Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([Cl:1])=[C:28]([O:31][CH3:32])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: COc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Cl)CCN2C1CCN(CCc2ccc(F)cc2)CC1
Yield: 21 %

Procedure:
N-Chlorosuccinimide (0.15 g) was added at room temperature to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline (0.39 g) in methylene chloride (5 ml) and the resultant mixture was stirred for 20 min. Then a 5 N aqueous solution of sodium hydroxide and ethyl acetate were added to the reaction solution and the layers were separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (methylene chloride/ethanol system) followed by conversion into a hydrochloride to give the hydrochloride (0.10 g) of the title compound as apale red powder (yield: 21%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]#[C:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]#[C:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])=[N:19][CH:20]=1.C(O)(=O)C.[H][H]>CN(C=O)C.[Pd]>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])=[N:19][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#Cc1ccc(C#CCN2C(=O)c3ccccc3C2=O)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Yield: 63.8 %

Procedure:
A mixture of 2-(3-{5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl-prop-1-ynyl]pyridin-2-yl}prop-2-ynyl)-1H-isoindole-1,3(2H)-dione (5-1) (200 mg), 10% Pd/C (50 wt %; 60 mg), and acetic acid (1 mL) in DMF (1 mL) was stirred at ambient temperature under 1 atmospheric pressure of hydrogen for 2 days. The catalyst was removed by filtration through Solka-floc and washed with ethanol. The filtrate and wash were combined and concentrated under reduced pressure to give 11-1 (130 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][CH2:22][C:23](=[O:25])[NH2:24])[C:18]([OH:20])=[O:19]>>[C:23]([CH2:22][CH2:21][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19])(=[O:25])[NH2:24]
Reactant: NC(=O)CCC(N)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: NC(=O)CCC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-4-carbamoyl-butyric acid to provide the title compound in moderate yield. LCMS m/z 352 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([CH:21]=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.S(=O)(=O)([OH:33])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:33])=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (412 mg, 0.93 mmol) was suspended in 1,4-dioxane (15 ml) and water (3 ml). The suspension was cooled to 0° C. and sulfamic acid (543 mg, 5.59 mmol) was added. Then, a solution of sodium chlorite (80%, 137 mg, 1.21 mmol) and potassium dihydrogen phosphate (1.52 g, 11.2 mmol) in water (9 ml) was added via dropping funnel over ˜20 min. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. THF (15 ml) was added and the reaction mixture was stirred at room temperature for an additional 3 h. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate/hexanes to afford 358 mg (84%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([N+:21]([O-])=O)=[C:19]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([NH2:21])=[C:19]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (647 mg, 1.3 mmol) was dissolved in ethyl acetate under nitrogen and then 10% Pd/C was added. The mixture was stirred at room temperature for 4 hours to afford 4-[5-amino-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester as a tan solid (535 mg, 89%). 1H NMR (CDCl3, 400 MHz) δ 1.77–1.67 (m, 4H), 1.48 (s, 9H), 3.04 (s, 3H), 3.31–3.24 (m, 2H), 3.82 (m, 2H), 5.32 (m, 1H), 6.96 (s, NH), 7.53 (t, NH), 7.70 (t, 1H), 7.71 (d, 2H), 8.16 (s, 1H). Exact mass calculated for C21H29N5O5S 463.19, found 464.3 (MH+).
Reaction SMILES: O.[CH3:2][C:3]1[C:4]([CH2:15][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C(N)(N)=[O:27].OO.C(N(CC)CC)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN1CCCC1=O.O>[CH3:2][C:3]1[C:4]([CH2:15][S:16]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:27])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:13])([F:12])[F:14]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: NC(N)=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 2.5 °C
Yield: 121.1 %

Procedure:
(i) 40 g (0.108 mole) 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole hydrate was dissolved in 120 ml of 1-methyl-2-pyrrolidone (NMP) at room temperature, then 0.263 g (1.077 mmole) of vanadium(V) oxytriisopropoxide were added and the reaction mixture was cooled to a temperature of from 0 to 5° C. 12.96 g (0.138 mole) of hydrogen peroxide urea adduct were suspended (optionally per partes) and the reaction was carried out at a temperature of from 0 to 10° C. for half an hour and then at a temperature of from 10 to 15° C. until the reaction was completed. At the end of the reaction, 5 ml of triethylamine and a solution of 5.68 g of sodium thiosulphate pentahydrate in 6 ml of water were added. The product was precipitated with water (280 ml at 20±5° C.) and filtered off to obtain 48.3 g of wet lansoprazole.
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH2:8][CH3:9])[CH2:3][C:4]([OH:6])=[O:5].CC(C(=O)C)C(O)=O>>[OH:1][C@H:2]([CH2:7][CH2:8][CH3:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC(=O)CC(=O)O
Agent: CC(=O)C(C)C(=O)O
Product: CCC[C@@H](O)CC(=O)O

Procedure:
In accordance with the procedure of Example 9, ethyl ester of 3-oxohexanoic acid as a substrate in place of ethyl ester of 2-methyl-3-oxobutyric acid was subjected to reduction by baker's yeast to obtain ethyl ester of (3R)-3-hydroxyhexanoic acid. This compound was subjected to methylation according to the process of the literature [G. Frater et al., Tetrahedron, 40, 1269 (1984)] as in Reference Example 3, to obtain ethyl ester of (2R, 3R)-3-hydroxy-2-methylhexanoic acid. This compound was converted to a methyl ether compound and then subjected to hydrolysis in accordance with the procedure of Example 11 to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[C:38]([O:37][C:35]([N:29]1[CH2:34][CH2:33][N:32]([CH2:14][C:11]2[C:12](=[O:13])[N:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)[CH:10]=2)[CH2:31][CH2:30]1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 78.8 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 78.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13]>C1(C)C(C)=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1C
Product: O=C1Nc2cc(Cl)ccc2Nc2ccccc21

Procedure:
A solution of 2-[(2-amino-4-chlorophenyl)amino]benzoic acid (11.8 g, 45 mmol) in xylene (150 mL) was heated to reflux in a Dean-Stark apparatus. The reaction mixture was stirred at reflux temperature for 31 h. After removal of the xylene in vacuo, the title compound was obtained. There was still starting material present. Therefore the product was dissolved in xylene (150 mL) again and stirring was continued overnight at reflux temperature in a Dean-Stark apparatus. After removal of the xylene under reduced pressure the title compound (12.4 g, 50.6 mmol) was obtained.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[CH:27]=[CH:26][N:25]=3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>CCO>[ClH:36].[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([C:15]([N:12]4[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]4)=[O:16])=[CH:22][CH:21]=3)[N:29]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.5 h
Yield: 171.6 %

Procedure:
(tert-Butoxy)-N-{1-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl](4-piperidyl)}carboxamide (4.00 g, 7.87 mmol) was stirred in 50 mL EtOH followed by addition of anhydrous HCl gas. The reaction was stirred for 30 min. then concentrated down to a residue. To this was added a small amount of EtOH followed by dilution with ether. A yellow solid formed which was filtered and dried to give 3.00 grams of 4-aminopiperidyl 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl ketone hydrochloride: HPLC Retention time; 5.89 min. (Method B) M+1; 408.4
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Br:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][CH2:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Nc1cc(COc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(COc4cccc(Br)c4)ccc3Sc3ccc(O)cc3)ccnc2n1
Temperature: 80 °C

Procedure:
The product from Example 1d (0.034 g, 0.193 mmol) was reacted with the product from Example 225c (0.078 g, 0.193 mmol) for 15 h following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 1d (0.019 g, 0.109 mmol) and continued heating at 80° C. (18 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.041 g, 32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 5.15 (s, 2H) 6.30 (d, J=7.35 Hz, 1H) 6.79 (d, J=8.46 Hz, 2H) 6.95-7.08 (m, 2H) 7.16 (d, 1H) 7.20-7.30 (m, 4H) 7.45-7.55 (m, 2H) 7.81 (d, J=8.82 Hz, 1H) 8.47 (d, J=7.35 Hz, 1H) 9.01 (d, J=8.46 Hz, 1H) 9.98 (s, 1H); Ms (ESI+) m/z 546.0 (M+H)+; (ESI−) m/z 542.0.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:23])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[C:9]1[Cl:22].[S]>CN(C)C=O>[CH3:1][C:2]1[NH:3][C:4](=[O:23])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[Cl:22]
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2Cl)SCC(=O)N1
Agent: [S]
Solvent: CN(C)C=O
Product: CC1=C(c2ccncc2Cl)SCC(=O)N1
Temperature: 160 °C
Reaction time: 5 h
Yield: 57.7 %

Procedure:
A mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-chloro-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (0.25 g) and sulfur sublimed (0.125 g) in N,N-dimethylformamide (2 ml) was stirred at 160° C. for 5 hours. The solvent was removed under reduced pressure and the residue was extracted with 2N hydrochloric acid. The insoluble matter was removed by filtration and the filtrate was washed with ether and was adjusted to pH about 7.5 by 2N aqueous sodium hydroxide. The resulting precipitates were extracted with chloroform. The extract was dried over magnesium sulfate and was evaporated to dryness. The residue was chromatographed on silica gel (Wakogel C-200) column, using chloroformmethanol (=30:1) as an eluant to give the titled compound (0.083 g, yield 57.8%) as milky white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:27])([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[CH3:28][S:29]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:27])([CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCO)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCOS(C)(=O)=O)cc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-methyl-2-(3-phenylpropyl)propionate (0.95 g), which is the product of Reference example 7(f), triethylamine (1.07 ml) and methanesulfonyl chloride (0.40 ml) and the reaction mixture was treated to afford the desired compound (1.16 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=CC=CC=1.Cl.Cl[CH2:18][CH2:19][NH:20]CCCl.[OH-].[Na+]>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[CH2:10][CH2:15][NH:20][CH2:19][CH2:18]1
Reactant: Clc1cccc(Cl)c1Nc1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(Cl)c1N1CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 2,6-dichlorophenylaniline (810 mg, 5 mmol, Aldrich) and bis(2-chloroethyl)amine hydrochloride (823 mg, 5 mmol, Aldrich) was subjected to microwave irradiation at 200° C. for 10 min. The reaction mixture was allowed to cool to room temperature then treated with 5N NaOH (5 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2+1% ammonia (30% in water) to give the title compound. MS (ESI, pos. ion) m/z: 231 (M+1).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN1CCCC1=O.[Cl-].[Na+].O>[N:14]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=3[N:3]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc2[nH]c(Cl)nc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]c(-n3ccnc3)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of 2-chloro-4-nitro-1H-benzimidazole (300 mg) in N-methyl-2-pyrrolidone (4 ml) was added imidazole (517 mg) and the mixture was stirred at 80° C. for 8 hours. The reaction mixture was poured into brine and extracted with a mixture of chloroform and methanol. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (100-0−30-1) to give 2-(1-imidazolyl)-4-nitro-1H-benzimidazole (175 mg).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]([CH3:38])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:35](O)=[O:36])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:51][S:52]([NH2:55])(=[O:54])=[O:53].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([C:8]1[N:13]=[C:12]([NH:14][C:15]2[C:16]([CH3:38])=[N:17][O:18][C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([C:35]([NH:55][S:52]([CH3:51])(=[O:54])=[O:53])=[O:36])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Nc1cccc(Cc2ccccc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1Nc1cccc(Cc2ccccc2)n1
Temperature: 70 °C

Procedure:
1-{4′-[4-(6-benzyl-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (sodium salt; 0.050 g, 0.083 mmol), carbonyldiimidazole (0.0676 g, 0.417 mmol), MeSO2NH2 (0.0789 g, 0.83 mmol) and DBU (0.0248 mL, 0.166 mmol) were combined in THF (1 mL) and the mixture was heated to 70° C. in a capped vial for 25 hours. The mixture was purified by preparative HPLC to yield the title compound.
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[Br:13][C:14]1[N:19]=[C:18]([NH:20][C:21]([NH:23]C(OCC)=O)=S)[CH:17]=[CH:16][CH:15]=1>CCO.CO>[Br:13][C:14]1[N:19]2[N:7]=[C:21]([NH2:23])[N:20]=[C:18]2[CH:17]=[CH:16][CH:15]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cccc(Br)n1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2cccc(Br)n2n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-d6) δ 7.43-7.34 (2H, m, 2×aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([F:20])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:16]1[N:15]=[C:14]([N:9]2[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])[CH:19]=[CH:18][N:17]=1
Reactant: C[C@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a round bottom flask containing (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (502 mg, 1.77 mmol) was added DCM (4 mL) and TFA (4 mL). Resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed and the residue neutralized with a saturated solution of NaHCO3. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a colorless residue of (R)-3-(2-fluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (382 mg, 1.68 mmol, 95% yield). LCMS m/z 228.1 (M+H)+, Rt 0.44 min.
Reaction SMILES: Br.[NH2:2][CH:3]([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:2][CH:3]([CH3:12])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(N)Cc1ccc(O)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Cc1ccc(O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A mixture of 2.32 g of 4-(2-aminopropyl)phenol hydrobromide, 4.2 g of sodium bicarbonate, 50 ml of water, 100 ml of ethyl acetate and 2.11 g of 4-chlorophenylsulfonyl chloride is stirred at room temperature for 3 hours. After the reaction, the ethyl acetate layer is separated therefrom, dried and evaporated to remove the solvent. 3.25 g of 4-[2-(4-chlorophenyl)sulfonylaminopropyl)phenol are obtained as brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:18][CH:17]=[CH2:16])=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 25, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and allyl magnesium bromide.