Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[CH3:12][C:13]1([CH3:25])[CH2:22][C:21](=O)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:24])[CH:19]=2)[S:14]1>C1COCC1.CCCCCC.CCOCC>[CH3:12][C:13]1([CH3:25])[CH:22]=[C:21]([C:4]2[S:3][C:2]([CH3:1])=[CH:6][CH:5]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:24])[CH:19]=2)[S:14]1
Reactant: Cc1cccs1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2S1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)s1
Temperature: 25 °C

Procedure:
To a cold (−78° C.) solution of 2-methylthiophene (1.2 g, 12.2 mmol) in THF (8 mL) was added n-BuLi in hexane (1.6M, 8.5 mL). The mixture was warmed to ambient temperature over 30 minutes. with stirring. The mixture was recooled to −78° C. and a solution of 2,2-dimethyl-6-bromo-thiochroman4-one (Compound M, 1.4 g, 5.2 mmol) in THF (10 mL) was added. The mixture was stirred for 16 hours at ambient temperature. Then the reaction mixture was diluted with ether (125 mL), washed with water (10 mL), brine (10 mL) dried and the solvent was removed by evaporation. The product was seperated by column chromatography and was dissolved in dichloromethane (5 mL). To this solution p-TSA (5 mg) was added and the mixture was stirred at ambient temperature for 5 min. The reaction was quenched with 10% NaHCO3 (3 mL), washed with brine (5 mL), dried and the solvent was removed by distillation. The residual crude a material was purified by column chromatography to obtain the title compound as a pale yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:26])([F:25])[CH:13]([OH:24])[CH2:14][C:15]([CH3:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:16].C(N(CC)CC)C>ClCCl>[F:26][C:12]([F:11])([F:25])[C:13](=[O:24])[CH2:14][C:15]([CH3:16])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:23]
Reactant: CC(C)(CC(O)C(F)(F)F)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(CC(=O)C(F)(F)F)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
A solution of 516 μL (1.03 mmol, 1.2 eq) of oxalyl chloride (2.0 M solution in dichloromethane) was diluted with 2 mL of dichloromethane. To this solution was added a solution of 146 μL (2.06 mmol, 2.4 eq.) of DMSO in 0.2 mL of dichloromethane at −60° C. and the mixture was stirred for 10 minutes at this temperature. Then to this mixture was added a solution of 200 mg (0.86 mmol) of 1,1,1-trifluoro-4-methyl-4-pyridin-2-ylpentan-2-ol in 2 mL of dichloromethane at −60° C. The resulting mixture was stirred at −60° C. for 15 minutes and then 600 μL (4.3 mmol, 5.0 eq.) of triethylamine was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and quenched with water. The organic layer was separated. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, providing 172 mg (86%) 1,1,1-trifluoro-4-methyl-4-pyridin-2-ylpentan-2-one as a brown oil.
Reaction SMILES: O.[NH2:2][NH2:3].Cl.CO[C:7]([C:9]1[CH:14]=[CH:13][N:12]2[CH:15]=[CH:16][N:17]=[C:11]2[CH:10]=1)=[NH:8]>CO>[N:17]1[CH:16]=[CH:15][N:12]2[CH:13]=[CH:14][C:9]([C:7]([NH:2][NH2:3])=[NH:8])=[CH:10][C:11]=12
Reactant: COC(=N)c1ccn2ccnc2c1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C(NN)c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrazine hydrate (80% in water, 0.25 ml, 2 equiv) was added to a mixture of imidazo[1,2-a]pyridine-7-carboximidic acid methyl ester hydrochloride (1.0 g, 4.7 mmol, 1 equiv) in methanol (30 ml). The mixture was heated to 70 deg C. for 1 hour then allowed to cool to room temperature. After leaving to stand overnight, any solid was removed by vacuum filtration and the solution was concentrated in vacuo and re-concentrated from methanol and was used crude without further purification in the cyclisation step
Reaction SMILES: C(OC([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([CH2:38][O:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=O)C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[CH2:43]([O:42][C:40]([O:39][CH2:38][C@H:36]1[O:37][C@@H:29]([O:28][C:13]2[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:20][CH:19]=3)=[C:15]([CH3:16])[NH:11][N:12]=2)[C@H:30]([OH:31])[C@@H:32]([OH:33])[C@@H:34]1[OH:35])=[O:41])[CH3:44]
Reactant: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(=O)OCc3ccccc3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)-methyl]-5-methylpyrazole (0.17 g) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder, and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The resulting insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.10 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.5 %

