Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[CH:14]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:16][CH2:15]1.O>C(Cl)Cl>[CH:14]1([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:10][O:11][CH3:12])=[CH:19][CH:18]=2)[CH2:16][CH2:15]1
Reactant: Oc1ccc(C2CC2)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C2CC2)cc1
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (77.6 mL) and chloromethyl methyl ether (33.7 mL) were added to a solution of 4-cyclopropylphenol (24.0 g) in methylene chloride (250 mL) to form a reaction solution. This reaction solution was stirred for 15 minutes under ice cooling, and then left overnight at normal temperature. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with a 1 mol/L sodium hydroxide aqueous solution, water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure to obtain the target product (27.6 g) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[C:16](C)=[CH:15][CH:14]=[CH:13][N:12]=1.[C:18](=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:18][C:15]1[CH:16]=[CH:11][N:12]=[C:13]([O:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)[CH:14]=1
Reactant: OCc1cccc(O)c1
Reactant: Cc1cccnc1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccnc(Oc2cccc(CO)c2)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
3-Hydroxymethyl-phenol (3.69 g, 29.7 mmol), 2-fluoro-3-methyl-pyridine (3.00 g, 27 mmol,) and cesium carbonate (9.68 g, 29.7 mmol) were suspended in dimethylsulfoxide (25 mL) and heated to 110° C. After stirring for 16 h, reaction partitioned between water (250 mL) and ethyl acetate (250 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (10-75%, EtOAc:heptane) to afford the desired product (4.75 g, 81%) as a thick oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][C:13]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[I-].[K+].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>O1CCCC1>[ClH:1].[ClH:1].[CH2:29]([N:31]([CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][C:13]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6])[CH3:30]
Reactant: CCNCC
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1S2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)CCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN(CC)CC)ccc1S2
Product: Cl
Temperature: 110 °C

Procedure:
A mixture of 32.6 g (0.08 mole) of 2,7-bis(4-chlorobutyryl)thioxanthene, 2 g of potassium iodide, 100 ml of diethylamine and 100 ml of tetrahydrofuran was heated for 24 hours with stirring in a Paar bomb at 110°C. Upon cooling the mixture was evaporated to near dryness. The residue was dissolved in methylene chloride, washed with water then with saturated NaCl solution, dried over magnesium sulfate and filtered. The filtrate was evaporated to near dryness and recrystallized several times from methanol-diethyl ether and from acetone-methanol to give the desired product. M.P. 188°-191°C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:10][CH2:11][OH:12].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:10][CH2:11][OH:12]
Reactant: CNc1ccccc1
Reactant: OCCI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CCO)c1ccccc1
Yield: 60 %

Procedure:
N-methylaniline (5 mls, 0.05 mol) was reacted with 2-Iodoethanol (3.599 mls, 0.05 mol) and diisopropylethylamine (8.039 mls, 0.05 mol) in ACN at 70° C. for 16 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound as a yellow orange oil, 2a (4.48 g, 0.03 mol, 64.5% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.27-7.15 (m, 2H), 6.81-6.67 (m, 3H), 3.74 (t, J=5.8 Hz, 2H), 3.42 (t, J=5.8 Hz, 2H), 2.92 (s, 3H).
Reaction SMILES: C(OC(C1O[C:8]2[C:13](C(=O)C=1)=[CH:12][CH:11]=[C:10]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:9]=2[CH:24]=CC)=O)C.I([O-])(=O)(=O)=[O:28].[Na+]>[Os](=O)(=O)(=O)=O>[F:22][C:19]([F:20])([F:21])[C:18]([NH:17][C:10]1[CH:11]=[CH:12][CH:13]=[CH:8][C:9]=1[CH:24]=[O:28])=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC=Cc1c(NC(=O)C(F)(F)F)ccc2c(=O)cc(C(=O)OCC)oc12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Product: O=Cc1ccccc1NC(=O)C(F)(F)F

