Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C#N)(CC)=O)C.[NH2:9][CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=3)[CH:17]=2)[CH2:12]1.Br.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](O)=[O:32].C(N(CC)CC)C>CN(C)C=O>[CH3:28][C:29]([CH3:34])=[CH:30][C:31]([NH:9][CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=3)[CH:17]=2)[CH2:12]1)=[O:32]
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CC(C)=CC(=O)O
Agent: Br
Agent: CCP(=O)(C#N)CC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)=CC(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
Under ice cooling, 1.71 g of diethylphosphoryl cyanide was added to 80 ml of a suspension containing 3.06 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide and 1.15 g of 3-methylcrotonic acid suspended in dimethylformamide, and then 20 ml of a solution containing 2.89 g of triethylamine dissolved in dimethylformamide was added dropwise to the mixture. The resulting mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration. The crystals obtained were washed with water, dried and then recrystallized from ethyl acetate-methanol to obtain 2.45 g of 2-[(3-methylcrotonoyl)amino]methyl-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: N.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[O:16][C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[O:18])=[N:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].CC[N:38]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C>[NH2:38][C:33](=[O:35])[CH2:32][C@H:29]1[CH2:28][CH2:27][C@H:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:17]([C:15]3[O:16][C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:2][CH3:3])[CH:6]=4)=[N:13][N:14]=3)=[O:18])=[CH:21][CH:22]=2)[CH2:31][CH2:30]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1cccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(=O)O)CC4)cc3)o2)c1
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(N)=O)CC4)cc3)o2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Ammonia (0.06 mL of a 28-30% wt % solution in water) was added to a stirred mixture of (trans-4-{4-[({5-[(3-ethoxyphenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid (Example 113, 65 mg), EDAC (32 mg), and HOBt (23 mg) in DMF (1 mL). The mixture was stirred for 16 h then was diluted with DMF (2 mL) and heated to 100° C. for 30 minutes in an Emrys Optimizer™ microwave. The crude mixture was purified directly by HPLC using a gradient of 25-75% acetonitrile/water with 1% ammonia as the eluent to give the title compound (10 mg) as a solid; 1H NMR δ 10.82 (2H, bs), 7.68 (2H, d), 7.22 (5H, m), 7.08 (1H, 1H), 6.67 (1H, s), 6.56 (1H, m), 4.00 (2H, quartet), 2.50 (1H+ DMSO, m), 1.96 (2H, d), 1.83-1.66 (5H, m), 1.42 (2H, m), 1.33(3H, t), 1.08 (2H, m); MS m/e MH+ 474.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:11]>CO.[Pd].C>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N+:3]=1[O-:11]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cc[n+]1[O-]
Yield: 96.2 %

Procedure:
4 g of 2-methyl-4-nitropyridine-N-oxide were dissolved in 90 ml of methanol and reduced with 1.2 g of 10% Pd/charcoal and H2. The catalyst was filtered off and the filtrate rotated in. The residue was boiled with 200 ml of ethyl acetate, filtered hot and the filtrate was mixed with 100 ml of hexane. The crystals precipitated after cooling the solution was sucked off, washed and dried. 3.1 g of 2-methyl-4-aminopyridine-N-oxide were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([OH:30])=[C:28]([O:31][CH3:32])[C:27]([O:33][CH3:34])=[CH:26][C:25]=1[CH3:35].[O:36]=O>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29](=[O:30])[C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26](=[O:36])[C:25]=1[CH3:35]
Reactant: O=O
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCCCCCO)c(O)c1OC
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Reaction time: 168 h

Procedure:
In dimethylformamide (200 ml) are suspended 6-(22-hydroxydocosyl)-2,3-dimethoxy-5-methyl phenol (300 mg) and bis(4-hydroxysalicylidene)ethylenediiminocobalt(II) (50 mg). The suspension is stirred in an oxygen gas stream at ambient temperature and atmospheric pressure for 7 days. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is diluted with water and extracted with ethyl acetate. The extract is treated in a conventional manner and the product is chromatographed on a silica gel column. The fractions obtained by elution with chloroform are pooled and recrystallized from ethanol to give orange-yellow needles of 6-(22-hydroxydocosyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I, n=22). m.p. 89°-90.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[C:18]([NH2:20])[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:20][C:18]1[N:19]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:16][C:17]=1[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(N)c(C(=O)c3cccc(F)c3)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(NC2CCNCC2)sc1C(=O)c1cccc(F)c1
Reaction time: 1 h
Yield: 72 %

