Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[I-].[K+].Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:20][O:19][C:17](=[O:18])[CH:16]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[CH:25][CH:26]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(Oc1cccc(N(C)C)c1)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Yield: 91.6 %

Procedure:
As described in Example 5, a mixture of 2.74 g of 3-dimethylaminophenol, 0.80 g of 60% sodium hydride-oil dispersion, 3.32 g of potassium iodide, one ml of hexamethylphosphoramide and 8.0 g of methyl bromo{p-[2-(p-chlorophenoxy)ethoxy]phenyl}acetate in 70 ml of tetrahydrofuran is refluxed for 18 hours and worked up to give 8.34 g of a gum. The gum is chromatographed on silica gel with dichloromethane as eluent to give 6.8 g of solid. Trituration with hexane-ether gives 3.50 g of crystals. Recrystallization gives crystals, mp 100°-101° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:35])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([C:21]2[C:22]([C:27]3[C:32](F)=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[N:23][O:24][C:25]=2[CH3:26])=[O:20])[N:13]=1)[CH3:8]>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:9][C:10](=[O:35])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:34])[C:27]=3[C:22]3=[N:23][O:24][C:25]([CH3:26])=[C:21]3[C:19]2=[O:20])[N:13]=1)[CH3:8]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(-n2c(=O)c3c(C)onc3c3c(Cl)cccc32)n1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Add powdered K2CO3 (0.661 g, 4.8 mmol) to a solution of (6-{[3-(2-Chloro-6-fluorophenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-pyridin-2-yl)-acetic acid ethyl ester (0.5 g, 1.2 mmol) in DMF (20 ml) under N2 and stirred overnight. Dilute with EtOAc, wash (H2O then brine), dry (MgSO4), filter, and concentrate. Column chromatography (silica gel, hexanes/EtOAc gradient) gives the title compound (0.376 g, 79%). Mass Spectrum (FIA) (m/z) 398.1 [M+1]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:12])([O-:3])=[O:2].[CH:19](O)=[O:20]>>[CH:19]([NH:12][N:11]([CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:20]
Reactant: O=CO
Reactant: NN(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Product: O=CNN(Cc1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A stirred solution of 48.66 g (0.2 mol) of 1-[(2-nitrophenyl)methyl]-1-phenylhydrazine and 200 ml of 97% formic acid solution was heated 4 hours under reflux and allowed to stand overnight (about 16 hours) at ambient temperature. Excess formic acid was removed on a rotary evaporator and the residue was dissolved in 1500 ml of CH2Cl2. The solution was washed with 10% NaOH and concentrated to dryness. Recrystallization from 600 ml of 95% ethanol afforded 44.0 g (81.8%) of 2-formyl-1-[(2-nitrophenyl)methyl]-1-phenylhydrazine, m.p. 140°-142.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.CCCCCC.Cl.[CH3:19][CH:20]([CH2:22][CH2:23][CH2:24][CH:25]([CH2:27][CH2:28][CH2:29][CH:30]([CH2:32][CH2:33][CH2:34][C:35]([OH:39])([CH:37]=[CH2:38])[CH3:36])[CH3:31])[CH3:26])[CH3:21]>[Cl-].[Zn+2].[Cl-].C(O)CCC>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:38][CH2:37][C@:35]([CH2:34][CH2:33][CH2:32][C@@H:30]([CH2:29][CH2:28][CH2:27][C@@H:25]([CH2:24][CH2:23][CH2:22][CH:20]([CH3:19])[CH3:21])[CH3:26])[CH3:31])([CH3:36])[O:39][C:3]=2[C:2]=1[CH3:1]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: CCCCO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 178.6 %

Procedure:
To a mixture consisting of 69.9 g (0.260 mol) of 2,3,5-trimethylhydroquinone, 52.5 g (0.386 mol) of zinc chloride, 142.5 ml of hexane, 7.5 ml of n-butanol and 7.5 g of concentrated hydrochloric acid, 138.3 g (0.459 mol) of isophytol (purity: 98.3%) were added dropwise under stirring at 30°-40° C. over 3 hours. At the same temperature, the reaction mixture was stirred for additional 2 hours. After the reaction mixture was washed with 30 ml of water, the solvents were distilled off. Toluene (300 ml) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl dried over magnesium sulfate and then concentrated under reduced pressure, whereby 200 g of the title compound were obtained as a brown oil (yield: 98.1%, GLC purity: 97.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11])=[O:5].[BH4-].[Na+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH:4]([OH:5])[C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11]
Reactant: COC(=O)c1ccc2sc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2sc(C)c(C(O)c3ccc(Cl)cc3Cl)c2c1
Reaction time: 0.67 h
Yield: 96.3 %

Procedure:
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]-thiophene (600 mg, 1.58 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (1 ml), and sodium borohydride (72 mg, 1.9 mmol) was added thereto under ice-cooling. The mixture was stirred for 40 min under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (580 mg, 96%) as colorless crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].CN1CCCN(C)C1=O.F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.[NH4+].[Cl-]>C1COCC1>[CH3:9][O:10][C:11]([C:13]1([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)C1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 30.3 %

Procedure:
To a solution of lithium diisopropylamide (12.2 mL, 22.0 mmol, 1.8 M) in 40 mL of THF at −78° C. was added tetrahydro-pyran-4-carboxylic acid methyl ester (2.88 g, 20.0 mmol) dropwise. The resulting mixture was stirred at −78° C. for 15 min, warmed to RT. 1,3-Dimethyl-tetrahydro-pyrimidin-2-one (2.69 g, 22.0 mmol) was added. The reaction was cooled to −78° C. again, 1-fluoro-4-nitro-benzene (3.10 g, 22.0 mmol) was added slowly. The resulting mixture was warmed to RT and stirred for 1 d under Ar. The reaction was treated with 30 mL of saturated NH4Cl and extracted with 80 mL of EtOAc. The organic extract was washed with H2O (50 mL), brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (5-20% EtOAc/hexane) to give 1.61 g (30%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.21 (d, 1H, J=9.0 Hz), 7.56 (d, 1H, J=9.0 Hz), 3.97 (m, 2H), 3.70 (s, 3H), 3.57 (m, 2H), 2.56 (m, 2H), 2.00 (m, 2H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[N:5][CH:4]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](OCC)=[O:19].Cl>C(O)C>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([C:18](=[O:19])[C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9]2)=[N:5][CH:4]=1
Reactant: CCOC(=O)c1cccs1
Reactant: O=C1Cc2ncc(Cl)cc2N1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2cc(Cl)cnc2C1C(=O)c1cccs1
Temperature: 0 °C