Procedure:
Compounds of the invention in which R1 is alkyl may be prepared from the 8-propenyl-7-trifluoroacetamido-4-oxo-4H-chromene-2-carboxylic acid ethyl ester described above in accordance with Scheme II. The rearranged olefin (5) is treated with osmium tetroxide and sodium periodate to give the o-trifluoroacetamidobenzaldehyde (8). Condensation with the appropriate triphenylphosphorylidene ketone under Wittig conditions gives the o-trifluoroacetamidostyryl ketone (9), which upon treatment with acid cyclizes to give the 5-oxa-1-aza-phenanthrene ring system of the title compounds (10). Reduction, re-aromatization and tosylation as above gives the 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-methyltosylate. Replacement of the tosylate with the appropriately substituted azaheterocycle as above gives the title compounds of the invention. Substitution of trimethyl phosphonoacetate for the triphenylphosphorylidene ketone in the Wittig procedure above, followed by cyclization in acid gives the compounds of the invention in which R1 is hydroxy. Alkylation of this hydroxy derivative by a suitable alkyl halide or tosylate in the presence of base gives the compounds of the invention in which R1 is alkoxy. Treatment of the hydroxy derivative with an inorganic acid chloride such as phosphoryl chloride or bromide gives the compounds of the invention in which R1 is halo. Substitution of diethyl cyanomethylphosphonate for the triphenylphosphorylidene ketone in the Wittig procedure above, followed by cyclization in acid gives the compounds of the invention in which R1 is amino.
Reaction SMILES: [F:1][CH:2]([F:39])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]2=[N:18][CH:19]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:39][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]([CH3:29])([CH3:30])[CH2:27][OH:28])=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a pale yellow solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34.4 mg, 61.4 μmol) in dichloromethane (1.44 mL) was added TFA (426 mg, 288 μL, 3.74 mmol, Eq: 60.9), the reaction mixture turned orange and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give a mixture of 2 compounds, no pure compound obtained. Mixture combined again and purified by preparative TLC (Silica GF 1000 μm, 20×40 cm (Gypsum Binder, Fluorescent Indicator)) to give the desired 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (20 mg, 46.5 μmol, 75.7%) as white needles. MS (M+H)+=431; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.80-7.90 (m, 2H), 7.35-7.42 (m, 1H), 7.18 (t, J=74.4 Hz, 1H), 4.95 (t, J=5.7 Hz, 1H), 4.19 (s, 3H), 3.62 (d, J=5.7 Hz, 2H), 1.42 (s, 6H).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[S:13]([NH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2)(=[O:15])=[O:14].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:11][C:9]([F:12])([F:10])[O:8][C:6]1[CH:7]=[C:2]2[C:3]([S:13](=[O:14])(=[O:15])[NH:16][C:17]3[C:18]2=[CH:19][CH:20]=[C:21]2[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]2)=[CH:4][CH:5]=1
Reactant: Nc1cc(OC(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(OC(F)(F)F)ccc21
Yield: 8.1 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-quinolin-8-yl-4-trifluoromethoxy-benzenesulfonamide (Intermediate 301) (350 mg, 0.91 mmol), t-butyl nitrite (0.16 ml, 1.37 mmol), AcOH (3.5 ml) and THF (3.5 ml) gave the title compound (27 mg, 8%) after purification by column chromatography with DCM/MeOH (99.8:0.2) as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.C(O)(=O)C.[C-:14]#[N:15].[K+]>CS(C)=O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:14]#[N:15]
Reactant: OCc1ccccc1O
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: N#CCc1ccccc1O
Temperature: 125 °C
Reaction time: 2 h

Procedure:
29.8g of 2-hydroxybenzyl alcohol are dissolved in 250 ml of dimethylsulfoxide, together with 18g of potassium cyanide, and the mixture is heated to 125°C. 16g of glacial acetic acid are then added dropwise over the course of 1 hour and the mixture is stirred for a further 2 hours at 125°C. The dimethylsulfoxide is removed in vacuo and the residue is stirred with 200 ml of water and 150 ml of chloroform. The chloroform phase is separated off and the aqueous phase is re-extracted with 150 ml of chloroform. The combined chloroform phases are extracted by shaking with water and dried with sodium sulfate. After distilling off the chloroform, an oil remains, which solidifies on cooling. Yield: 19.8g = 60.5% of theory. Recrystallization from benzene/ligroin: melting point 118°C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[OH:10].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:36](OC)(OC)(OC)[CH3:37]>CCO>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]2[N:1]=[C:36]([CH3:37])[O:10][C:3]=2[CH:4]=1
Reactant: COC(C)(OC)OC
Reactant: Nc1c(O)cc(Br)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: Cc1nc2c(F)cc(Br)cc2o1
Temperature: 90 °C
Yield: 73 %