Procedure:
4-[4-Amino-5-(3-fluorobenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 1.95 mmol) (Example 3) was dissolved in a mixture of trifluoroacetic acid (16 mL) and methylene chloride (30 mL). After 1 hr, all solvent was removed and the residue dissolved in methylene chloride (300 mL). This was washed with 10% Na2CO3 (50 mL), dried (Na2SO4) and concentrated to give a semi solid. This was triturated with ethyl ether and filtered to give 450 mg (72% yield) of [4-amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluorophenyl)methanone. 1H NMR (DMSO−d6, 300 MHz) δ1.38 (m, 2H, CH2), 1.88 (m, 2H, CH2), 2.95 (m, 2H, CH2), 3.32 (brd, 2H, CH2), 3.6-4.0 (broad, 1H, CH), 3.78 (s, 3H, OCH3), 7.31 (t, 1H, Aromatic), 7.38 (d, 1H, Aromatic), 7.48 (t, 1H, Aromatic), 7.51 (q, 1H, Aromatic), 8.01 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.70 (brd, 1H, NH). LR-MS-ES(±): Compatible with 320 MW.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:11]([Cl:17])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:25](O)[CH3:26]>>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH2:25][CH3:26])=[O:15])=[C:11]([Cl:17])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccccc1
Agent: Cl
Product: CCOC(=O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of ethanol was dissolved 6.53 g of 1-benzyl-2-phenyl-4-chloroimidazole-5-acetic acid and under ice-cooling, hydrogen chloride was introduced until saturation. The solution was further stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and the concentrate was run onto a column of 200 g silica gel, elution being carried out with benzene-chloroform (1:1). By the above procedure was obtained 2.28 g of 1-benzyl-2-phenyl-4-chloro-5-ethoxycarbonylmethylimidazole as crude crystals, which were then recrystallized from diethyl ether-hexane. Colorless needles, m.p. 72°-73° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:38]5[CH2:39][CH2:40][N:35]([C:30]6[N:31]=[CH:32][CH:33]=[CH:34][N:29]=6)[CH2:36][CH2:37]5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(c5ncccn5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In THF (7ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150mg), and to the mixture was added 1-(2-pyrimidyl)piperazine (190mg). The mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-[4-[1-(2-pyrimidyl)-4-piperazinylmethyl]-phenyl]-3,4-dihydronaphthalene-2-carboxamide (Compound 42) (166mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:16])[F:15])[C@H:10]([O:17]COC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(OC(C)(C)C)OC(C)(C)C>C(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:15])[F:16])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(F)F
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(F)F)[C@H](O)C1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of (±)-trans-4-difluoromethyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.52 mmol, 0.45 g) in DCM (2 mL) was added 4 N HCl in dioxane (3 mL). The solution was stirred for 1 hour. The solvents were removed with reduced pressure. The crude amine hydrochloride was dissolved in DCM (3 mL), and saturated NaHCO3 (3 mL). To this suspension was added di-tert-butyl carbonate (4.12 mmol, 0.90 g) and the reaction was stirred for 30 minutes at room temperature. The layers were separated and the DCM layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified on a 12 g SiO2 cartridge using a 0-30% ethyl acetate/hexanes gradient to give (±)-trans-4-difluoromethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.14 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>>[N:12]1([CH2:2][C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][N:4]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: c1nc[nH]n1
Reactant: BrCc1noc2ccccc12
Product: c1ccc2c(Cn3cncn3)noc2c1

Procedure:
Similarly condensation of 3-bromomethyl-1,2-benzisoxazole with 1,2,4-triazole affords 3-[(1H-1,2,4-triazol-1-yl)methyl]-1,2-benzisoxazole, m.p. 102°-104° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5][CH:6]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Yield: 101.3 %

Procedure:
A solution of 1.33 g (4.96 mmol) [4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and 0.72 ml (9.92 mmol) thionylchloride in 30 ml dichloromethane was stirred for 1 h at RT. The reaction mixture was concentrated under reduced pressure to give 1.44 g of pure 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:7]=1)=O)C.[BH4-].[Na+]>CO>[F:21][C:18]([F:19])([F:20])[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[C:6]([CH2:4][OH:3])[S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc(-c2ccc(OC(F)(F)F)cc2)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
To a solution of 3-(4-trifluoromethoxyphenyl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (0.11 g, 0.35 mmol) in MeOH (10 ml) was added sodium borohydride (0.022 g, 0.59 mmol) portion wise. The resulting reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0° C., quenched it with 2 ml of water and concentrated under vacuum. Added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to get the product (0.10 g) that was carried forward to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16].[OH-].[Na+].[Br:21][CH2:22][CH2:23]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:21][CH2:22][CH2:23][O:18][N:17]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: ON=C(Cc1ccccc1F)c1ccccc1F
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Fc1ccccc1CC(=NOCCBr)c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the above oxime (7.0 g, 29 mmol), 1,2-dibromoethane (50 ml) and N,N,N,N-tetrabutylammonium bromide (1.0 g, 3 mmol) was carefully added 9N sodium hydroxide (33 ml) while the temperature was kept below 20° C. After stirring at ambient temperature for 3 h the phases were separated and the organic phase was washed with water (2×100 ml) and saturated aqueous ammonium chloride (30 ml). The solvent was evaporated in vacuo and the residue co-evaporated in vacuo with absolute ethanol (100 ml) to give 8.1 g of 1,2-bis(2-fluorophenyl)ethanone O-(2-bromoethyl)oxime.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1.[CH2:22]([SH:24])[CH3:23].O>CN1C(=O)CCC1>[CH2:22]([S:24][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1)[CH3:23]
Reactant: CCS
Reactant: FC(F)(F)c1ccc2sc(-c3sccc3Br)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCSc1ccsc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.11 g of sodium hydride (60%) was added to a solution of 0.65 g of 2-(3-bromothiophen-2-yl)-5-(trifluoromethyl)benzothiazole and 0.15 ml of ethanethiol in NMP 6 ml 0° C., and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous salt solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.61 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethyl)benzothiazole (Compound of Present Invention (37)).
Reaction SMILES: [OH:1][C:2]([CH:27]1[CH2:32][CH2:31][C:30]([CH3:37])([C:33]([O:35]C)=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>O1CCCC1.CO>[OH:1][C:2]([CH:27]1[CH2:32][CH2:31][C:30]([CH3:37])([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: COC(=O)C1(C)CCC(C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(O)C3CCC(C)(C(=O)O)CC3)s2)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}-1-methylcyclohexanecarboxylate (37.8 mg, 0.071 mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) was added sodium hydroxide (1.0 M in water, 0.283 mL, 0.283 mmol). The reaction mixture was irradiated to 160° C. for 5 min in a microwave oven. After cooling to room temperature, hydrochloric acid (2.0 M in water, 0.145 mL, 0.290 mmol) was added. The mixture was partitioned between 10% IPA:CHCl3 and brine, and then the layers were separated. The aqueous layer was extracted with 10% IPA:CHCl3, and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}-1-methylcyclohexanecarboxylic acid. MS ESI calc'd. for C25H27F3N4O3S [M+H]+ 521. found 521. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.24 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 7.95 (s, 2H), 7.45 (s, 1H), 7.27 (d, J=4.9 Hz, 1H), 7.14 (s, 1H), 5.83 (s, 1H), 2.31 (s, 3H), 1.70-1.38 (m, 6H), 1.48 (s, 3H), 1.36-1.28 (m, 1H), 1.26-1.16 (m, 2H), 1.02 (s, 3H). rhSyk (isomer 3)=+++
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:4]=1[CH2:5][N:6]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][N:40]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[C:25]([N+:35]([O-])=O)=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:28]=2)=[CH:12][C:11]=1[F:38])(=[O:9])=[O:8].C1COCC1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.C(O)C>[NH2:35][C:25]1[C:24]([C@H:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:18]2[O:17][C:13]2[C:14]([CH3:16])=[CH:15][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:45]=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:3]=3[O:2][CH3:1])[C:39]3[CH:44]=[CH:43][N:42]=[CH:41][N:40]=3)(=[O:9])=[O:8])=[C:11]([F:38])[CH:12]=2)=[CH:28][N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[N:26]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3N)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.1 %

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (193 mg, 0.272 mmol) prepared in Example 68a and bis(acetylacetonato)copper (II) (21.3 mg, 0.0815 mmol) in a mixed solvent of THF (4.0 mL) and ethanol (4.0 mL), sodium borohydride (101 mg, 2.66 mmol) was added, and the reaction solution was stirred at room temperature for 20 minutes. To the reaction solution, a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and ethyl acetate (10 mL) were added, the mixture was filtered through celite, and the filtrate was subjected to extraction. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (78 mg, 42%) as a light brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[C:12]([NH:15]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=[C:10]([CH:35](OCC)[O:36]CC)[N:9]=2)=[C:4]([F:42])[C:3]=1[O:43][CH3:44].CC#N>O>[NH2:15][C:12]1[C:13]([F:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:43][CH3:44])[C:4]=2[F:42])[N:9]=[C:10]([CH:35]=[O:36])[CH:11]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C=O)cc(N)c2F)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (2.117 g, 3.44 mmol), CH3CN (15 mL), water (15 mL) and 1 normal (N)H2SO4 (7.5 mL) was placed in an oil bath and heated to 80° C. After 2 h at 80° C., an aliquot of the reaction mixture was partitioned between EtOAc and 10% sodium bicarbonate (NaHCO3) and analyzed by high-performance liquid chromatography (HPLC) and TLC (80/20 hexanes/EtOAc). TLC and HPLC analyses showed only a trace of the starting material remaining (˜2% by HPLC) and essentially one, more polar product.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>[Pt]>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Sc2c(NCC(C)C)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1

Procedure:
The mixture of 3.5 g of 4-(4-acetamidophenylmercapto)-3-isobutylamino-5-sulfamoylbenzoic acid, 35 ml of 2 N aqueous sodium hydroxide and some colloidal platinum is refluxed for 1 hour under nitrogen, during which time the platinum coagulates. After cooling it is filtered, the filtrate acidified with acetic acid to a pH of 4-5, the precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-isobutylamino-5-sulfamoylbenzoic acid melting at 250°-252°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH:15]([NH:18][C:19]([C@@H:21]1[C@H:26]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=2[NH2:36])[C@@H:25]2[CH2:37][C@H:22]1[CH:23]=[CH:24]2)=[O:20])([CH3:17])[CH3:16].C([O-])(=O)C.[NH4+]>>[CH:15]([NH:18][C:19]([C@@H:21]1[C@H:26]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]3[NH:35][C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[N:3][C:2]=4[Cl:1])=[N:36][C:29]=23)[C@@H:25]2[CH2:37][C@H:22]1[CH:23]=[CH:24]2)=[O:20])([CH3:17])[CH3:16]
Reactant: O=Cc1sc(N2CCOCC2)nc1Cl
Reactant: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCOCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 9 %

Procedure:
In a similar fashion to Compound LXXXVII 4-Chloro-2-morpholin-4-yl-thiazole-5-carbaldehyde (75.00 mg, 0.3223 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid isopropylamide (97.42 mg, 0.2901 mmol), and Ammonium acetate (44.72 mg, 0.5802 mmol were reacted to produce 14.26 mg (9%) of the title compound. (300 MHz, DMSO-d6) 12.78 (s, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 6.95 (s, 1H), 6.39-6.29 (m, 2H), 4.98 (t, J=17 Hz, 8.5 Hz, 1H), 3.88 (m, 1H), 3.73 (m, 4H), 3.49 (m, 4H), 2.83 (s, 1H), 2.83 (s, 1H), 2.76 (s, 1H), 2.54 (d, J=8 Hz, 1H), 2.54 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.07 (d, J=6.5 Hz, 3H, 1.00 (d, J=6.5 Hz, 3H). MS=547 (M+H), HPLC: 2.92 min. (G Method)