Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([F:16])[C:7]=1C(N)=O.Br[N:18]1[C:22](=[O:23])CCC1=O>CO>[CH3:1][O:2][C:22](=[O:23])[NH:18][C:7]1[C:11]([F:16])=[C:12]([CH3:15])[CH:13]=[CH:14][C:6]=1[Cl:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(C(N)=O)c1F
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)Nc1c(Cl)ccc(C)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium methoxide is generated by treating metallic sodium (29 g, 1.26 mol) with 1000 mL of anhydrous methanol by dropwise addition under an inert atmosphere. After the metal is completely consumed, the solution is heated at reflux temperature for 30 minutes and then cooled to room temperature. 2-Chloro-5-methyl-6-fluorobenzamide (42 g, 0.22 mol) is added and stirring continued for an additional 30 minutes at room temperature. N-Bromosuccinimide (78 g, 0.44 mol) is then slowly added via a powder additional funnel. The reaction mixture is warmed to 60° C. for 3 hours during which time foaming is observed. The reaction mixture is cooled to room temperature and most of the solvent is removed by rotary evaporator. The residue is partitioned between EtOAc (1000 mL) and water (1000 mL). The organic layer is separted and washed with water (500 mL) and then brine (2×500 mL). The organic layer is dried (MgSO4), filtered and concentrated by rotary evaporator the crude product is then purified using flash chromatography, eluting with 4:1 hexanes/EtOAc to give N-(2-chloro-5-methyl-6-fluorophenyl)-carbamic acid methyl ester as a white solid (m.p. 109–112° C.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(O[CH:16]=[C:17]([C:23]#[N:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>CCO>[CH2:21]([O:20][C:18]([C:17]1[CH:16]=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[C:23]=1[NH2:24])=[O:19])[CH3:22]
Reactant: CS(=O)(=O)c1cccc(NN)c1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(S(C)(=O)=O)c2)c1N

Procedure:
A solution of the above crude (3-methanesulfonyl-phenyl)-hydrazine (0.86 g, 4.6 mmol) and ethyl (ethoxymethylene)cyanoacetate (0.78 g, 4.6 mmol) in EtOH (23 mL) is heated at 80° C. for 2 h before removal of the solvent. The residue is purified by silica gel chromatography to provide 5-amino-1-(3-methanesulfonyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester as a light yellow solid; HPLC-MS calculated for C13H15N3O4S (M+H+) 310.1, found 310.1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2([NH:18][C:19]([C:21]3([NH:24][C:25]([C:27]4[N:31]5[C@@:32]([CH2:45][C:46]6[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=6)([CH3:44])[C:33](=[O:43])[N:34]([C:35]6[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=6)[C:30]5=[N:29][CH:28]=4)=[O:26])[CH2:23][CH2:22]3)=[O:20])[CH2:17][CH2:16]2)[CH:10]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2([NH:18][C:19]([C:21]3([NH:24][C:25]([C:27]4[N:31]5[C@@:32]([CH2:45][C:46]6[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=6)([CH3:44])[C:33](=[O:43])[N:34]([C:35]6[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=6)[C:30]5=[N:29][CH:28]=4)=[O:26])[CH2:22][CH2:23]3)=[O:20])[CH2:16][CH2:17]2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C2(NC(=O)C3(NC(=O)c4cnc5n4[C@](C)(Cc4ccc(C#N)cc4)C(=O)N5c4cc(Cl)cc(Cl)c4)CC3)CC2)c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN)ccn5)CC4)CC3)n21
Yield: 164.3 %

