc1nc(-c2ccc(F)cc2)c(-c2ccnc(Nc3ccccc3)c2)[nH]1

Procedure:
Using the general method C, the title compound was prepared from 25b (0.2 g; 0.7 mmol) and aniline (0.65 g; 7.0 mmol) after a reaction time of 6 hours under reflux and separation by column chromatography (SiO2 60, CH2Cl2/EtOH 9+1). M.p. 228° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[O:6]
Reactant: COC(=O)C(C)(C)CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
3-Hydroxy-2,2-dimethyl-propionic acid methyl ester (15 g, 113 mmol) in 200 mL dichloromethane was cooled to 0° C. Pyridinium chlorochromate (43 g, 200 mmol) was added. The mixture was slowly warmed to room temperature and stirred 24 h. The crude in dichloromethane was filtered through silica gel. Celite was added to the remaining black viscous oil from the reaction mixture until the viscous oil is all absorbed to the celite. Dichloromethane was added to this slurry and the dichloromethane solution was filtered through silica gel. Dichloromethane was removed at reduced pressure (80 Torr) to give a pale yellow crude. Distillation removed residue dichloromethane and obtained 2,2-dimethyl-3-oxo-propionic acid methyl ester as a colorless oil (7 g, 48% yield). 1H NMR (300 MHz, CDCl3, δ): 9.60 (s, 1H); 3.70 (s, 3H); 1.29 (s, 6H). 13C NMR (75 MHz, CDCl3, δ): 199.1, 173.2, 53.9, 52.6, 19.7. IR (NaCl, thin film): 2988, 2958, 1726, 1468, 1278, 1151, 866.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH3:14].CCN(CC)CC>C1COCC1.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=2)=[CH:19][CH:20]=1)[CH2:12][CH2:13][CH3:14]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(C=O)c(F)c2)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 4-bromo-2-fluoro-benzaldehyde (10.0 g, 49.3 mmol), 1-butyl-4-ethynyl-benzene (8.57 g, 54.2 mmol), CuI (94 mg, 0.49 mmol) and of Et3N (9.9 g) in anhydrous THF (120 mL) were added PPh3 (258 mg, 1 mmol) and Pd(OAc)2 (221 mg). The reaction mixture was heated under argon for 3 hours. After cooling to rt, the salts were filtered off, then charcoal and silica gel were added to the solution. After filtration, the solution was concentrated under reduced pressure and the residual oil was dissolved in petroleum ether (100 mL) and stored in the freezer. The solids were filtered off and washed with cold petroleum ether to give the title compound as a white powder (5.53 g, 40%). 1H NMR (CDCl3) δ 10.33 (s, 1H), 7.82 (t, J=7.7 Hz, 1H), 7.45 (d, J=7.9 Hz, 2H), 7.38 (d, J=8.3 Hz, 1H), 7.30 (d, J=10.9 Hz, 1H), 7.18 (d, J=8.3 Hz, 2H), 2.62 (t, J=7.7 Hz, 2H), 1.58 (m, 2H), 1.36 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). HPLC, Rt: 5.26 min (purity: 99.4%).
Reaction SMILES: Cl.[CH2:2](N(CC)CC)C.C=O.[C:11]1([CH2:17][CH2:18][CH:19]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:17]([C:18](=[CH2:2])[CH:19]=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CC
Reactant: O=CCCc1ccccc1
Agent: C=O
Agent: Cl
Product: C=C(C=O)Cc1ccccc1
Temperature: 20 °C
Yield: 71 %

Procedure:
To a mixture of triethylamine hydrochloride 27.5 g (0.20 mol) and 37% formalin 16.3 g (0.201 mol) was added dropwise β-phenylpropionaldehyde 25 g (0.183 mol) at 20° to 35° C. and the mixture was reacted at 110° to 115° C. for 4 hours. After the completion of the reaction, the reaction mixture was cooled to 20° C. and extracted with 100 ml of diethyl ether. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was distilled to give 2-benzyl-2-propenal (bp10 : 99° to 101° C.) in a yield of 71%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:19])[CH2:17]Cl)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.[OH-].[Na+].O>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:19])[CH2:17][O:34][C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)CCl)cs1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)COc2ccc(-c3ccc(F)cc3)cc2)cs1

Procedure:
2-{[4-(Chloroacetyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (23.8 g) and 4′-fluorobiphenyl-4-ol (12.00 g) obtained in Example 1 were dissolved in toluene (650 mL), aqueous sodium hydroxide solution (1 mol/L, 71 mL), tetrabutylammonium iodide (2.62 g) and water (71 mL) were added, and the mixture was heated under reflux for 3 hr, and allowed to cool to perform partitioning. The organic layer was washed twice with 1 mol/L aqueous sodium hydroxide solution (300 mL) and twice with saturated aqueous sodium chloride solution (200 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Moritex Purif Pack SI 60 μm size 200 was used. elution solvent: hexane/ethyl acetate=95/5→70/30) to give the title compound as a pale-yellow oily substance (1.128 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]=O)(=[O:10])=[O:9].ClCCl.B(F)(F)F.CCOCC.[CH2:31]([SH:35])[CH2:32][CH2:33][SH:34]>O>[Cl:1][C:2]1[C:3]([CH3:18])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[CH:16]1[S:35][CH2:31][CH2:32][CH2:33][S:34]1)(=[O:10])=[O:9]
Reactant: SCCCS
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C=O)c1Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccsc2C2SCCCS2)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-formylthiophene-3-sulfonamide described in Production Example 1-3 (4.9 g, 16 mmol) and dichloromethane (100 mL) was successively added boron trifluoride diethyl etherate (8.1 mL, 64 mmol) and 1,3-propanedithiol (1.9 mL, 19 mmol) under ice cooling, followed by stirring at room temperature for 90 minutes. Water was added under ice cooling to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide as a crude product. To a mixture of crude N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide and tetrahydrofuran (50 mL) was added dropwise n-butyl lithium (9.7 mL, 16 mmol, 1.6 M n-hexane solution) at −78° C., followed by stirring for 20 minutes at an internal temperature of −35° C. The reaction mixture was cooled to −78° C., and 5-(chloromethyl)-6-methyl-1,3-dihydro-2-benzofuran described in Production Example 1-6 (960 mg, 5.3 mmol) was added at that temperature and stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.90 mL, 16 mmol) and tetrahydrofuran (7 mL) was added at that temperature. The reaction mixture was gradually returned to room temperature, water and an aqueous citric acid solution were added at that temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=4:1) to give the title compound (1.6 g, 54% yield).
Reaction SMILES: C1[O:8][C:6](=[O:7])[CH2:5][O:4]C1=O.[Sn]>>[C:6]([OH:8])(=[O:7])[CH:5]([CH:5]([C:6]([OH:8])=[O:7])[OH:4])[OH:4]
Reactant: O=C1COC(=O)CO1
Agent: [Sn]
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 0.83 h

Procedure:
The L(+)-tartaric acid was previously dried over silica gel (Riedel-de Haen, Seelze, Germany) in an Abderhalden drying apparatus for about 10 hours. The reactor (connected to a pump via a liquid nitrogen trap) was then put under vacuum (0.04 mbar) with stirring for about 50 minutes to remove toluene. The reactor, under an atmosphere of oxygen-free nitrogen (BOC gases, Dublin, Ireland, moisture content of 8 VPM), was then immersed in an oil bath (Temperature=˜180° C.) and stirring was increased to 125 rpm. Prior to immersion, a heating tape (Thermolyne type 45500, input control setting=4) was placed on the reactor lid. The time taken to completely melt the reactor contents was noted, typically about 15 minutes for a load of 300 g at about 180° C. Samples were taken every hour during synthesis and analyzed by GPC to determine the percentage residual monomer and to obtain values for average molecular weight by number (Mn) and by weight (Mw) distributions. Typical reaction times were of the order of about 15 hours. The final polymer was also analyzed by titration to determine an acid number in meq/g and by GC to determine residual unreacted monomer content. Further analyses include IR (detection of characteristic C═O peak); NMR (determination of lactide and glycolide content in polymer) and residual tin (determination of residual tin due to use of stannous 2-ethyl hexanoate as catalyst).
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:21][C:22](=[CH2:24])[CH3:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:22]([O:10][C:9](=[O:11])[C@H:8]([O:12][C:13](=[O:15])[CH3:14])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(=O)O[C@H](Cc1ccccc1)C(=O)O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Cool to -30° to -20° C., 3-phenyl-2(R)-acetoxypropionic acid (10.5 g) in CH2Cl2 (200 mL), add conc. H2SO4 (0.5 mL) and isobutylene (120 mL), seal the vessel, and stir at room temperature for 2 days. Vent the vessel, pour the reaction mixture into NaHCO3 solution, and extract with CH2Cl2. Dry the CH2Cl2 extract (MgSO4), then concentrate in vacuo to give 3-phenyl-2(R)-acetoxypropionic acid t-butyl ester.