Procedure:
A mixture of 2-amino-5-bromo-3-fluorophenol (1 equiv), ytterbium(iii) trifluoromethanesulfonate (0.01 equiv), and trimethyl orthoacetate (1.2 equiv) in EtOH (1.3 M) was heated to 90° C. for 2 h. The reaction mixture was filtered through celite and washed with EtOH. The residual filtrate was concentrated in vacuo, then saturated aqueous sodium bicarbonate added and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel chromatography (0 to 60% ethyl acetate in hexane) to afford the title compound (73% yield). MS (ESI) m/z 232.2 [M+H]+.
Reaction SMILES: C(O[CH2:5][CH:6]=[C:7]([CH3:24])[CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])(=O)C.[C:25]1([P:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[S:44](=[O:48])(=[O:47])([OH:46])[OH:45]>>[S:44](=[O:46])(=[O:45])([OH:48])[O-:47].[CH3:24][C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH3:23])[CH:12]=[CH:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:20])[CH3:21])=[CH:6][CH2:5][P+:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)OCC=C(C)C=CC=C(C)C=CC=C(C)CCC=C(C)C
Product: CC(C)=CCCC(C)=CC=CC(C)=CC=CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=S(=O)([O-])O

Procedure:
3,7,11-Trimethyl-dodeca-1,4,6,10-tetraen-3-ol is prepared in accordance with German Pat. No. 1,115,238 from pseudoionone by reaction with sodium acetylide in liquid ammonia, followed by hydrogenation of the triple bond. The phosphonium bisulfate is prepared therefrom in the conventional manner, according to German Pat. No. 1,068,710, by reaction with triphenylphosphine and sulfuric acid. This phosphonium salt is reacted with β-formylcrotyl acetate, in accordance with German Pat. No. 1,068,710, to give 1-acetoxy-3,7,11,15-tetramethyl-hexadeca-2,4,6,8,10,14-hexaene. Crystalline 3,7,11,15-tetramethylhexadeca-2,4,6,8,10,14-hexaen-1-yl-triphenylphosphonium bisulfate is prepared from this ester, in accordance with German Pat. No. 1,068,709, by reaction with triphenylphosphine and sulfuric acid. Melting point 150° - 155° C.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.[C:22]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccnc1Br
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cccc(NC(=O)c2cccnc2Br)c1
Reaction time: 12 h
Yield: 59 %

Procedure:
To a stirred solution of 2-bromonicotinic acid (1.01 g, 5 mmol) dissolved in anhydrous dichloromethane (8 mL) were added EDCI (1.34 g, 7 mmol) and 3-tert-butylaniline (0.74 g, 5 mmol) at room temperature and the reaction mixture was stirred for 12 hours. The mixture was then diluted with dichloromethane, followed by saturated sodium bicarbonate and water wash. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain 2-bromo-N-(3-tert-butylphenyl)nicotinamide in 59% yield (950 mg). Rt: 2.44 min (20-100-5 method). MS: (ES) m/z 333, 335 (MAI).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[NH2:3].[F:10][C:11]([F:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[F:10][C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[N:2]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:3]=1)([F:18])[CH3:17]
Reactant: NNc1cccnc1
Reactant: CC(F)(F)C(=O)CC#N
Agent: Cl
Product: CC(F)(F)c1cc(N)n(-c2cccnc2)n1
Yield: 9 %

Procedure:
3-Hydrazinopyridine hydrochloride (435 mg, 3.0 mmol) was treated with 4,4-difluoro-3-oxopentanenitrile (400 mg, 3.0 mmol) (prepared as described in Example 152A Step 1) according to the procedure in Example 161A Step 3 to afford 3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-amine (62 mg, 0.27 mmol, 9%). 1H NMR (300 MHz, MeOD) δ 8.86 (s, 1H), 8.60 (d, 1H), 8.12 (d, 1H), 7.62 (t, 1H), 5.82 (s, 1H), 1.92 (t, 3H); LC-MS (ESI) m/z 225 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([O:16][C:17]1[N:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>O.C(OCC)(=O)C>[CH:13]([O:16][C:17]1[N:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)nc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogen carbonate (2.57 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(6-isopropoxypyridin-3-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.98 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.40 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.81 g, 73%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[C:8](Cl)(=[O:10])[CH3:9].[H][H]>[Pd].C(O)(=O)C>[C:1]([O:4][CH:5]([O:7][C:8](=[O:10])[CH3:9])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)OC(C)OC(C)=O
Reaction time: 4 h