Procedure:
To a suspension of 2,6-dichloronicotinic acid (1.92 g), N,O-dimethylhydroxylamine hydrochloride (1.46 g) and triethylamine (2.1 mL) in N,N-dimethylformamide (30 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g), and then the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous solution of potassium hydrogen sulfate and a saturated aqueous solution of sodium hydrogen carbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (1.61 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([O:17][CH3:18])(=[O:16])[C:12](OC)=[O:13]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:10][C:12](=[O:13])[C:11]([O:17][CH3:18])=[O:16])=[CH:9][C:2]=1[NH:1][C:12](=[O:13])[C:11]([O:17][CH3:18])=[O:16])#[N:5]
Reactant: COC(=O)C(=O)OC
Reactant: N#Cc1ccc(N)cc1N
Product: COC(=O)C(=O)Nc1ccc(C#N)c(NC(=O)C(=O)OC)c1
Yield: 80.7 %

Procedure:
A mixture of 29.0 grams (0.218 mole) of 2,4-diaminobenzonitrile and 255 grams of dimethyl oxalate is refluxed for 3 hours. The excess dimethyl oxalate is distilled off in vacuo. The residue is boiled with 150 ml. of methanol and filtered. The filtrate is poured into 900 ml. of water and the tan precipitate removed by filtration. There is obtained 53.7 grams (81%) of tan needles melting at 155°-160°. The product is boiled in 1800 ml. of methanol and the insoluble material removed by filtration. The filtrate is poured into 2 liters of water, refrigerated, and the precipitate removed by filtration. There is obtained 23.8 grams of fine yellow needles melting at 160°-163°.
Reaction SMILES: [Si]([O:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[N:23]=[C:22]([C@@H:24]([N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]4=[O:32])[CH3:25])[NH:21][C:20]=3[CH:33]=2)[N:11]1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.C(#N)C.O>FC(F)(F)C(O)=O>[OH:8][C@H:9]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@@H:10]1[NH:11][C@H:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[N:23]=[C:22]([C@@H:24]([N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]4=[O:32])[CH3:25])[NH:21][C:20]=3[CH:33]=2)[CH2:13][CH2:14]1
Reactant: C[C@@H](c1nc2ccc(C[C@@H]3CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c4ccccc4)N3C(=O)OC(C)(C)C)cc2[nH]1)n1cccnc1=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](c1nc2ccc(C[C@@H]3CC[C@H]([C@H](O)c4ccccc4)N3)cc2[nH]1)n1cccnc1=O

Procedure:
A solution of 0.017 g (0.026 mmol) of tert-butyl(2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-({2-[(1S)-1-(2-oxopyrimidin-1(2H)-yl)ethyl]-1H-benzimidazo-6-yl}methyl)pyrrolidine-1-carboxylate from Step B above in 2 mL of a 3:3:1 trifluoroacetic acid:acetonitrile:water mixture was stirred at 70° C. for 3 h. All volatiles were removed in vacuo and the crude light brown residue was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to afford the title compound as a white solid. 1H-NMR (500 MHz, CD3OD) δ 8.85-8.62 (m, 1H), 8.57-8.31 (m, 1H), 7.91-7.65 (m, 2H), 7.64-7.24 (m, 9H), 6.86-6.59 (m, 1H), 6.19-5.87 (m, 1H), 4.85-4.67 (m, 2H), 4.04-3.68 (m, 4H), 3.28-3.10 (m, 2H), 2.30-1.62 (m, 4H). LC/MS: m/z (ES) 430.2 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl phenylacetate (5.03 g, 33.5 mmol) was treated with 1N aqueous NaOH (22 mL, 22 mmol) in THF (40 mL) and MeOH (4 mL), and stirred overnight at room temperature. Additional 1N aqueous NaOH (22 mL, 22 mmol) was added, and the reaction was stirred for 6 hours at room temperature. The mixture was acidified with 1N aqueous HCl to pH 3-4 and extracted with EtOAc three times. The combined organic layers were dried and concentrated to give phenyl-acetic acid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>>[OH:8][C:4]1[CH:3]=[C:2]([C:11]#[C:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CC(=O)OCC
Reactant: Oc1cccc(I)c1
Product: CCOC(=O)C#Cc1cccc(O)c1
Yield: 73.1 %

Procedure:
According to the method of (Reference Example 3), from 3-iodophenol (1.18 g) and ethyl propiolate (1.0 g), the subject compound (746 mg) was obtained as a yellow solid.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[CH2:16]([N:23]1[CH:28]2[CH:29]([C:31]#[N:32])[CH2:30][C:24]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:25](O)[CH2:26][CH2:27]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH2:16]([N:23]1[C@@H:28]2[C@@H:29]([C:31]#[N:32])[CH2:30][C@@:24]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:25]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:26][CH2:27]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#CC1CC2(c3ccccc3)C(O)CCC1N2Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1
Reaction time: 0.25 h

Procedure:
t-Butyldimethylsilyl trifluoromethanesulphonate (23 ml, 76 mmol) was added dropwise to a stirred solution of (1R*,2R*5S*,6S*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 41; 31 g), triethylamine (18 ml, 243 mmol) in dichloromethane (100 ml) at room temperature over 30 minutes. The reaction mixture was stirred for 15 minutes, quenched with saturated aqueous NaHCO3 and extracted into diethyl ether (3×100 ml). The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[OH-].[NH4+:11]>C(O)C>[OH:9][C:3]1[C:4](=[O:5])[CH:6]=[CH:7][NH:11][C:2]=1[CH3:1]
Reactant: [NH4+]
Reactant: Cc1occc(=O)c1O
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]ccc(=O)c1O
Temperature: 66 °C
Yield: 24 %

Procedure:
A 500-mL high-pressure reaction vessel equipped with a magnetic stir bar and a thermometer was charged with maltol (20 g, 0.16 mol), ethanol (40 mL) and ammonium hydroxide solution (28.0-30.0%, 35 mL, 0.52 mol). The reaction vessel was sealed and heated at 66° C. for 2.5 h. HPLC analysis (HPLC Method 1, Example 24) indicated that only 26% of product (peak percent area) was formed. Another 30 mL of conc. ammonium hydroxide (28.0-30.0%, 0.45 mol) was added, and the resulting mixture was sealed and heated to 75° C. for overnight. Upon cooling, a solid separated, and it was collected by suction filtration (8.7 g). HPLC analysis of the solid indicated presence of the desired product and maltol in about 4/1 ratio. The solid was slurried in methanol (30 mL), and the resulting mixture was stirred. The solid 3-hydroxy-2-methyl-1H-pyridin-4-one was collected by suction filtration (4.8 g, 24% yield, HPLC purity (peak percent area): 99.7% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 11.6 (br s, 1H), 7.40 (d, J=6.8 Hz, 1H), 6.09 (d, J=6.8 Hz, 1H), 2.17 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3ccccc3)c(=O)c2c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (32.5 mg, 0.16 mmol) in DMF (1.50 mL) was added potassium carbonate (66 mg, 0.48 mmol) and benzyl bromide (38.1 μL, 0.32 mmol). The reaction mixture was heated to 60° C. and stirred for 5 h. The mixture was then cooled to rt and concentrated. Water was added and the reaction mixture was extracted with DCM (5 mL, 3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford methyl 2-benzyl-1-oxo-1,2-dihydroisoquinoline-7-carboxylate. LC-MS: (FA) ES+ 294.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]([F:38])([F:37])[C:30](=O)[C:31](OCC)=[O:32]>C(O)C>[O:32]=[C:31]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:12][CH:11]=3)[C:7]=2[N:8]=[C:30]1[C:29]([F:38])([F:37])[F:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)c2ccccc12
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3[nH]c(=O)c(C(F)(F)F)nc23)c2ccccc12
Temperature: 25 °C

Procedure:
To tert-butyl 4-(2,3-diaminopyridin-4-yloxy)naphthalen-1-ylcarbamate (1.00 g, 2.73 mmol) dissolved in 20 mL of anhydrous ethanol under argon and at reflux was added the ethyl trifluoropyruvate (697 mg, 0.50 mL, 4.10 mmol). The reaction mixture was stirred at reflux for 3 hours. After cooling at RT, a precipitate was formed, filtered off and rinsed with Et2O. tert-butyl 4-(3-oxo-2-(trifluoromethyl)-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)naphthalen-1-ylcarbamate was obtained as a white solid (116 mg, 0.246 mmol, 9%). The filtrate was evaporated under vacuum. The residue was chromatographied (eluent: CH2Cl2/EtOAc: 4/1 towards 0/1) to afford the second isomer as a slightly yellow solid (540 mg, 1.14 mmol, 42%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:17]=1[OH:24].C(OC(C)C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH2:12]([NH:13][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([OH:24])[CH:18]=1)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCN
Reactant: COc1ccc(C=O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNCc1ccc(OC)c(O)c1
Yield: 80.9 %

Procedure:
In a 100-ml round-bottomed flask were placed n-laurylamine (11.1 g (60 mmol)) and isovaniline (1.52 g (10 mmol)) under nitrogen. While stirring, diisopropylether (17.5 ml) and glacial acetic acid (5 ml) were sequentially added dropwise. After completion of addition, the mixture was stirred for approximately 2 hours at room temperature, followed by the addition of a borane-pyridine complex (1.2 ml (10 mmol), product of Aldrich) over 10 minutes. The mixture was stirred for a further 2 hours. Subsequently, 5N-HCl (12 ml) was added dropwise and the resultant mixture was stirred for 10 minutes. The pH of the mixture was turned to basic using an aqueous 5N--NaOH solution. The product formed was extracted using diisopropyl ether, concentrated, and purified via silica gel column chromatography n-hexane:ethyl acetate=2:1), thereby obtaining 2.6 g of N-lauryl-3-hydroxy-4-methoxybenzylamine as mud yellow crystals (yield: 82%).
Reaction SMILES: [NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:3][S:4]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(S)C>[NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:3][SH:4].[F:43][C:44]([C:45]([OH:47])=[O:46])([F:49])[F:48]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCS
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CS)C(=O)O
Reaction time: 0.5 h