Procedure:
(2-{1-[(1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-amino]-cyclopropyl}-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (45 mg, 0.06 mmol) was placed in RBF with CH2Cl2 and TFA was added. The reaction was diluted with 10 mL 10% MeOH/CH2Cl2 and washed with water (2×5 mL). The organic layer was separated, dried (MgSO4), and concentrated. Reverse Phase HPLC purification (30-100% CH3CN/H2O as gradient) yielded 66 mg of the title compound as a bis-TFA salt, m/z=669.5 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][I:11].[CH:12]1[CH:17]=[CH:16][C:15]([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[I-:11].[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]1[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1ccc(CCI)c(Br)c1
Solvent: Cc1ccccc1
Product: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Br)c1
Product: [I-]
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-(2-iodoethyl)benzene (2.23 g, 6.78 mmol) in toluene (15 ml) was added Ph3P (1.778 g, 6.78 mmol) and the mixture was heated at 100° C. for 16 h. The mixture was cooled to rt, solids were filtered and washed with toluene and ether, dried under high vac to afford (2-bromo-4-fluorophenethyl)triphenylphosphonium, iodide salt (3 g, 5.07 mmol, 74.8% yield) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.01-7.87 (m, 9H), 7.85-7.77 (m, 6H), 7.66-7.51 (m, 1H), 7.35-7.24 (m, 1H), 7.20-7.07 (m, 1H), 3.93-3.80 (m, 2H), 3.07-2.86 (m, 2H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3]>C(O)CO>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:4][CH2:5][CH2:6][OH:11])=[O:3]
Reactant: COc1ccccc1OC(=O)Cl
Solvent: OCCO
Product: COc1ccccc1OC(=O)OCCO

Procedure:
The reaction of 2-methoxyphenyl chloroformate with ethylene glycol is conducted on a 0.01 mole scale employing the same conditions as described in Example III. A 0.7 g yield of the pure product is obtained as an oil. The product is unstable and decomposes quantitatively after standing at room temperature for several hours.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=[C:6]2[CH:5]=[C:4]([CH3:14])[N:3]=1.[NH2:15][C@@H:16]([CH3:33])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[C:29]([F:31])[C:26]([C:27]#[N:28])=[C:25]([Cl:32])[CH:24]=2)=[N:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:11]([C:9]3[N:10]=[C:6]4[CH:5]=[C:4]([CH3:14])[N:3]=[C:2]([CH3:1])[N:7]4[CH:8]=3)=[O:13])[CH3:33])[N:19]=2)[CH:30]=[C:29]([F:31])[C:26]=1[C:27]#[N:28]
Reactant: Cc1cc2nc(C(=O)O)cn2c(C)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc2nc(C(=O)N[C@@H](C)Cn3ccc(-c4cc(F)c(C#N)c(Cl)c4)n3)cn2c(C)n1
Yield: 18.5 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5,7-dimethyl-imidazo[1,2-c]pyrimidine-2-carboxylic acid (0.753 mmol, 0.144 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (0.538 mmol, 0.2 g). DMF (6 ml) was used as a solvent and HBTU (0.054 mmol, 0.020 g) was used instead of HOBt. The crude product was purified by trituration from ACN. 0.045 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.26 (d, 3H), 2.53-2.56 (m, 3H), 2.82 (s, 3H), 4.30 (dd, 1H), 4.48 (dd, 1H), 4.60-4.72 (m, 1H), 6.63 (d, 1H), 7.23-7.26 (m, 1H), 7.52 (d, 1H), 7.75-7.83 (m, 2H), 8.00-8.06 (m, 1H), 8.27 (d, 114).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=O)[C@@H:3]([CH3:5])[OH:4].[OH-].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1SCl)([O-:13])=[O:12].[S:22](=O)(=O)(O)[O-].[K+]>O.O1CCOCC1>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:1][C@H:2]([C:6]([OH:8])=[S:22])[C@@H:3]([CH3:5])[OH:4])([O-:13])=[O:12]
Reactant: O=S(=O)([O-])O
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1SCl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](O)[C@H](Nc1ccccc1[N+](=O)[O-])C(O)=S