Procedure:
Pellets of sodium metal (3.4 g, 0.15 mmol) were added to dry ethanol (90 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 6-chloro-4-azaoxindole (5.0 g 29.7 mmol) was added followed by ethyl 2-thiophenecarboxylate (8 mL, 55 mmol). The mixture was heated under nitrogen at reflux overnight during which a precipitate formed. The mixture was cooled, poured into ice/water and acidified to pH 3 with 6N HCl solution. The solid azaoxindole (7.8 g, 94%) (m.p. 250°) was collected by filtration washing with water and ether and dried in vacuo with heating.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[O:6][CH:7]1[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:18]=[CH:19][C:20]([CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:8]1
Reactant: COc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC2CNC2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A solution of 7B (2.1 g, 5.47 mmol) in DCM (20 mL) was treated with TFA (10 g, 88 mmol) and stirred at RT for 2 h. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 (sat.) and extracted several times with DCM and the organic solutions were filtered through a phase separator. The solvent was removed by evaporation and the residue was purified by column chromatography on SiO2 using 10% triethylamine and 10% MeOH in EtOAc as eluent. There was obtained 1.0 g (66%) of 7C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.40-2.53 (m, 4H), 3.47 (s, 2H), 3.66-3.74 (m, 4H), 3.78 (s, 3H), 3.77-3.84 (m, 2H), 3.89-3.97 (m, 2H), 4.94-5.04 (m, 1H), 6.23 (d, 1H), 6.37 (s, 1H), 7.19 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20].O=S(Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(Cl)cc1C(=O)OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CCc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of methyl 5-chloro-2-ethylbenzoate (5.12 g, 25.77 mmol) in concentrated H2SO4 (31 ml, 587 mmol) was cooled to −5° C. in an acetone/ice bath in air. A mixture of concentrated nitric acid (2.15 ml, 33.51 mmol) and concentrated H2SO4 (2 ml, 37.52 mmol) was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes. The pale yellow reaction mixture was stirred at −5 to 0° C. for 1 hour before being poured onto ice (500 ml) and this was extracted with EtOAc (3×100 ml). The combined organic phases was washed with deionized water (100 ml) and then brine (100 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. LCMS and NMR showed ˜30% hydrolysis of the ester. The crude material was dissolved in Methanol (30 ml) and cooled to 0° C. under nitrogen where SOCl2 (2.25 ml, 30.93 mmol) was added slowly. The reaction mixture was then heated to reflux for 6 hours before being concentrated under reduced pressure to give 6.18 g (98.4%) of methyl 5-chloro-2-ethyl-3-nitrobenzoate as an orange oil. Product contained 1:1 mixture of 3-nitro:6-nitro isomers along with some ethyl ester which was suitable for use without any further purification.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH:7]([NH:12][C:13](=[O:47])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[S:22][S:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:32](=[O:46])[NH:33][CH:34]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:39]([CH:34]([NH:33][C:32]([C:25]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[S:23][S:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:48])=[O:5])=[O:47])=[O:46])[CH2:35][CH:36]([CH3:38])[CH3:37])([OH:41])=[O:40]
Reactant: COc1ccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(SSc2cc(OC)ccc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1ccc(C(=O)NC(CC(C)C)C(=O)O)c(SSc2cc(OC)ccc2C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 7.9 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-methoxy-phenyldisulfanyl]-4-methoxy-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester (1.2 g, 17.0 mmol) from Example 30, 10 mL dichloromethane, 10 mL trifluoroacetic acid, and 1 mL anisole. The crude product was recrystallized from methanol/water to afford 0.8 g of the title compound, mp 230-231° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[C:22]([O:30][CH2:31][C@@H:32]2[CH2:34][O:33]2)[CH:21]=1>>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:34][C@H:32]([OH:33])[CH2:31][O:30][C:22]4[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=[CH:24][C:23]=4[NH:26][C:27](=[O:29])[CH3:28])[CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Reactant: COc1ccc(NC(C)=O)c(OC[C@@H]2CO2)c1
Product: COc1ccc(NC(C)=O)c(OC[C@@H](O)CN2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 30 above from 5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one and N-{4-methoxy-2-[(2S)oxiranylmethoxy]phenyl}acetamide. The product was purified by preparative HPLC (Kromasil column; eluent: acetonitrile/water) to afford a colourless solid (84%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH:14][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(CNCc1ccc(F)cc1)OC
Reaction time: 8 h
Yield: 93.9 %

Procedure:
12.4 g of 4-fluorobenzaldehyde were dissolved in 100 mL of toluene and reacted with 10.5 g of 2-aminoacetaldehyde dimethylacetal and 1.90 of p-toluenesulfonic acid monohydrate for two hours at a Dean Stark apparatus. The solution was allowed to cool down, extracted with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated to dryness. The crude product was dissolved in 100 mL of ethanol. 1.89 g of sodium borohydride were added portionwise. Stirring was continued overnight. For workup, acetic acid was added until no gas evolution could be observed. Then the solution was evaporated to dryness, taken up in dichloromethane and washed twice with water. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used for further reactions without purification. Rt=0.86 min (Method B). Detected mass: 182.1 (M-OMe−), 214.2 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:26]([C:25]1[CH:28]=[CH:29][C:22]([N:19]([CH2:13][CH2:14][CH2:16][CH2:17][CH2:18][CH2:31][CH3:32])[CH2:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=2)=[N:23][CH:24]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-{[4-(3-aminopropyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 33 and 6-chloronicotinonitrile as starting materials and by operations similar to those of Example 265-1 and Example 265-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[C:8]([C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Br:7][C:5]1[CH:6]=[C:2]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH:11]=2)[C:8]#[N:9])[S:3][CH:4]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1C#N
Reactant: Brc1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)Oc1ccc(-c2cc(Br)cs2)cc1C#N

