Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH:18]=[O:19])[C:5]([NH:7][C:8]1[S:9][C:10]([S:13]([CH3:15])=[O:14])=[N:11][N:12]=1)=[O:6])[C:2]#[CH:3].Cl>O>[CH3:15][S:13]([C:10]1[S:9][C:8]([N:7]2[CH:18]([OH:19])[CH2:17][CH2:16][N:4]([CH2:1][C:2]#[CH:3])[C:5]2=[O:6])=[N:12][N:11]=1)=[O:14]
Reactant: C#CCN(CCC=O)C(=O)Nc1nnc(S(C)=O)s1
Agent: Cl
Solvent: O
Product: C#CCN1CCC(O)N(c2nnc(S(C)=O)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-propargyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-3-propargyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:27][CH2:26]2)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([O:31][CH:32]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:29][CH2:30]2)=[O:21])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COCCOCOc1ccc(C=CC=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C=CC=CC(=O)NCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)ccc1O
Yield: 63.5 %

Procedure:
To a solution of 690 mg (1.15 mmol) of the amide compound in methanol (14 ml) was added 212 mg (1.12 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 25 minutes. Water was added to the reaction mixture, which was adjusted to a pH value of 11 by the addition of an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (50:1), to give 393 mg (0.730 mmol) of 1-[2-[5-(3-methoxy-4-hydroxyphenyl)-2,4-pentadienoyl]aminoethyl]4-benzhydroxypiperidine.
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][CH:6]([F:18])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][C:9]=1[O:16][CH3:17].S(=O)(=O)([OH:21])N.C(O)(=O)C>O>[F:5][CH:6]([F:18])[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:21])=[O:13])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: NS(=O)(=O)O
Reactant: COc1cc(C=O)ccc1OC(F)F
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)ccc1OC(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7.3 g of 80% strength sodium chlorite in 15 ml of water is added dropwise with continuous stirring to a mixture of 10.0 g of 4-difluoromethoxy-3-methoxybenzaldehyde, 6.5 g of sulphamic acid and 50 ml of glacial acetic acid. The internal temperature is kept between 30° and 35° C. by cooling with ice water. After dropwise addition is complete, the mixture is stirred for a further 1 h and then diluted with water. The precipitated 4-difluoromethoxy-3-methoxybenzoic acid is filtered off with suction, washed with water, dried in vacuo and crystallized from acetonitrile/petroleum ether (b.p. 40°) 2/8. Yield 7.1 g; m.p. 170° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C>C1COCC1>[F:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:27]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (200 mg, 0.66 mmole), 2,4-difluoro-benzoyl chloride (140 mg, 1.2 eq), and triethylamine (0.2 mL, 2 eq) in 3 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give title compound as a white solid (99 mg, 34%). 1H NMR (Acetone-d6, 400 MHz) δ 2.92-3.06 (m, 2H), 3.13-3.17 (i, 2H), 3.50-3.58 (m, 4H), 3.68 (s, 3H), 3.82-3.85 (m, 2H), 4.36 (t, 2M), 6.29 (s, 1H), 7.24 (d, J=9.09 Hz, 2H), 7.44 (dt, J=10.1, 2.78 Hz, 1H), 7.49 (s, 1H), 7.67 (s, 1H), 7.72-7.79 (m, 1H), 7.81 (dd, J=9.09, 2.78 Hz, 1H). Exact mass calculated for C23H24F2N4O3 442.2. found 443.5 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:15]1([O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[O:13][CH3:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OC2CCCC2)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-hydroxy-3-methoxybenzoate (7.17 g), cyclopentyl bromide (4.7 ml) and potassium carbonate (7.6 g) in N,N-dimethylformamide (70 ml) was stirred at 80° C. for 3 hours. Then the mixture was poured into water and extracted with ethyl acetate twice. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 4:1) to give ethyl 4-cyclopentyloxy-3-methoxybenzoate (8.58 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[CH2:12][CH3:13].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH2:17][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31]1
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(F)cc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)Nc2c(Cl)cc(F)cc21

Procedure:
The title compound is prepared according to process H using processing method 1 from 7-chloro-3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl)-piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.C(O[C@@H:26]1[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]1[O:28][C:29](=[O:31])[CH3:30])(=O)C>ClCCl.C1(C)C=CC=CC=1>[C:29]([O:28][C@@H:27]1[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[O:43][C@H:26]1[O:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a suspension of ethyl (E)-3-[4-(2-hydroxybenzyl)phenyl]acrylate (0.34 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (1.4 g) in dichloromethane (3 mL) and toluene (9 ml) was added boron trifluoride-diethyl ether complex (0.45 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethylacetate=4/1) to give (E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.47 g). To a solution of the obtained (E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.46 g) in methanol (5 mL) was added sodium methoxide (0.010 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give (E)-2-[4-(2-ethoxycarbonylvinyl)benzyl]phenyl β-D-glucopyranoside (0.31 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([CH2:14][NH:15][CH2:16][CH2:17][NH2:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)(=O)C>[C:8]1([CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccccn1
Reactant: NCCNCc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(CNCCNc2ccccn2)cc1
Yield: 39.2 %

Procedure:
2-Bromopyridine (6.1 mL, 64 mmol) was added to N-(phenylmethyl)-1,2-ethanediamine (50 ml, 322 mmol) and the mixture was heated at 130–140° C. for 2 hours. The mixture was cooled, diluted with ethyl acetate (500 mL), washed with water (3×150 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (90:8:1), to give the title compound as a yellow oil (5.7 g, 40%). m/z (ES+) 228 (M+1).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:22]([S:23][CH2:24][CH3:25])=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=[N:19][N:18]3[CH:29]=2)=[CH:11][CH:10]=1)#[N:8]>O.CC(C)=O>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:22]([S:23]([CH2:24][CH3:25])=[O:1])=[C:21]([C:26]([NH2:28])=[O:27])[CH:20]=[N:19][N:18]3[CH:29]=2)=[CH:11][CH:10]=1)#[N:8]
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3ccc(C#N)cc3)cc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3ccc(C#N)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of oxone (3.30 g, 5.37 mmol) in water (Volume: 40 mL) was added dropwise to a yellow suspension of impure 6-(4-cyanophenyl)-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.787 g, 2.441 mmol) in acetone (Ratio: 1.000, Volume: 40 mL) at rt. The resulting suspension was stirred at rt for 3 h. LCMS and HPLC showed that the starting material was consumed and the desired product was formed. The suspension was filtered, washed with water (2×10 mL), and dried under high vacuum to give a green-yellow solid. 1H NMR and HPLC indicated that the desired product was the major component, but the material was impure. The amount of the material is more than theoretical weight and the material is not totally soluble when making NMR solution, indicating the possible presence of inorganic salt. The material was treated with water (10 mL), stirred for 15 min, filtered, washed with H2O (2×5 mL), and dried under high vacuum to give a green-yellow solid (591.3 mg; 44% yield over 2 steps). 1H NMR, LCMS and HPLC indicated that the material was not pure, but the major component is consistent with the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1 H, d, J=1.54 Hz), 8.54 (1 H, s), 8.28 (1 H, br. s.), 8.07 (1 H, d, J=1.54 Hz), 8.03 (2 H, d, J=8.36 Hz), 7.89 (2 H, d, J=8.36 Hz), 7.80 (1 H, br. s.), 3.31-3.46 (2 H, m), 1.35 (3 H, t, J=7.48 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:12])[CH2:8][C:9](=O)[CH3:10])[CH:2]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=O>C(OCC)(=O)C>[N:13]1([C:9]([CH3:10])=[CH:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(=O)CC(=O)c1cccnc1
Reactant: O=C1CCCN1
Solvent: CCOC(C)=O
Product: CC(=CC(=O)c1cccnc1)N1CCCC1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
To a solution of 16.32 g of 1-(3-pyridinyl)butan-1,3-dione in 200 ml of ethyl acetate was added 7.11 g of pyrrolidone. The mixture was stirred at room temperature and then the crystals were collected giving 7.0 g of 3-(1-pyrrolidinyl)-1-(3-pyridinyl)-2-buten-1-one, mp 116°-118° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8].C([O-])(=O)C.[Na+].[N+:25]([C:28]1[CH:38]=[CH:37][CH:36]=[C:30]2[C:31]([O:33][C:34](=O)[C:29]=12)=[O:32])([O-:27])=[O:26]>C(O)(=O)C.C(Cl)Cl>[N+:25]([C:28]1[CH:38]=[CH:37][CH:36]=[C:30]2[C:29]=1[C:34](=[O:33])[N:5]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8])[C:31]2=[O:32])([O-:27])=[O:26]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CCOc1cc(C(N)C#N)ccc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1cc(C(C#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 87.4 %

Procedure:
A mixture of 2-amino-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile acetate (8.0 g, 28.5 mmol), sodium acetate (2.6 g, 31 mmol) and 3-nitrophthalic anhydride (5.5 g, 28.5 mmol) in glacial acetic acid (60 mL) was heated to reflux for 5 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in CH2Cl2, and washed with water and brine, and dried over MgSO4. Solvent was removed and the residue was purified by chromatography (SiO2, Hexane: EtOAc 6:4) to give 9.5 g (84%) of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile; mp 155-157° C.; 1H NMR(DMSO-d6) δ 8.31 (d, J=7.8 Hz, 1H), 8.20 (d, =7.2 Hz, 1H), 8.09 (t, J=7.8 Hz, 1H), 7.06-6.91 (m, 3H), 5.59 (t, J=8.0 Hz, 1H), 4.04-3.96 (q, J=7 Hz, 2H), 3.74 (s, 3H), 3.66 (d, J=8 Hz, 2H), 1.31 (t, J=7 Hz, 3H); 13C NMR (DMSO-d6) δ 165.46, 162.69, 149.07, 147.78, 144.45, 136.63, 132.81, 128.81, 128.52, 127.24, 122.39, 119.77, 118.08, 112.46, 111.68, 63.80, 55.48, 50.36, 20.30, 14.60. Analy. Calculated For C20H17N3O6: C 60.75; H 4.34; N 10.63. Found: C 60.95; H 4.37; N 10.50.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([Mg]Br)[CH:16]=[CH2:17].P([O-])(O)(O)=O.[Na+]>C(OCC)C>[CH2:17]([C:11]1([OH:14])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]1)[CH:16]=[CH2:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=CC[Mg]Br
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCOCC
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
Into a solution of 4.98 g of 1-(tert-butoxycarbonyl)-4-piperidone in diethyl ether (150 ml) was dropped at 0° C. in a nitrogen atmosphere 30 ml of a 1.0 M solution of allylmagnesium bromide in diethyl ether and the resulting mixture was stirred for 3 hours. Then the reaction mixture was poured into an aqueous solution of sodium dihydrogenphosphate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.12 g of the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[O:5][CH2:6][CH:7]([OH:29])[CH2:8][NH:9][C:10]([CH3:28])([CH3:27])[CH2:11][N:12](CC1C=CC=CC=1)CC1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:2][C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[O:5][CH2:6][CH:7]([OH:29])[CH2:8][NH:9][C:10]([CH3:28])([CH3:27])[CH2:11][NH2:12]
Reactant: Cc1ccccc1OCC(O)CNC(C)(C)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1OCC(O)CNC(C)(C)CN
Reaction time: 24 h
Yield: 90.6 %

Procedure:
Concentrated hydrochloric acid (1.4 ml) and 5% palladium carbon was added to a solution of 3 g of 1-(2-methylphenoxy)-3-(1,1-dimethyl-2-dibenzylaminoethylamino)-2-propanol in 10 ml of ethanol, and the mixture was hydrogenated at room temperature for 24 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in water, made alkaline with potassium carbonate, then extracted with chloroform, and dried over anhydrous magnesium sulfate. 1.585 g of 1-(2-methylphenoxy)-3-(1,1-dimethyl-2-aminoethylamino)-2-propanol was obtained as a colorless oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]([CH2:25][C:26](OCC)=[O:27])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)=O.CCOC(C)=O>[C:1]([N:5]1[C:9]2[NH:10][C:26](=[O:27])[CH:25]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC(C)(C)n1nc(-c2ccccc2)cc1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(-c2ccccc2)c2c(-c3ccccc3)cc(=O)[nH]c21
Temperature: 110 °C
Yield: 15.7 %

Procedure:
To a stirring solution of crude 2-tert-butyl-5-phenyl-2H-pyrazol-3-ylamine (4.0 g, 18.6 mmol) in AcOH (25 mL) was added ethyl benzoylacetate (6.6 mL, 37.2 mmol). The reaction was then heated to 110° C. for 48 hr, at which time the reaction was cooled to room temperature, diluted with EtOAc, and quenched with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered through a fritted funnel, and concentrated under reduced pressure. Purification of this material was accomplished by flash chromatography, using an ISCO column (ISCO, Inc., Lincoln, Nebr.), eluting with 15% EtOAc/hexanes. The product-containing fractions were collected and concentrated under reduced pressure to give the title compound (1.0 g, 16% yield) as a tan solid. LRMS m/z (APCl) 344 (M+1).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Si:8]([O:15][CH2:16][CH:17]=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Si:8]([O:15][CH2:16][CH:17]=[N:7][S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (R)-2-methylpropane-2-sulfinamide (2.5 g, 20.6 mmol) and {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (4.32 ml, 22.7 mmol) in CH2Cl2 (30 ml) was added CuSO4 (7.23 g, 45.32 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was filtered through Centel), washed with CH2Cl2 and concentrated in vacuo. Column chromatography (0-30% EtOAc in hexanes) gave the desired product (R)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropane-2-sulfinamide (Tetrahedron Lett. 2001, 42, 2051-54). 1H NMR (300 MHz, CDCl3) δ 7.86-8.24 (m, 1H) 4.53 (d, J=3.01 Hz, 2H) 1.15-1.23 (m, 9H) 0.90 (s, 9H) 0.08 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@@H:29]([OH:31])[CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@@H:29]([OH:31])[CH3:30])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@H](O)CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: C[C@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
86 mg of (S)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 275 mg of (S)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 220 mg of (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+
Reaction SMILES: [C:1]([N:8]([CH3:17])[C@H:9]([C:14](O)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([CH2:14][OH:15])[C@@H:10]([CH3:11])[CH2:12][CH3:13])[CH3:17])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](CO)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
39.3 g Boc-MeIle-OH (0.160 mol; Synthetech) were dissolved in 160 ml THF and cooled to 0° C. 240 ml 1M BH3-THF (0.24 mol; Fluka) were added at 0° C. over 1 h and the clear, colorless reaction mixture was warmed up and stirred at RT for 1 h. The reaction mixture was again cooled to 0° C., 100 ml deionized water were carefully added at 0-5° C. over 0.5 h and after warming up to RT stirring was continued for 1 h. To the colorless solution were added 250 ml 10% Na2CO3 all at once and after stirring for 1 h the reaction mixture was extracted with 1000 ml and 500 ml ethyl acetate. The organic layers were washed with brine and dried (Na2SO4). Removal of the solvent by rotary evaporation gave 36.9 g (99.7%) product as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
To a solution of 2.4 g (10 mmol) of 2-bromo-4,5-difluorobenzoic acid [prepared according to the procedure of Braish et al., Syn. Comm., 3067-3074 (1992)] in 75 mL of tetrahydrofuran was added 2.43 g (15 mmol) of carbonyldiimidazole. The solution was heated under reflux for 3.5 h, cooled to ambient temperature and 0.38 g (10 mmol) of sodium borohydride in 15 mL of water was added. The reaction was stirred for 10 min and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer was washed twice with warm water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.9 g of 2-bromo-4,5-difluorobenzyl alcohol. To a solution of 1.9 g (8.4 mmol) of 2-bromo-4,5-difluorobenzyl alcohol in 30 mL of dichloromethane at 0° C. was added 3.4 g (10 mmol) of carbon tetrabromide and 2.7 g (10 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 20:1 hexane:ethyl acetate) to afford 2-bromo-4,5-difluorobenzyl bromide contaminated with carbon tetrabromide which was used without further purification. Using the procedures outlined for the preparation of Intermediates 2-4, the benzyl bromide derivative was converted to the title compound. LC/MS 394 and 396 (M+1).