Procedure:
L-threonine (11.9 g) is added to dioxane (125 ml) and 2N sodium hydroxide (50 ml). To the vigorously stirred solution, o-nitrophenylsulfenyl chloride (20.9 g) is added in ten equal portions over fifteen minutes, while 2N sodium hydroxide (60 ml) is slowly added dropwise. After five more minutes the reaction mixture is diluted with water (400 ml) and acidified to pH 2.5 with 10% potassium bisulfate. The organic layer is immediately extracted with ethyl acetate (three 200 ml portions), and the combined extracts are dried over sodium sulfate, and then concentrated to an oil. The product crystallizes on scratching (20.0 g). Recrystallization of 17 g from acetone/hexane affords 9.5 g of crystals, melting point 145°-148° C. which are stored in a freezer and used promptly.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][C:6]#[CH:7].I[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1>>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][C:6]#[C:7][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=1
Reactant: C#CCCC(=O)OC
Reactant: FC(F)(F)Oc1ccc(I)cc1
Product: COC(=O)CCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 8 a], pent-4-ynoic acid methyl ester (W. D. Wulff, S. J. McCallum, F. A. Kunng, J. Am. Chem. Soc. 1988, 110, 7419-7434) was reacted with 1-iodo-4-trifluoromethoxy-benzene in the presence of PdCl2(Ph3P)2 and cuprous iodide to give the title compound as brown oil.
Reaction SMILES: [CH3:1][NH2:2].Cl[S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1)[O:13][CH2:12][CH2:11][CH2:10]2)(=[O:6])=[O:5]>>[CH3:1][NH:2][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=1)[O:13][CH2:12][CH2:11][CH2:10]2)(=[O:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCC2
Reactant: CN
Product: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCC2

Procedure:
207 g of a 40% aqueous solution of methylamine were introduced into a 1-liter round-bottomed flask and 123 g of finely ground 6-chlorosulphonylchroman-8-carboxylic acid were then added in portions, while maintaining the temperature between 0° C. and 5° C., by cooling.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:18]1([CH:25]=[CH:24][C:22]([OH:23])=[CH:21][CH:20]=1)[OH:19]>CN(C=O)C>[CH3:11][N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:19][C:18]1[CH:25]=[CH:24][C:22]([OH:23])=[CH:21][CH:20]=1
Reactant: CN(CCCl)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 20 %

Procedure:
A mixture of compound 2b (500 mg, 2.95 mmol), K2CO3 (815 mg, 5.9 mmol), and KI (480 mg, 2.95 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (649 mg, 5.9 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide compound 2 as a white solid (143 mg, 0.59 mmol, 20% yield). HRMS (ESI, positive) m/z calcd. for C15H18NO2 [M+H]+: 244.13321, found: 244.13323. 1H NMR (400 MHz, Chloroform-d) δ 7.29 (ddd, J=7.3, 5.6, 2.0 Hz, 2H), 6.84-6.72 (m, 7H), 4.98 (broad s, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.76 (t, J=6.1 Hz, 2H), 3.08 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][NH2:8]
Reactant: COc1ccccc1OCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1OCCN
Temperature: 23 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
tert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8 g, 89 mmol) was cooled to 0° C. and stirred as a mixture of trifluoroacetic acid:dichloromethane (1:1, 40 mL) was added dropwise. The mixture was allow to warm to 23° C., stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 mL) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3×20 mL) and aqueous sodium hydroxide (10%, 3×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphenoxy)ethylamine (13 g, 88% yield) a light yellow solid; MS (PB-PCI) C9H13NO2 m/e calc 167.21; found 168 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH3:17])[CH2:15]O)([O-:7])=[O:6].N1C=CC=CC=1.C(Cl)[Cl:25]>C1(C)C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH3:17])[CH2:15][Cl:25])([O-:7])=[O:6]
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(CCl)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 98 %

