Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1.CN(C)C1SC(C(Cl)=O)=C(C)N=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:32][CH:33]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:34]#[N:35]>C(N(CC)CC)C>[C:34]([CH:33]([NH:32][C:9]([C:5]1[S:4][C:3]([N:2]([CH3:1])[CH3:12])=[N:7][C:6]=1[CH3:8])=[O:11])[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)#[N:35]
Reactant: N#CC(N)c1cccs1
Reactant: Cc1nc(N(C)C)sc1C(=O)O
Agent: Cc1nc(N(C)C)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N(C)C)sc1C(=O)NC(C#N)c1cccs1
Yield: 33.7 %

Procedure:
1.2g of 2-dimethylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-dimethylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.3g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.1g of amino-thiophen-2-yl-acetonitrile hydrochloride and 2.5ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.65g (Yield 36%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>O.C(O)C>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nnc(SCc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
In 35 ml of water and 70 ml of ethanol, 12.8 g of 2-amino-5-mercapto-1,3,4-thiadiazol and 43 g of sodium hydroxide were added. To this mixture, 14.8 g of 4-chlorobenzyl chloride was added and the mixture was stirred at room temperature for 1 hour. Water was added and the reaction mixture was filtered The residue was washed with water and an ethanol/n-hexane (1:1) mixture, and was dried under reduced pressure, and thus 23.1 g of 2-amino-5-(4-chlorobenzylthio)-1,3,4-thiadiazole was obtained. m.p. 162°~164° C. Yield 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10](N(CC)CC)C.O1CCCC1.[S:22]1[C:26]2[C:27]3[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=3[O:29][CH2:30][CH2:31][C:25]=2[CH:24]=[C:23]1[C:36](Cl)=[O:37]>>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]([CH3:10])[C:36]([C:23]1[S:22][C:26]2[C:27]3[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=3[O:29][CH2:30][CH2:31][C:25]=2[CH:24]=1)=[O:37]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: Nc1ccc(F)cc1Cl
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(F)cc1Cl

Procedure:
To a solution of 2-chloro-4-fluoroaniline (0.110 g, 0.755 mmol) and triethylamine (0.105 mL, 0.755 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added portion wise as a solid 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.100 g, 0.378 mmol). Reaction mix was stirred at room temperature with monitor for formation of desired product. The reaction was stirred overnight. The mixture containing the alkylated product was concentrated in vacuo to a solid residue, then taken into N,N-dimethylformamide (1.5 mL, 19 mmol) and treated with sodium hydride (0.0181 g, 0.755 mmol) followed by the addition of methyl iodide (0.0470 mL, 0.755 mmol). Reaction stirred at room temperature for about 1 hr with complete conversion to desired N-methyl derivative. After aqueous work up, the crude was taken into DMF at 100 mg/l mL and purified by preparative RP-HPLC to give 107. Yield=22% of theoretical. MS: (ESI+) 375
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:11]>CO.O>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:11]
Reactant: O=C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccccc1