Procedure:
A 300-ml Fisher-Porter bottle was charged with 61.2 g (0.60 mol) of acetic anhydride, 0.3 g of a 5% palladium-on-carbon catalyst, and 0.8 g of acetyl chloride. The bottle was pressurized to 80-95 psig with hydrogen. After 4 hours at 90° C., a gas chromatographic analysis showed 18% conversion, with about equal amounts of ethylidene diacetate and acetic acid formed.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.CS[S:8][CH3:9].[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([CH3:17])=[CH2:16])=[CH:13][CH:12]=1>COCCOC>[Cl:4][CH2:16][C:15]([C:14]1[CH:18]=[CH:19][C:11]([F:10])=[CH:12][CH:13]=1)([CH3:17])[S:8][CH3:9]
Reactant: CSSC
Reactant: O=S(=O)(Cl)Cl
Reactant: C=C(C)c1ccc(F)cc1
Solvent: COCCOC
Product: CSC(C)(CCl)c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
While cooling to −40° C., sulfuryl chloride (2.9 mL, 37 mmol) was added dropwise to a solution of dimethyl disulfide (3.3 mL, 37 mmol) in 1,2-dimethoxyethane (20 mL) under nitrogen atmosphere, and the mixture was stirred for 10 min. The obtained solution was added dropwise to a solution of 4-fluoro-α-methylstyrene (10 g, 73 mmol) in 1,2-dimethoxyethane (20 mL) while maintaining a temperature below −30° C. After stirring for 1 hour at room temperature, the solution was evaporated to give a crude product of the title compound. The obtained product was used in the next step without further purification.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@@H:15]1[CH2:19][NH:18][C:17](=[O:20])[CH2:16]1.Cl>CN(C)C=O>[C:9]([Si:6]([CH3:8])([CH3:7])[O:14][C@@H:15]1[CH2:19][NH:18][C:17](=[O:20])[CH2:16]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1C[C@H](O)CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
Imidazole (93.73 g, 1.26 mol) and tert-butyldimethylsilyl chloride (145.3 g, 0.96 mol) were added to a solution of (S)-4-hydroxy-2-pyrrolidone (92.8 g, 0.92 mol) in dimethylformamide (560 mL). The mixture was then stirred at room temperature for 16 hours, after which time it was poured over ice and an aqueous solution of hydrochloric acid (0.2 M, 300 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then extracted with ethyl acetate (4×500 mL). The combined organic extracts were washed with brine (1000 mL), dried over sodium sulphate, filtered, and evaporated under reduced pressure to give (S)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-2-one as a solid (200 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[S:7][C:8]=1[C:9]1[N:13]=[CH:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:10]=1)[CH3:2].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:21]=2)[S:7][C:8]=1[C:9]1[N:13]=[CH:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:10]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOc1nc(-c2ccnc(N)c2)sc1-c1ncn(C2CCCCO2)n1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(-c2nc(OCC)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of 4-{4-ethoxy-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridin-2-amine (100 mg, 0.268 mmol) obtained by similar manner with Example 47-B(ii) in pyridine (2.7 mL), was added ethyl chloroformate (100 μL, 1.08 mmol) at 0° C., and the mixture was stirred for 3 h. The reaction mixture was diluted with water (20 mL), and the mixture was stirred for 1 h. The resulting precipitate was collected by filtration and was washed with water and diethyl ether to give the title compound (99.1 mg, 83%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2[S:8][CH:7]=1)C.CO.C1COCC1.O.[OH-].[Li+]>O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:10]2[C:6]([CH2:5][C:4]([OH:25])=[O:3])=[CH:7][S:8][C:9]=2[CH:14]=1
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of ethyl(6-((2,4-dichlorobenzyl)oxy)-1-benzothiophen-3-yl)acetate (200 mg), MeOH (2.0 mL), THF (dry) (3.0 mL) and water (1.0 mL) was added lithium hydroxide hydrate (63.7 mg). The mixture was stirred at room temperature for 1 h. After the mixture was concentrated, the residue was neutralized with 1M HCl, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residual solid was crystallized from EtOAc-hexane to give the title compound (177.7 mg).