Procedure:
12.16 g thionyl chloride (7.5 ml, 102 mmol) in 10 ml toluene (abs.) are added quickly in a drop-wise manner to 6.2 g 2-(2-nitrophenyl)propanol (34 mmol) in 90 ml abs. toluene and 2 ml pyridine. The reaction solution is heated 1 h under reflux. After cooling, this is poured onto 100 g ice and mixed with 80 ml CH2Cl2. The H2O phase is extracted 2× each with 80 ml CH2Cl2. The combined organic phases are neutralized with 120 ml saturated bicarbonate solution, dried over Na2SO4 and rotary evaporated. 6.62 g (33 mmol, 98%) 2-(2-nitrophenyl)propyl chloride are obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+:12]([O-])([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 116.4 %

Procedure:
4-Chloro-2-nitroaniline (40 g, 0.23 mol) was dissolved in 12N-hydrochloric acid (100 ml). Sodium nitrate (16 g, 0.23 mol) dissolved in water (50 ml) was slowly added in drops at 0° C., and the mixture was stirred for 30 min at 0° C.˜room temperature. The temperature was lowered to 0° C., and tin(II) chloride (132 g, 0.70 mol) dissolved in 12N-hydrochloric acid (100 ml) was slowly added in drops. The mixture was stirred for 3 h at 0° C.˜room temperature. The resulting yellow solid was filtered, washed with a small amount of 6N—HCl and dried to give the title compound (30 g, Yield, 63%).
Reaction SMILES: [CH2:1]=[C:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].C1C=C(Cl)C=C(C(OO)=[O:17])C=1.S(C1C=C(C)C(O)=C(C(C)(C)C)C=1)C1C=C(C)C(O)=C(C(C)(C)C)C=1>ClCCCl>[CH2:7]([C:2]1([C:3]([O:5][CH3:6])=[O:4])[CH2:1][O:17]1)[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CC)C(=O)OC
Agent: Cc1cc(Sc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Solvent: ClCCCl
Product: CCC1(C(=O)OC)CO1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-methylenebutanoate (140 mmol), mCPBA (77%, 67 g, 300 mmol) and 4,4′-thiobis(2-tert-butyl-6-methylphenol) (250 mg, 0.7 mmol) in 100 ml of dry 1,2-dichloroethane was refluxed at 80° C. for 2 d. It was then cooled down, solid filtered. Filtrate washed by Na2SO3, NaHCO3, brine and water until clear. It was then concentrated to a light yellow liquid (7.5 g, 41%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (td, J=7.4, 1.3 Hz, 3 H) 1.78 (dq, J=14.6, 7.3 Hz, 1 H) 2.10 (dq, J=15.4, 7.6 Hz, 1 H) 2.80 (dd, J=5.8, 1.0 Hz, 1 H) 3.05 (dd, J=5.8, 1.0 Hz, 1 H) 3.77 (d, J=1.5 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([O:11]CC)=[O:10])[N:3]=1.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[N:3]=1
Reactant: CCOC(=O)Cn1nc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.7 %