Procedure:
50 mmol benzoic acid is dissolved in 50 mL of methanol. 50 mmol NaOH dissolved in 50 mL water is added slowly to the benzoic acid solution prepared while stirring to obtain sodium benzoate. 50 mmol silver nitrate dissolved in 50 mL water is added to the sodium benzoate solution, and then white precipitate forms fast. The precipitate is washed to remove unreacted silver nitrate and NaOH with water, filtered and washed several times to remove unreacted benzoic acid with methanol. The filtrant white silver benzoate is sensitive to light and should be dried and stored in dark room or under yellow light.
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[O:18][C@H:15]2[CH2:16][OH:17])=[CH:10][CH:9]=1.COCCO[AlH2-]OCCOC.[Na+].Cl>C(OCC)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]([OH:18])[CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=1
Reactant: OC[C@@H]1O[C@@H]1c1ccc(Cl)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: OCC[C@H](O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
500 ml of a dimethoxyethane solution of 15.0 g of (2S,3R)-3-(4-chlorophenyl)-2,3-epoxy-1-propanol was cooled to -25° C., and 25.1 ml of a red-Al solution (3.4 mol/l toluene solution) was added dropwise over 0.5 hour. After stirred at 20° C. for 2 hours, the mixture was brought to 0° C. over 1 hour, and 300 ml of diethyl ether was added thereto. While the mixture was kept below 5° C., 100 ml of 2N hydrochloric acid was added dropwise. After stirring for 15 minutes, the mixture was filtered through celite. Then, 100 ml of ethyl acetate was added, and the resulting mixture was allowed to separate. The aqueous layer was extracted again with ethyl acetate. The organic layers were combined, dried over sodium sulfate and filtered through celite. The solvent was distilled off the filtrate, and the resulting residue was purified by silica gel column chromatography (eluent; methanol/chloroform=5/95). It was crystallized to obtain 14.56 g of the title compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH2:3][CH:4]([C:17]([OH:19])=[O:18])[CH2:5][C:6](=[O:16])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[CH:22]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:22][O:18][C:17]([CH:4]1[CH2:3][C:2](=[O:1])[C:7]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([OH:16])[CH2:5]1)=[O:19]
Reactant: O=C1CC(C(=O)O)CC(O)=C1N=Nc1ccccc1
Reactant: c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1CC(=O)C(N=Nc2ccccc2)=C(O)C1

Procedure:
60 G. of 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid, 200 ml. of methanol, 1200 ml. of benzene and 5 g. of p-toluenesulfonic acid were heated together at reflux for 18 hours on a water separator. After cooling, the solution was washed with 500 ml. of a 5% sodium bicarbonate solution, washed with water, dried and evaporated. The residue was dissolved in ethyl acetate and purified on an aluminum oxide column (500 g., activity stage I). After evaporation of the ethyl acetate, there was obtained 3-hydroxy-5-keto-4-phenylazo-3-cyclohexenecarboxylic acid methyl ester of melting point 144° C. (from benzene/petroleum ether).
Reaction SMILES: S(O[CH2:6][CH:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8]OS(=O)(=O)C)(=O)(=O)C.[S-2:22].[Na+].[Na+]>C(O)C>[C:18]([O:17][C:15]([NH:14][CH:7]1[CH2:8][S:22][CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)COS(C)(=O)=O
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CSC1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A solution of N-(tert-butyloxycarbonyl)-2-amino-1,3-propanediol dimesylate [prepared according to E. Benoist et al., Synthesis 1998, (8), 1113-1118] (25 g, 72.0 mmol) in ethanol (375 ml) is treated with sodium sulfide (Na2S.xH2O 32-38%, 16.82 g, ˜75.4 mmol) and the mixture is stirred at a temperature of 50° C. (bath 60° C.) for 45 minutes. The cooled reaction mixture is concentrated under reduced pressure and the solid residue poured into water, extracted with Et2O, the combined organic layers washed with brine, dried (Na2SO4), filtered, and concentrated. The crude solid product (12.6 g, 92%) is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:28])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC(O)(C)C>[F:28][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([N:43]=[N+:44]=[N-:45])=[O:25])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:5])([F:6])[F:4]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1

Procedure:
A solution of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzoic acid (1.67 g, 4.2 mmol), diphenylphosphoryl azide (1.26 g, 4.58 mmol) and triethylamine (0.5 g, 5 mmol) in 10 mL of dry t-BuOH was heated to 75° C. for 90 min, resulting in dissolution of the starting acid and subsequent precipitation of the azide. The cooled solution was then poured onto 10 g of ice, and the resulting mixture was filtered and dried to furnish 0.80 g of the azide as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.65 (s, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H); ESIMS 399.2 (M+H); mp 175° C. dec.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH2:50][CH3:51]>O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:50][CH3:51])[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(O)cc(Br)c2)c1CCC(=O)OCC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a mixture of 4-[3-[6-(3-bromo-5-hydroxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (163 mg, 0.28 mmol) and potassium carbonate (117 mg, 0.84 mmol) were added dimethylformamide (4 mL), acetone (8 mL), and iodoethane (219 mg, 1.4 mmol) at room temperature. The resulting suspension was heated to reflux for 2 days. Then, the reaction mixture was cooled to room temperature and diluted with water (20 mL). The organic compound was extracted into ethyl acetate (2×25 mL) and the combined organic extracts were washed with water (50 mL) and brine solution (50 mL). The organic layers were dried over anhydrous magnesium sulfate and filtration of the drying agent and concentration of the solvent gave the crude product which was purified by using an ISCO 40 g column, eluting with 0-30% ethyl acetate in hexanes to afford 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (166 mg, 98%) as a colorless oil: ES(+)-HRMS m/e calcd for C31H43BrO7 (M+H)+ 607.2265. found 607.2270.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:52])([CH3:51])[C:15]([CH3:50])([CH3:49])[O:16][C:17]1[CH: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>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:51])([CH3:52])[C:15]([CH3:50])([CH3:49])[O:16][C:17]1[CH: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
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogen carbonate (2.62 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.96 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 (0.41 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 amorphous solid (0.78 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7](F)=[CH:6][C:5]=1[Cl:12].Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:16]([CH3:17])[CH3:15])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1cc(F)c(F)cc1Cl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)c(N(C)C)cc1Cl
Temperature: 60 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
To a stirred solution of 23.1 g (112 mmol) 22a and 231 ml dimethylsulphoxid were added 10.0 g (123 mmol) dimethylamine hydrochloride and 32.4 g (234 mmol) potassium carbonate. The reaction mixture was stirred for 24 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 22b was obtained in 89.5% yield (23.1 g 100 mmol).
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[NH2:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C.O>C(#N)C>[N:19]1[CH:18]=[CH:17][N:16]2[C:15]=1[CH2:14][C:13]1[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=1[NH:11][C:2]2=[O:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccccc1Cc1ncc[nH]1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2Cc2nccn21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 32.4 g of phenyl chloroformate in 100 ml of acetonitrile is added dropwise under nitrogen while stirring to a mixture of 34.6 g of 2-(2-aminobenzyl)imidazole and 71 g of triethylamine in 600 ml of acetonitrile at room temperature. After addition is complete, the reaction mixture is heated under reflux for 12 hours, and allowed to cool to room temperature. Water (150 ml) is added, the mixture is stirred at room temperature for 0.5 hour and cooled to 5°. The resulting precipitate is filtered off, washed first twice with 50 ml of water, then 3 times with 33 ml of cold acetone and dried to give 11H-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one, m.p. 255°-7°.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:16]#[N:17])[CH:7]=2.S(=O)(=O)(O)[OH:19]>>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([C:16]([NH2:17])=[O:19])[CH:7]=2
Reactant: O=S(=O)(O)O
Reactant: Cn1c2c(c3cc(C#N)ccc31)C(=O)CCC2
Product: Cn1c2c(c3cc(C(N)=O)ccc31)C(=O)CCC2

Procedure:
A solution of the product of Stage (i) cyanonitrile (2.7 g) in concentrated sulphuric acid (30 ml) was heated at 80° for 1 h. The mixture was poured onto ice (ca. 500 g) to precipitate a solid which was filtered, washed with water (3×50 ml) and dried in vacuo to leave a solid (3.1 g). This was extracted with boiling absolute ethanol (1.5 l), the extract was evaporated to ca 2 ml, diluted with a mixture of chloroform:methanol (1:1, ca 20 ml) and filtered to give the title compound (0.53 g) as a solid m.p. 295°-298°.
Reaction SMILES: [C:1]([C:6]1[CH:18]=[C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12]CC)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:18]=[C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(C(C)(C)CC)cc1C(C)(C)CC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)(C)c1ccc(OCC(=O)O)c(C(C)(C)CC)c1
Reaction time: 6 h
Yield: 133.8 %

