Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH:4]=[CH:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH3:3].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:12]([CH:11]1[O:10][C:2]([CH3:3])([CH3:1])[CH:4]=[CH:5][C:6]([CH3:9])([CH3:7])[O:8]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC=O
Reactant: CC(C)(O)C=CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1OC(C)(C)C=CC(C)(C)O1
Yield: 70.3 %

Procedure:
A mixture of 720 g (5 moles) of 2,5-dimethylhex-3-ene-2,5-diol, 3 g of p-toluenesulfonic acid, 500 g (5 moles) of n-hexanal and 1 l of toluene was refluxed, and the resulting water of reaction (115 ml) was separated off in the course of 5.5 h. The mixture was then left to cool, 10 ml of a 25% strength aqueous sodium hydroxide solution were added, the mixture was washed neutral with a little water and the toluene was removed under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 796 g of 2-pentyl-4,4,7,7-tetramethyl-4,7-dihydro-1,3-dioxepin of boiling point 75° C./0.1 mbar.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](OC)=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:11][CH2:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][N:1]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2cnn(C(=O)OC(C)(C)C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2ccc(CO)cc21
Reaction time: 1.5 h
Yield: 14.6 %

Procedure:
A solution of 1-tert-butyl 6-methyl 1H-indazole-1,6-dicarboxylate (766 mg, 2.76 mmol) in anhydrous THF (11 mL) was cooled to −30° C., LiAlH4 (210 mg, 5.53 mmol) was added in portions below −30° C., and the mixture was stirred at this temperature for 1.5 h, added water: 10% NaOH:water=0.8 mL:2.4 mL:0.8 mL carefully, filtered, and the filtrate was concentrated and purified by silica gel chromatograph to afford 100 mg of the title compound (14%). 1H NMR (400 MHz, CDCl3): δ 1.72 (9H, s), 4.86 (2H, s), 7.33 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=8.4 Hz), 8.13 (1H, s), 8.21 (1H, s). [M+H] Calc'd for C13H16N2O3, 249. Found, 249.
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1O>CCCCCC.C(OCC)(=O)C>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:17]3[C:16]([CH3:15])=[CH:21][CH:20]=[C:19]([CH3:22])[C:18]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C)c2c1OC(=O)C2c1ccc(C(C)C)cc1
Yield: 20 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid and 2,5-dimethylphenol synthesized in Reference Example 1, the title compound was synthesized in the same manner as in Reference Example 2. Yield 20%. Melting point: 107-109° C. (hexane-ethyl acetate).
Reaction SMILES: OC1C=CC=CC=1/C=[N:5]\[C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10]([CH2:27][S:28][C:29]1[N:30]([CH3:37])[NH:31][C:32](=[O:36])[C:33](=[O:35])[N:34]=1)=[C:11]2[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16].O.CS(O[C:48](=[O:59])/[C:49](/[C:53]1[N:54]=[C:55]([NH2:58])[S:56][CH:57]=1)=[N:50]\[O:51][CH3:52])(=O)=O.ClCCl>C(OC)(C)(C)C>[NH2:58][C:55]1[S:56][CH:57]=[C:53](/[C:49](=[N:50]/[O:51][CH3:52])/[C:48]([NH:5][C@@H:6]2[C:13](=[O:14])[N:12]3[C@@H:7]2[S:8][CH2:9][C:10]([CH2:27][S:28][C:29]2[N:30]([CH3:37])[NH:31][C:32](=[O:36])[C:33](=[O:35])[N:34]=2)=[C:11]3[C:15]([OH:17])=[O:16])=[O:59])[N:54]=1
Reactant: CO/N=C(\C(=O)OS(C)(=O)=O)c1csc(N)n1
Reactant: COc1ccc(COC(=O)C2=C(CSc3nc(=O)c(=O)[nH]n3C)CS[C@@H]3[C@H](/N=C\c4ccccc4O)C(=O)N23)cc1
Solvent: O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(=O)[nH]n3C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with (6R,7R)-4-methoxybenzyl 7-((Z)-(2-hydroxybenzylidene)amino)-3-(((2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1 eq), water (6-9 weight % relative to the Schiff base), (Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[O:16]1[CH2:33][C@@H:17]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](OCC#N)=[O:28])=[CH:22][CH:21]=1>C1COCC1>[O:16]1[CH2:33][C@@H:17]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)=[O:28])=[CH:24][CH:25]=1
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: N#CCOC(=O)Cc1ccc(OC[C@H]2CO2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OC[C@H]2CO2)cc1)NCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 10.7 g (52.1 mmol) 1-(2-aminoethyl)-4-phenylpiperazine and 13.5 g (54.6 mmol) (R)-4-(2,3-epoxypropoxy)phenylacetic acid, cyanomethyl ester in 125 dry THF was stirred at room temperature for 40 hours. The solvent was removed in vacuo and the residue was triturated with ether to give the crude amide as a white solid. The solid was dissolved in 35 ml. CH2Cl2 and placed on a column of 170 g Woelm basic alumina (grade 3) made up in CHCl2. Elution with 1 liter CH2Cl2 furnished essentially pure material. Crystallization from acetone afforded the end product, m.p. 124°-125°. A second crop, m.p. 121°-123° was obtained from the mother liquors.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:21])([CH3:20])[C:4](=[O:19])[C:5]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[BH4-].[Na+]>C(O)(C)C>[Cl:1][CH2:2][C:3]([CH3:21])([CH3:20])[CH:4]([OH:19])[C:5]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: CC(C)(CCl)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(CCl)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Yield: 96 %

Procedure:
162 g (0.5 mol) of 1-chloro-5-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-4-penten-3-one (prepared as described in Example III-2) were dissolved in 500 ml of isopropanol, and 9.5 g (0.25 mol) of sodium borohydride were added in portions to the solution, while stirring. The reaction mixture was stirred for 10 hours at room temperature, and was then concentrated in vacuo. The residue was taken up in toluene, and the solution was washed with dilute acetic acid and then with water, and was dried over sodium sulphate and concentrated in vacuo. 156.6 g (96% of theory) of 1-chloro-5-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-4-penten-3-ol of refractive index nD20 =1.5579 were obtained as an E/Z isomer mixture.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:3]1.C(O)C.[BH4-].[Na+]>O>[OH:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N[C@@H]1CC[C@@H](O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 19.2 g. of N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide and 275 ml. of absolute ethanol is stirred under a nitrogen atmosphere and 3.58 g. sodium borohydride added. The reaction mixture is stirred at room temperature for 16 hours, then 200 ml. of water is added and the stirring continued for 4 hours. Next, the reaction mixture is evaporated to dryness in vacuo and the residue treated with 250 ml. of water. The mixture is cooled in an ice bath and acidified with concentrated hydrochloric acid. The precipitated yellow solid is collected and dried; weight 6 g., m.p. 120°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([Cl:11])=[CH:4][C:3]=1[CH:12]([CH3:16])[C:13]([OH:15])=[O:14]>C(O)(=O)C.O.[Fe]>[NH2:8][C:6]1[C:5]([Cl:11])=[CH:4][C:3]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C(=O)O)c1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1cc(Cl)c(N)cc1Cl
Temperature: 95 °C
Yield: 78.6 %

Procedure:
23 g (87 mmoles) of 2-(2,5-dichloro-4-nitrophenyl)propionic acid are heated to 95° C. in 100 ml of glacial acetic acid and 30 ml of water, and 14 g (0.25 mole) of iron powder are added in portions. After the exothermic reaction subsides, heating (to 95° C.) is effected for a further hour. Pouring onto 500 g of ice is effected, followed by extracting twice with, in each case, 200 ml of diethyl ether, washing the organic phase with water, drying, and concentrating in a vacuum to obtain 16 g (78.6% of theory) of 2-(4-amino-2,5-dichlorophenyl)propionic acid (m.p. 140° to 141° C.).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[CH3:10][CH:4]([CH2:3][CH2:2][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)CCBr
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 40.0 g. (0.19 mole) of ethyl 4-bromo-2-methylbutyrate (Tetrahedron 21, 2966 (1965)), 66.0 g. (0.76 mole) of morpholine and 750 ml. of benzene was heated at 60°C. for 5 hours and stirred at room temperature for a total of 40 hours. A colorless solid was removed by filtration, and the mother liquor was evaporated to give a colorless, mobile residue. This material was combined with 250 ml. of ether and filtered to remove a small amount of additional solid. The solution was concentrated and the residue distilled to give the desired material as 38.0 g. (93%) of colorless liquid (b.p. 71°-73°C. at 0.10 mm).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15]1>C(#N)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CN1CCCC(N)C1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CC#N
Product: CN1CCCC(Nc2ccnc3cc(Cl)ccc23)C1

Procedure:
4 g from 11.29 g of 4,7-dichloroquinoline and 6.5 g of 3-amino-1-methyl-piperidine; colourless crystals from acetonitrile, m.p.: 149°-150° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([NH2:16])=[O:15].Br[C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:22][N:23]=3)=[C:3]([C:14]([NH2:16])=[O:15])[N:4]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1nc(-c2ccc(Cl)cc2)sc1N
Reactant: CC(C)(O)c1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(Nc2sc(-c3ccc(Cl)cc3)nc2C(N)=O)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar, 5-amino-2-(4-chlorophenyl)-1,3-thiazole-4-carboxamide (150 mg, 0.59 mmol), 2-(6-bromopyridin-3-yl)propan-2-ol (for preparation, see WO 2004/050024 A2 Example 120 Step A) (128 mg, 0.59 mmol), Pd2(dba)3 (33 mg, 0.035 mmol), X-PHOS (85 mg, 0.177 mmol), and potassium carbonate (90 mg, 0.65 mmol). The tube was evacuated, and backfilled with argon three times. Fully degassed tert-amyl alcohol (1.2 mL) was added to the reaction vessel, which was sealed and left to stir at 100° C. overnight. The reaction vessel was removed then cooled to room temperature, and the crude reaction mixture was taken up in ethyl acetate and washed with 100 mL water. The water layer was treated with concentrated ammonium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, and filtered. To the filtrate was added 1.5 g of silica gel and the solvent was removed in vacuo. The compound on silica was purified via flash chromatography (silica, 0-3% methanol/ethyl acetate) to afford the title compound. 1H NMR (500 MHz, d6-DMSO): δ 11.26 (s, 1H), 8.24 (d, 1H), 7.98 (d, 2H), 7.82 (m, 2H), 7.73 (s, 1H), 7.35 (d, 2H), 7.17 (d, 1H), 5.14 (s, 1H), 1.44 (s, 6H). LRMS (APCI) calc'd for C18H18ClN4O2S [M+H]+: 389.1, found 389.0
Reaction SMILES: Cl.[CH2:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=O)=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(OC(=O)C(=COCC)C(OCC)=O)C.CC[O-].[Na+].C(O[C:39]([C:41]1[C:42](O)=[N:43]C(C2C=CC(CCCCCC)=CC=2)=[N:45][CH:46]=1)=O)C.P(Cl)(Cl)(Cl)=O.C(OC(C1C(Cl)=NC(C2C=CC(CCCCCC)=CC=2)=NC=1)=O)C>C(O)C>[C:46]([C:41]1[CH:39]=[N:14][C:12]([C:11]2[CH:15]=[CH:16][C:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][CH:10]=2)=[N:43][CH:42]=1)#[N:45]
Reactant: CCCCCCc1ccc(C(N)=O)cc1
Reactant: CCCCCCc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Agent: CCCCCCc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 366 from p-n-hexylbenzamide hydrochloride and ethoxymethylenemalonic acid diethyl ester with sodium ethylate in ethanol and subsequent treatment of the obtained 2-(p-n-hexylphenyl)-4-hydroxy-5-pyrimidine carboxylic acid ethyl ester (melting point 186.6°-191.0° C) with phosphorus oxychloride. The melting point of 2-(p-n-hexylphenyl)-4-chloro-5-pyrimidinecarboxylic acid ethyl ester is 59.4°-60.5° C.
Reaction SMILES: COC([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:9][CH2:8][C:7]2([CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]2)[C:6]1=[O:17])=O.C(N(CC)CC)C.Cl.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CN(C)C(=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH:5]2[CH2:9][CH2:8][C:7]3([CH2:10][O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14]3)[C:6]2=[O:17])=[CH:20][CH:21]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC2(COC(C)(C)OC2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OCC2(CCC(Cc3ccc(Cl)cc3)C2=O)CO1
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
In 2-(4-chlorobenzyl)-8,8-dimethyl-1-oxo-7,9-dioxaspiro[4.5]decane-2-carboxylic acid methyl ester (2.0 g, 0.00546 mol), N,N-dimethylacetamide (2 mL), triethylamine (0.20 mL, 0.00546×0.3 mol), and triethylamine hydrochloride (1.13 g, 0.0546×1.5 mol) were added and stirred at 155° C. for 1.5 hours. In the reaction liquid, toluene and saturated sodium bicarbonate water were added, and the mixture was partitioned. After extracting the aqueous layer using toluene, the organic layer was dried using anhydrous sodium sulfate and concentrated. Thereafter, the dried and concentrated product was purified using a silica gel column, and a target product was obtained.
Reaction SMILES: [OH-].[Na+].C([S:6][CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)C>CO>[SH:6][CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C)CSC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(C)CS
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
At -20° C., 3N NaOH (150 mL, 450 mmol) was added dropwise to a solution of ethyl 3-(acetylthio)-2-methylpropanoate (66.47 g, 349 mmol, Step 5) in 700 mL of MeOH and the mixture was stirred at that temperature for 30 min. 25% Ag NH4OAc was then added and the title thiol was extracted with EtOAc, dried over MgSO4, concentrated and distilled to yield 42.52 g (82%) of the title compound as an oil; bp: 96°-98° C./15 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[C:5](Br)=[C:6]([CH3:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[C:15]1([O-:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[K+]>CN(C)C=O>[N+:1]([C:4]1[C:5]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH3:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Br
Reactant: [O-]c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Oc1ccccc1
Temperature: 0 °C
Yield: 17.7 %