Procedure:
A solution of ethyl 3,5-dichloro-1H-pyrazole-1-acetate (1.29 g, 5.8 mmol) (i.e. the product of Example 12, Step E) in tetrahydrofuran (10 mL) was treated with sodium hydroxide (5 mL, 15% aqueous solution) in water (3 mL), and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was then diluted with water (15 mL) and was concentrated under reduced pressure. The aqueous solution was acidified with concentrated hydrochloric acid to pH 1. The reaction mixture was then extracted with ethyl acetate and the extract was dried over MgSO4. The extract was then concentrated and recrystallized from 20% ethyl acetate in hexanes to give 370 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][SH:4].BrCCC([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:20])=O.Cl.O1C[CH2:25][CH2:24][CH2:23]1>CO>[CH3:23][CH2:24][CH2:25][C:3]([C:10]1[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[CH:13]=[CH:12][C:11]=1[OH:20])=[S:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccc(O)c(C(=O)CCBr)c1
Reactant: CS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CCCC(=S)c1cc(C(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixed solution of 1.65 g of sodium hydride (content 63%) and 15 ml of methanol were added 7.2 ml of 30% methylmercaptan in methanol and stirred at room temperature for 15 minutes. The solution was added dropwise to 4.289 g of 2-(3-bromopropionyl)-4-tert-butylphenol [described in Reference Example 3(h)] dissolved in 37.6 ml of tetrahydrofuran at room temperature and stirred at the same temperature for one hour. The reaction mixture was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, and saturated brine successively, dried over sodium sulfate anhydride and concentrated at reduced pressure. The residue was chromatographed on silica gel column using a mixed solvent of cyclohexane and ethyl acetate (30:1) as an eluting agent to give 2.304 g of the title compound of the following physical properties as pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:19][O:20][C:21](=[O:31])[C:22]1[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[NH2:30].C(OCC)(=O)C>C(OCC)C>[CH3:19][O:20][C:21](=[O:31])[C:22]1[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[NH:30][C:11](=[O:13])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:14]
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Yield: 99.1 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-nitro-phenyl)-propionic acid (1.40 g, 7.17 mmol), SOCl2 (5.1 mL, 71.7 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (1.6 g, 5.74 mmol). After normal workup, the pure objective compound (2.26 g, 99%) was obtained as pale yellow solid by recrystallization (ethyl acetate:ethyl ether=1:5): 1H NMR (200 MHz, CDCl3) δ 1.63 (d, J=7.1 Hz, 3H, CH3), 3.85-3.86 (m, 4H, CO2CH3 & CH), 7.18 (d, J=2.0 Hz, 1H, ArH), 7.54 (d, J=8.7 Hz, 2H, ArH), 8.24 (d, J=8.7 Hz, 2H, ArH), 8.45 (d, J=2.0 Hz, 1H, ArH), 9.59 (br s, 1H, ArH).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[O:24])[CH:17]=[CH:16]2.[CH3:25][S:26]SC.Cl>C1COCC1>[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([CH:23]=[O:24])[C:17]([S:26][CH3:25])=[CH:16]2
Reactant: Cc1ccc2cc(C=O)ccc2c1
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1cc2cc(C)ccc2cc1C=O
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
A 200 ml three-neck flask equipped with a dropping funnel was heated and dried, and air in the flask was replaced with nitrogen. N,N,N′-trimethyldiamine (1.22 ml, 9.6 mmol) and anhydrous THF (40 ml) were added into the flask and cooled down to −30° C. A butyllithium hexane solution (1.57 M, 6.14 ml, 9.6 mmol) was added thereto and stirred for 15 minutes. The temperature in the flask was brought back to −20° C., and an anhydrous THF (40 ml) solution of 6-methyl-2-naphthaldehyde (1.0 g, 5.9 mmol) was slowly dropped therein and stirred for 15 minutes. Further, after a butyllithium hexane solution (1.57 M, 11.2 ml, 0.017 mol) was added therein and stirred for 3.5 hours, dimethyldisulfide (2.6 ml, 0.029 mol) was added. The temperature was increased to a room temperature, and an obtained solution was stirred for 2 hours. Then, 1 M hydrogen chloride was added to stop the reaction, an obtained reaction solution was extracted with methylene chloride, and an organic layer was dried with anhydrous magnesium and filtrated. A filtrate was concentrated by use of a rotary evaporator. A residue was purified by silica gel column chromatography by use of a mixture solvent of hexane and ethyl acetate (hexane:ethyl acetate=9:1) as a mobile phase, so as to obtain 6-methyl-3-methylthio-2-naphthaldehyde (386 mg, 1.8 mmol, 30%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Clc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(Cl)cccc32)nc(N2CCOCC2)cc1=O
Yield: 21.6 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 4-chloroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 84 mg of 2-[2-(4-chloro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a slightly pinkish powder, the characteristics of which are the following: