Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][NH2:8])=[C:5]([N+:9]([O-])=O)[C:4]([CH3:12])=[N:3]1.[ClH:13].O>C(O)C.[Pd]>[ClH:13].[ClH:13].[NH2:9][C:5]1[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][NH2:8]
Reactant: Cc1nn(C)c(NN)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c(NN)c1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 8.6 g (0.05 mol) of 1,3-dimethyl-5-hydrazino-4-nitropyrazole and 1.5 g of 5% by weight palladium-on-charcoal containing 50% water in 200 cm3 of ethanol was placed in a hydrogenator. After stirring under a hydrogen pressure of 10 bar, at a temperature of 75° C. for 3 hours, the reaction medium was poured into a solution of 60 cm3 of ethanol and 20 cm3 of 12N hydrochloric acid cooled to 0° C. The solution was clarified by filtration on a sinter funnel and then evaporated to dryness under reduced pressure. The brown solid obtained was taken up, at reflux, in 50 cm3 of 5N hydrochloric ethanol and 14 cm3 of water and was then cooled to room temperature. The white precipitate obtained was filtered off on a sinter funnel and then dried under vacuum at room temperature. 9.5 g of 4-amino-1,3-dimethyl-5-hydrazinopyrazole dihydrochloride were obtained in the form of white crystals, the melting point of which was from 202 to 204° C. The elemental analysis calculated for C5H11N5.2HCl was:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][CH:6]([F:34])[C:7]1[N:11]([C:12]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:15]=[C:14]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:13]=2)[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=2[N:8]=1.C1COCC1>O>[C:1]([N:27]1[CH2:26][CH2:25][N:24]([C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=[C:12]([N:11]3[C:10]4[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=4[N:8]=[C:7]3[CH:6]([F:34])[F:5])[N:13]=2)[CH2:29][CH2:28]1)(=[O:3])[CH3:2]
Reactant: FC(F)c1nc2ccccc2n1-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 770 %

Procedure:
Acetyl chloride (0.14 ml, 2.0 mmol) was added dropwise to a mixture of 2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-6-(piperazin-1-yl)-1,3,5-triazine (417 mg, 1.0 mmol) and THF (10 ml). The reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was poured into water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column to give the target compound 4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine (354 mg, 7.7 mmol) in a yield of 77% as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[I:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[I:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([I:1])[C:10]([OH:11])=[C:9]([I:12])[CH:8]=1
Reactant: ClCc1ccccc1I
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1I)c1cc(I)c(O)c(I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
A suspension of 3,5-diiodo-4-hydroxybenzoic acid (1 95 mg, 0.5 mmol, 2-iodo benzyl chloride (320 mg, 1.25 mmol), and cesium carbonate (490 mg, 1.5 mmol) in 5 mL DMF was stirred for 15 hours at room temperature. The mixture was then poured into 1 M HCl (100 mL) and a white precipitate formed. The precipitate was isolated filtration and was recrystallized from hot isopropanol/chloroform, yielding the title compound as bright white crystals (140 mg, 61%). 1H NMR (400 MHz, CDC13): δ 8.40 (s, 2H), 7.90 (dd, J=8.0, 1.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.06 (td, J=8.0, 2.0 Hz, 1H), 6.14 (s, 1H), 5.35 (s, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(OCC)C.[C:12]([NH:16][C:17]1[O:18][C:19]([C:26](Cl)=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1)([CH3:15])([CH3:14])[CH3:13]>CCCCCC>[CH3:15][C:12]([NH:16][C:17]1[O:18][C:19]([C:26]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:27])=[C:20]([C:22]([F:24])([F:25])[F:23])[N:21]=1)([CH3:13])[CH3:14]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Reactant: CC(C)(N)CO
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)NC(C)(C)CO)o1

Procedure:
A reaction vessel fitted with a calcium sulfate drying tube was charged with 4.9 g (55 mmol) of 2-amino-2-methyl-1-propanol and 50 ml of anhydrous ethyl ether. With this mixture stirred at 0°-5° C., there was added dropwise over a period of 45 minutes a solution of 50 ml anhydrous ethyl ether containing 6.5 g (25 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride. The reaction mixture was stirred at ambient temperature for 11/2 hours, then filtered to remove the HCl salt of 2-amino-2-methyl1-propanol. The ether filtrate was washed successively with one molar oxalic acid and saturated brine, then dried under magnesium sulfate, and concentrated under reduced pressure to yield 8.2 g of a colorless, viscous oil. This oil was mixed with hexane and heated to reflux to yield a white solid material. The material was cooled and filtered to yield 7.7 g of a white crystalline product (m.p.=140°-144° C.) identified in Table I.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][C:41]([O:47][CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])=[CH:42][CH:43]=2)[CH:38]=1.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][C:41]([O:47][CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:53])([CH3:55])[CH3:54])=[CH:42][CH:43]=3)[CH:38]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Reactant: C[Si](C)(C)CCOCOc1ccc2ccc(CCl)cc2c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3ccc(OCOCC[Si](C)(C)C)cc3c2)cc1

Procedure:
reacting the product of step c) with 2-chloromethyl-7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene and sodium hydride to form (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][CH:5]([F:21])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][C:8]=1[O:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1>O.CN(C=O)C>[F:4][CH:5]([F:21])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:1]#[N:2])=[CH:9][C:8]=1[O:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: OCc1ccc(OC(F)F)c(OC2CCOC2)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: 80 °C
Yield: 80.4 %

Procedure:
A mixture of KCN (0.076 mol) in H2O (4 ml), heated to 80° C., was added dropwise to a mixture of intermediate 3 (0.038 mol) in DMF (82.4 ml), stirred at 60° C. The resulting reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, washed with water, extracted with DIPE. The extract was dried, filtered, and the filtrate was evaporated, yielding 8.23 g (80%) of (±)-4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]benzeneacetonitrile (intermediate 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 87 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.19-3.33 (m, 4H), 3.72-3.77 (m, 4H), 4.13 (s, 3H), 6.79-7.66 (m, 7H), 7.71 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]([O:48][C:49]([NH:51][CH2:52][C:53](O)=[O:54])=[O:50])([CH3:47])([CH3:46])[CH3:45].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)(Cl)Cl>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([C:53](=[O:54])[CH2:52][NH:51][C:49](=[O:50])[O:48][C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CNC(=O)OC(C)(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in chloroform (2 mL), and stirred at room temperature for 4 hours after adding N-(tert-butoxycarbonyl)glycine (Tokyo Chemical Industry Co., Ltd.; 55 mg, 0.250 mmol), diisopropylethylamine (0.146 mL, 0.833 mmol), and HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (Aldrich; 127 mg, 0.333 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3) to give tert-butyl 2-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)-2-oxoethylcarbamate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc([N+](=O)[O-])cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc([N+](=O)[O-])cc1
Yield: 91.5 %

Procedure:
A mixture of 1-ethyl-4-nitro-benzene (3.4 mL, 25 mmol), N-bromosuccinimide (4.38 g, 24.6 mmol) and benzoylperoxide (0.04 g, 0.18 mmol) in carbon tetrachloride (30 mL) was refluxed 1 h, cooled and filtered, washing with 1:1 ethyl acetate:hexanes. The filtrate was evaporated and purified by flash chromatography (SiO2) eluted with 2:98 ethyl acetate:hexanes to provide 1-(1-bromo-ethyl)-4-nitro-benzene (5.18 g, 90% yield) as a yellow oil. 1H-NM (CDCl3, 500 MHz) 8.22 (d, 2H), 7.62 (d, 2H), 5.22 (q, 1H), 2.08 (d, 3H) ppm; HPLC (Method A) 3.837 min.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:19]=1[CH2:20][N:21]([CH:42]([CH3:44])[CH3:43])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:17][C:18]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:19]=1[CH2:20][N:21]([CH:42]([CH3:44])[CH3:43])[C:22](=[O:23])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:35][CH2:36][CH:37]([CH2:40][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH2:38][CH2:39]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CC(C)N(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Yield: 29.3 %