Procedure:
A mixture of 6 gm of 3,5-dinitro-2-bromotoluene and 3 gm of potassium phenolate in 20 ml of dimethyl formamide was boiled under reflux for 20 hours. Subsequently, the solution was poured on 200 gm of ice and the precipitate was filtered off. After recrystallization from ethanol, there was obtained 1.1 gm of yellow crystals with a melting point of 103° C. The mass spectrum showed a molecular mass of 274 (calculated 274).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([S:14][CH3:15])=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>CC(=O)OCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:15][S:14][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([C:20]2[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=2)=[N:3][CH:4]=1
Reactant: CSc1cnc(Cl)nc1N1CCOCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Reaction time: 12 h
Yield: 48.8 %

Procedure:
A mixture of 4-(2-chloro-5-(methylthio)pyrimidin-4-yl)morpholine (0.3 g, 1.22 mmole), 4-aminophenylboronic acid pinacol ester (0.58 g, 2.68 mmole), sodium bicarbonate (0.28 g, 2.68 mmole), Pd(PPh3)4 (0.14 g, 0.122 mmole), dioxane (15 ml) and H2O (3.5 ml) was heated to reflux. After 12 hrs, the reaction mixture was cooled, diluted with EA, washed with brine, and dried (MgSO4), and the solvent was removed in vacuo. Purification on silica gel (EA/Hex=1/2) yielded the desired compound (180 mg, 49%).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[CH2:20]1[O:22][CH2:21]1.O>O1CCCC1>[OH:22][CH2:21][CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7]
Reactant: C1CO1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(1,1-dimethylethyl)benzenesulfonamide (40.0 g) in 550 ml dry tetrahydrofuran was cooled to 0° and 250 ml of 1.6M n-butyllithium added dropwise at 0°. After the addition of one equivalent of base, the solution turned yellow. After stirring for 2 hours at room temperature, the resulting suspension was cooled to 0° and 13 ml of ethylene oxide added dropwise. After stirring for 3.5 hours at room temperature, the homogeneous yellow solution was poured into water. The product was extracted with ether and dried (Na2SO4). Concentration gave a yellow oil which was purified by column chromatography [400 g silica gel, ether/hexane (1:1) followed by ethyl acetate]. Pure 2-(2-hydroxyethyl)-N-(1,1-dimethylethyl)benzenesulfonamide was obtained as a colorless oil which solidified after several days; m.p. 43°-45°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C1C=CC=CC=1.C(OCC)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([O:4][CH3:3])[O:16][CH3:17])=[CH:7][CH:8]=2)[C:13](=[O:15])[CH3:14])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: COC(OC)c1ccc(CC(C)=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(OC)c1ccc(C(Cc2ccc(Cl)c(Cl)c2)C(C)=O)cc1
Yield: 46 %

Procedure:
0.15 g of 60% oily sodium hydride was dissolved in a liquid mixture of 1.5 ml of dimethylformamide and 1.5 ml of benzene, and a dimethylformamide 2 ml/benzene 2 ml solution of 0.72 g of 4-dimethoxymethylphenylacetone was dropwise added thereto with stirring under cooling with ice. The mixture was stirred at the same temperature for 15 minutes. To this solution, a dimethylformamide 2 ml/benzene 2 ml solution of 0.65 ml of 3,4-dichlorobenzyl chloride was dropwise added with stirring under cooling with ice. The mixture was stirred at the same temperature for 40 minutes. Then, a 3% citric acid aqueous solution and ethyl ether were added for liquid separation. The organic layer was collected by separation, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was subjected to medium pressure liquid chromatography (Lobar column™, size B, Lichroprep™ Si60F, manufactured by Merck Co.; hexane/ethyl acetate=10/1→6/1) to obtain 0.64 g (yield: 46%) of 4-(3,4-dichlorophenyl)-3-(4-dimethoxymethylphenyl)-2-butanone as colorless oily substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:9]=1[CH3:10])=[O:4].O[Li].O>C1COCC1.O>[OH:21][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][NH:12][C:11]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[CH:8]=2)=[O:22])[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1sc(C(=O)NCCc2cccc(O)c2)cc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)NCCc2cccc(O)c2)sc1C(=O)O
Yield: 69.5 %

Procedure:
A solution of 5-[2-(3-hydroxy-phenyl)-ethyl-carbamoyl]-3-methyl-thiophene-2-carboxylic acid methyl ester (260 mg, 0.81 mmol) in THF/water (8 ml/4 ml) was treated with LiOH.H2O (171 mg, 4.1 mmol) at 40° C. for 1.5 h. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The layers were separated. The organic layer was washed with brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (172 mg, 70% yield).