Procedure:
The above ethyl 2-(2,4-di-t-amylphenoxy)acetate (293 g) and 27% aqueous sodium hydroxide (401.4 g) were placed in a 3-liter flask. The mixture was kept at 98° C. for 6 hours, and the hydrolysis reaction was completed. After completion of the reaction, the mixture was adjusted to pH 2 or lower by the addition of 40% aqueous sulfuric acid (349.9 g) and water (250 g), and toluene (289.5 g) was added thereto, followed by extraction. The water layer was separated with a separatory funnel, and the toluene layer was washed with water (289.5 g). Then, the toluene layer was concentrated by distillation under ordinary pressure for the recovery of toluene, which afforded a concentrated solution (357.6 g) of the carboxylic acid compound in toluene. The analysis revealed that the concentrated solution contained the desired carboxylic acid compound in a yield of 99% on the basis of the raw material ester compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]([CH3:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][N:17]=1.Br[CH2:34][CH:35]1[CH2:37][C:36]1([F:39])[F:38].C(N(CC)CC)C>CN(C=O)C>[F:38][C:36]1([F:39])[CH2:37][CH:35]1[CH2:34][N:11]1[CH2:10][CH2:9][CH:8]([C:6]2[C:5]([CH3:14])=[CH:4][C:3]([NH:15][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=4)[C:19]([C:29]([F:32])([F:30])[F:31])=[CH:18][N:17]=3)=[C:2]([F:1])[CH:7]=2)[CH2:13][CH2:12]1
Reactant: FC1(F)CC1CBr
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2C(F)(F)F)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC5CC5(F)F)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 60 °C

Procedure:
A mixture of N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (100 mg, 0.22 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (76.4 mg, 0.45 mmol) and triethylamine (60.6 μL, 0.42 mmol) in 1 mL of DMF was heated at 60° C. in a microwave reactor for 2 h. The crude product was purified by RP-HPLC to afford N2-(4-(1-((2,2-difluorocyclopropyl)methyl)piperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; ESMS m/z 540.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=4)=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCn1nccc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A dry flask was charged with 2-Ethyl-2H-pyrazole-3-carboxylic acid (0.111 g, 0.792 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 2-Ethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.200 g, 0.534 mmol, 68%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].Br[CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][OH:39])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>C(#N)C>[OH:39][CH2:38][CH2:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:26]1[CH2:25][CH2:24][C:22]2([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]3[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=3)=[O:17])[CH2:23]2)[CH2:28][CH2:27]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cccc(CBr)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Reaction time: 2 h

Procedure:
A mixture of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.85 g) and 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.432 g) in acetonitrile (10 mL) at 20° C. was treated with triethylamine (0.616 mL) and then stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 1% triethylamine and 3% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.71 g.
Reaction SMILES: O[CH:2]([N:4]1[CH2:8][CH:7]([CH2:9][CH3:10])[O:6][C:5]1=[O:11])[CH3:3].OS([O-])(=O)=O.[Na+]>>[CH:2]([N:4]1[CH2:8][CH:7]([CH2:9][CH3:10])[O:6][C:5]1=[O:11])=[CH2:3].[CH2:9]([CH:7]1[O:6][C:5](=[O:11])[NH:4][CH2:8]1)[CH3:10]
Reactant: CCC1CN(C(C)O)C(=O)O1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: C=CN1CC(CC)OC1=O
Product: CCC1CNC(=O)O1

Procedure:
3-(1-Hydroxyethyl)-5-ethyl-2-oxazolidinone is prepared from 72 g (0.626 mole) of 5-ethyl-2-oxazolidinone by the procedure described in Example 1. A total of 96 g of 3-(1-hyroxyethyl)-5-ethyl-2-oxazolidinone is obtained (87 percent conversion). The 3-(1-hydroxyethyl)-5-ethyl-2-oxazolidinone is dehydrated in the hot tube filled with steel helices which is coated with a catalyst of NaHSO4. The dehydration is conducted at 260° C. under 40 mm Hg pressure. A dark red liquid (83 g) is collected which gives 64.6 g of N-vinyl-5-ethyl-2-oxazolidinone and 10.4 g of 5-ethyl-2-oxazolidinone upon fractionation. The yield is 87 percent based on 86 percent conversion of 5-ethyl-2-oxazolidinone.