Procedure:
The title compound was prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.154 g, 0.63 mmol), 1-(2,5-difluoro-benzyl)-3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-1-isopropyl-urea (1.0 mmol), glacial acetic acid (0.036 g, 0.63 mmol) and sodium cyanoborohydride (0.039 g, 0.63 mmol) according to the general procedure used for example 84 (Step E) to give the final product (0.131 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[CH3:23][O:24][CH:25]([CH2:28][O:29][CH3:30])[CH:26]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:26][CH:25]([O:24][CH3:23])[CH2:28][O:29][CH3:30]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: COCC(C=O)OC
Product: COCC(C=NOCCC1=C(C)/C(=C/c2ccncc2)c2ccc(F)cc21)OC

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2,3-dimethoxypropanal by the method of Example 1.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([O:17]CC)=[O:16])=[C:4]([CH3:14])[N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:20][O-:21].[Na+].Cl>CO.[Cu]I>[CH3:20][O:21][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[C:4]([CH3:14])[N:5]([CH3:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1c(Br)c(-c2ccccc2)n(C)c1C
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1c(C(=O)O)c(C)n(C)c1-c1ccccc1
Yield: 105 %

Procedure:
The mixture of the 4-bromo-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (2.91 g, 9.91 mmol), NaOMe (11.3 mL, 25% wt in MeOH) and CuI (566 mg, 2.97 mmol) in MeOH (35 mL) was refluxed overnight. The reaction mixture was poured into 1M HCl solution (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated under vacuum to provide the title compound (2.56 g, 10.4 mmol, 105%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([CH3:20])[CH2:5][C@@H:6]1[CH2:10][N:9]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:8](=[O:19])[CH2:7]1.[H-].[Na+].[CH3:23]I>CS(C)=O.O>[CH3:23][O:1][CH2:2][CH2:3][CH:4]([CH3:20])[CH2:5][C@@H:6]1[CH2:10][N:9]([C@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[C:8](=[O:19])[CH2:7]1
Reactant: CC(CCO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCC(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To alcohol 89 (2 g, 7.66 mmol) in DMSO (60 mL) at room temperature was added NaH (368 mg, 60% in oil). After 30 minutes the methyl iodide (1.08 g, 7.66 mmol) was added and the solution stirred at room temperature overnight, upon which the reaction was diluted with water (500 mL). The solution was extracted with ether, and the combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (90% to 50% hexane/acetone) of the residue gave the product 90 as an oil (1.1 g, 52%). MS m/z 290 (M+H, 100%).
Reaction SMILES: [OH-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH2:41][C:42]([O:44]CC)=[S:43])([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:25][CH:24]=2)[CH3:22])=[CH:17][CH:16]=1>O1CCOCC1.C(O)C>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH2:41][C:42]([OH:44])=[S:43])([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:28]=2)[CH3:22])=[CH:17][CH:16]=1
Reactant: CCOC(=S)CC(C)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(CC(O)=S)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1N sodium hydroxide (0.5 mL) was added to a solution of ethyl 1,1-bis(4-(2-quinolylmethoxy)phenyl)eth-1-ylthioacetate from above in dioxane (10 mL) and ethanol (5 mL), and the resulting mixture was stirred at ambient temperature for 3 hours. The organics were removed in vacuo, the residue was diluted with water and acidified to pH 3. The solid was filtered, washed with water, dried under reduced pressure and recrystallized from methylene chloride-hexane to provide 170 mg of the title compound: mp 92°-94° C.; 1H NMR (300 MHz, DMSO-d6)δ 2.00 (s, 3 H), 3.32 (s, 2 H), 5.34 (s, 4 H), 7.02 (d, J=9 Hz, 4 H), 7.30 (d, J=9 Hz, 4 H), 7.63 (m, 4 H), 7.78 (m, 2 H), 8.00 (m, 4 H), 8.41 (d, J=8 Hz, 2 H); MS (DCI-NH3) m/z 587 (M+H)+. Anal. Calc'd. for C36H30N2O4S: C, 73.70; H, 5.15; N, 4.77. Found: C, 74.24; H, 5.28; N, 4.34.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 0 °C
Yield: 80.6 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 3-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxycarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b) of Example 1, and triphenylphosphine (525 mg,. 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 H and at room temperature for 3 H. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:3 ethyl acetate/hexane) to give the tide compound as a colorless liquid (800 mg, 81%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[SH:11][C:12]1[N:17]2[N:18]=[C:19]([C:21](OC)=[O:22])[N:20]=[C:16]2[N:15]=[C:14]([CH3:25])[CH:13]=1.Cl>CO>[OH:10][NH:9][C:21]([C:19]1[N:20]=[C:16]2[N:15]=[C:14]([CH3:25])[CH:13]=[C:12]([SH:11])[N:17]2[N:18]=1)=[O:22]
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(S)n2nc(C(=O)NO)nc2n1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
Triethylamine (1.35 g) (13.37 mmol) are added dropwise at 0° C. to a solution of 0.62 g (8.92 mmol) of hydroxylamine hydrochloride in 15 ml of absolute methanol. The mixture is stirred for 10 minutes and subsequently a solution of 1.0 g (4.46 mmol) of methyl 7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxylate (known from EPOS 303,172) in 30 ml of absolute methanol is added dropwise. After stirring at room temperature for 3 days the beige suspension is made acid (pH 4) with 1N aqueous hydrochloric acid and suction filtered. The filter material is washed with water and diethyl ether and crystallized from methanol/dichloromethane. There are obtained 510 mg of N-hydroxy-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide as beige crystals of m.p. 213° C. (dec.).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][CH:11]([F:36])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33](O)=[O:34])[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[CH3:37][C:38]1[C:42]([S:43]([NH2:46])(=[O:45])=[O:44])=[C:41]([CH3:47])[O:40][N:39]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:10][CH:11]([F:36])[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]([NH:46][S:43]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:47])(=[O:44])=[O:45])=[O:34])[O:30][C:31]=3[CH3:32])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccc(OC(F)F)cc2)cc1
Reactant: Cc1noc(C)c1S(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(C)c1S(=O)(=O)NC(=O)c1cc(CNc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.7 %

Procedure:
Diisopropylethylamine (60 μl, 0.339 mmoles) and a solution of 4-(4′-difluoromethoxy-biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (171) (50 mg, 0.103 mmoles) in N,N-dimethylformamide (11.0 ml) were added to a stirred solution of 3,5-dimethyl-isoxazole-4-sulphonic acid amide (55 mg, 0.308 mmoles) in N,N-dimethylformamide (5.0 ml). A solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.124 mmoles) in N,N-dimethylformamide (11.0 ml) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 174 (2 mg) as a solid. LC/MS System D; Rt=10.35 mins, m/z (ES+)=532 (M+H for C25H23F2N3O6S).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])N)[CH3:2].N([O-])=[O:13].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:8]=[CH:9][C:10]=1[CH3:11])[CH3:2]
Reactant: CCOc1cc(N)ccc1C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A suspension of 3-(ethyloxy)-4-methylaniline (Intermediate 89, 300 mg) in a mixture of water/concentrated sulfuric acid 98% (20 mL/7 mL) under argon was cooled at 0° C. A solution of sodium nitrite (151 mg, 2.182 mmol) in 4 mL of water was slowly added. The reaction mixture was stirred at 0° C. for 1 hour 30. The reaction mixture was then slowly added to a solution of water/concentrated sulfuric acid (18 mL/5 mL) pre-heated at 90° C. The reaction mixture was stirred at 90° C. for 1 hour 15. After cooling down, the reaction mixture was extracted with ethyl ether (4 times). The gathered organic phases were dried over sodium sulphate, filtered and concentrated under vacuum to afford the compound (276 mg).