Procedure:
A 2 mL microwave vial was charged with 2,4-dibromothiophene (20 mg, 0.08 mmol), (3-cyano-4-isopropoxyphenyl)boronic acid (17 mg, 0.08 mmol), potassium carbonate (35 mg, 0.25 mmol) and 3:1 mixture of DME/H2O (4 mL). The reaction mixture was degassed by bubbling N2 through the stirred solution for 10 min. Pd(PPh3)4 (7 mg, 0.006 mmol) was added and the solution degassed for an additional 2 min. The vial was subjected to microwave irradiation at 70° C. for 30 min or until starting material consumed. 5-(4-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-3 was used in the next experiment without purification. LCMS-ESI (m/z) calculated for C14H12BrNOS: 320.9; no M+ observed, tR=4.15 min.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[C:20]([F:31])([F:30])[C:21]([NH:23][CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22]>CC(C)=O.C(OCC)(=O)C>[F:31][C:20]([F:30])([O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[F:1])[C:21]([NH:23][CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: O=C(NCc1ccco1)C(F)(F)Br
Reactant: Oc1ccc2ccccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccco1)C(F)(F)Oc1ccc2ccccc2c1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 112.1 %

Procedure:
To a solution of 1-fluoronaphthalen-2-ol (280 mg, 1.73 mmol) and K2CO3 (1.2 g, 8.65 mmol) in 10 mL of acetone, 2-bromo-2,2-difluoro-N-(furan-2-ylmethyl)acetamide (527 mg, 2.08 mmol) were added. The resulting mixture was stirred at 40° C. overnight. The reaction was cooled at room temperature, diluted with ethyl acetate (30 mL) and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2,2-difluoro-2-[(1-fluoronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)acetamide as red oil (650 mg) which was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:14]Cl)=[N:5][CH:6]=[CH:7][C:8]=1[N:9]([CH2:11][CH2:12][Cl:13])[CH3:10].[C:16]([O-:19])(=[O:18])[CH3:17].[K+]>C(O)(=O)C>[C:16]([O:19][CH2:14][C:4]1[C:3]([Cl:2])=[C:8]([N:9]([CH2:11][CH2:12][Cl:13])[CH3:10])[CH:7]=[CH:6][N:5]=1)(=[O:18])[CH3:17]
Reactant: CN(CCCl)c1ccnc(CCl)c1Cl
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1nccc(N(C)CCCl)c1Cl

Procedure:
3.0 g (10.3 mmol) of (3-chloro-2-chloromethylpyridin-4-yl)-(2-chloroethyl)methylamine hydrochloride and 3.0 g (31 mmol) of potassium acetate are heated at 100° C. for 27 h in 50 ml of glacial acetic acid. The glacial acetic acid is then distilled off and the residue is taken up in 60 ml of ethyl acetate/water (1:1). The mixture is adjusted to pH 8 using sodium bicarbonate solution and extracted with 3×30 ml of ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: toluenelethyl acetate=1:1). The fractions of Rf =0.25 are concentrated (yield: 1.84 g, 64%) and employed directly for the synthesis of the compound of Example C2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:23])[CH:7]=[C:8]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-])=O)[CH:9]=2)[N:4]=1.C>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:23])[CH:7]=[C:8]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[CH:9]=2)[N:4]=1
Reactant: COc1ccc2cc(Nc3ccccc3[N+](=O)[O-])cc(C)c2n1
Solvent: CCO
Product: COc1ccc2cc(Nc3ccccc3N)cc(C)c2n1

Procedure:
A solution of 2-methoxy-6[(N-2-nitrophenyl)-amino]-8-methylquinoline (0.2 g) in absolute ethanol (20 cm3) was hydrogenated at 60° and 60 p.s.i. (4.13×105Pa) pressure over 10% palladised charcoal (0.03 g) for 4 hours. The cooled solution was then filtered through "Solkafloc" (Trade Mark for a cellulose-based filtering aid), evaporated to dryness in vacuo, characterised spectroscopically and used directly in Preparation 16 without further purification.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:38]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:38])=[N:4][CH:5]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@H](Cc2ccccc2)C(N)=O)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@H](Cc2ccccc2)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-phenylpropanamide (21 mg, 0.051 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (17 mg). MS 428.3 (M+H); UV 204.7, 265.7, 297.7 nm; t 0.465 min.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.COC1C=CC(B(O)O)=CC=1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH3:12])=[C:15]([CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: COc1ccc(B(O)O)cc1
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Br)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester and 4-methoxyphenylboronic acid.