Procedure:
564 mg (0.97 mmole) of H-Cys(Trt)-Ser-Leu-OH.H2O (Chem. Ber. 103, 2034 (1970)) are dissolved in a mixture of 2.5 ml of ethylmercaptan and 2.5 ml of trifluoroacetic acid. The mixture is left to stand for 30 minutes at room temperature and the batch is poured into 50 ml of water. The aqueous phase is extracted three times with ether and is freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[S:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.I[CH3:31]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20]([S:22][CH3:31])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:28])([F:27])[F:29])[CH:3]=1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CI
Product: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodomethane following General Procedure B.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C:25](OC1C=CC([N+]([O-])=O)=CC=1)=[O:26].Cl.Cl.[CH:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)([CH3:41])[CH3:40]>>[CH:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH:48][C:25]([NH:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([NH:12][CH:9]2[C:8]4[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=4[O:11][CH2:10]2)[CH:22]=[CH:21]3)=[O:26])[CH2:44][CH2:43]1)([CH3:41])[CH3:40]
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C(C)C)CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine (Example 173) (200 mg, 0.62 mmol), 4-nitrophenyl chloroformate (125 mg, 0.62 mmol) and 1-isopropyl-piperidin-4-ylamine dihydrochloride (CAS no: 534596-29-7) (140 mg, 0.65 mmol) in accordance with the general method 4 described in example 170 step C and was obtained as an off-white solid (190 mg, 61%); MS: m/e=476.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:21]4[N:20]([C@@H:22]5[O:43][C@H:42]([CH2:44]O)[CH2:41][C@H:32]([O:33][CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C@H:23]5[O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:19]5[C:14](=[CH:15][C:16]([F:46])=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:47](=[O:51])[NH:48][C:49](=[O:50])[C:11]=4[C:10]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Na+].[I-:65]>ClCCl.CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:21]4[N:20]([C@@H:22]5[O:43][C@H:42]([CH2:44][I:65])[CH2:41][C@H:32]([O:33][CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C@H:23]5[O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:19]5[C:14](=[CH:15][C:16]([F:46])=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:47](=[O:51])[NH:48][C:49](=[O:50])[C:11]=4[C:10]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c1c3cc(F)ccc3[nH]c1c1c2c2cc(F)ccc2n1[C@@H]1O[C@H](CO)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2c1c1c3cc(F)ccc3[nH]c1c1c2c2cc(F)ccc2n1[C@@H]1O[C@H](CI)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
A mixture of 3,9-difluoro-12-(2,3-di-O-benzyl-4-deoxy-β-D-glucopyranosyl)-6,7,12,13-tetrahydro-(5H)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (0.312 g, 0.45 mmol) and freshly activated, pulverized 4A molecular sieves (0.5 g) in 15 mL of dichloromethane was cooled at 5° C. under Ar and then triethylamine (0.095 mL, 0.68 mmol) and methanesulfonyl chloride (0.039 mL, 0.50 mmol) were added sequentially. The mixture was stirred at the same temperature for 3 h and then the mixture was quenched with 10% saturated aqueous NaHCO3, diluted with ethyl acetate and then filtered. The filtrate was washed (H2O, brine), dried (Na2SO4) and evaporated to give a yellow glass. This material was taken up in 15 mL of acetone, NaI (0.675 g, 4.50 mmol) was added and the mixture was heated to reflux under Ar for 17 h. The cooled mixture was then evaporated to dryness and the residue was taken up in ethyl acetate, washed (H2O, brine) dried (Na2SO4) and evaporated. The resulting solid was chromatographed (SiO2/ethyl acetate-hexane, 1:1) to give 3,9-difluoro-12-(2,3-di-O-benzyl-4,6-dideoxy-6-iodo-β-D-glucopyranosyl)-6,7,12,13-tetrahydro(5H)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (0.276 g, 77% overall) as a yellow glass. To an ice-cold solution of this iodide in 10 mL of dry THF was added DBU (0.157 mL, 1.05 mmol) and the solution was then kept at room temperature for 5 days. The resulting mixture was quenched with saturated aqueous NH4Cl, diluted with ethyl acetate and then washed (H2O, brine), dried (Na2SO4) and evaporated to give the product (0.232 g, 99%) as a yellow glass. To a solution of this material in dry THF was added 20% Pd(OH)2/C and the mixture was hydrogenated (balloon pressure) until the reaction was complete by tlc. The mixture was then filtered (Celite) and the flitrate evaporated to give a yellow glass. Column chromatography (Sephadex LH-20/methanol) afforded the pure title compound as a yellow solid: