Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N([O-])=[O:23].[Na+].OS([O-])=O.[Na+]>Cl.O>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18]([OH:23])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CC3CC2CN3Cc2ccccc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(N2CC3CC2CN3Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1.17 g (122) in 17 mL concentrated HCl: 0.35 g NaNO2 in 5 mL water were added slowly dropwise, so that the temperature remained below 5° C. The solution was agitated for 2 hours at 60° C., neutralized with NaHSO3 and extracted with ether (4×50 mL). The combined organic phases were dried with Na2SO4, evaporated and distilled in a bulb tube (Kp: 0.05 mbar; 140° C.): 0.1 g (123) (123) as colorless oil. DC: CHCl3/methanol (9:1).
Reaction SMILES: C(O)(=O)C.C[Si](N[Si](C)(C)C)(C)C.[I:14][C:15]1[S:19][C:18]([C:20](=O)[CH3:21])=[CH:17][C:16]=1[CH3:23].[C:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])#[N:25]>CCOC(C)=O>[CH2:30]([O:29][C:27](=[O:28])[C:26]([C:24]#[N:25])=[C:20]([C:18]1[S:19][C:15]([I:14])=[C:16]([CH3:23])[CH:17]=1)[CH3:21])[CH3:31]
Reactant: CC(=O)c1cc(C)c(I)s1
Reactant: CCOC(=O)CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1cc(C)c(I)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
Acetic acid (9.4 ml) was placed in a flask at rt and HMDS (3.0 ml, 14.1 mmol) was added dropwise. After the exotherm subsided, 1-(5-Iodo-4-methyl-thiophen-2-yl)-ethanone (2.5 g, 9.4 mmol) was added as a solid followed by ethyl cyanoacetate (2.0 ml, 18.8 mmol). The reaction was stirred at 80° C. for 8 h, cooled to rt and concentrated by rotary evaporation to give a brown residue. The residue was taken up in EtOAc, washed with NaHCO3 (aq, sat.) and then with H2O. The organics were dried (NaSO4), filtered and concentrated to give a brown solid. The solid was triturated with EtOH and filtered to give 2-Cyano-3-(5-iodo-4-methyl-thiophen-2-yl)-but-2-enoic acid ethyl ester (2.0 g, 5.5 mmol, 58%) as a light yellow solid. MS (ESI) m/z 362.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27 (t, 1H) 2.21 (s, 1H) 2.66 (s, 1H) 4.26 (q, 1H) 7.67 (s, 4H).
Reaction SMILES: [C:1]([N:4]([C:10](=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[CH:5]([C:7]([OH:9])=O)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:32][CH:33]([C:35]([OH:37])=[O:36])[CH3:34]>O1CCCC1.[OH-].[Na+]>[C:1]([N:4]([C:10](=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[CH:5]([C:7]([NH:32][CH:33]([C:35]([OH:37])=[O:36])[CH3:34])=[O:9])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)c1ccccc1O)C(C)C(=O)O
Reactant: CC(N)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)c1ccccc1O)C(C)C(=O)NC(C)C(=O)O
Reaction time: 6 h

Procedure:
Acetylsalicyloyl-(DL)-alanine (2.5 g) was dissolved in dry tetrahydrofuran (15.0 ml) and dry triethylamine (1.36 ml) was added. The reaction mixture was brought to -5° C. and ethyl chloroformate (0.96 ml) was added dropwise over a period of 10 min. (DL)-Alanine (0.89 g) dissolved in aqueous sodium hydroxide (1 M, 10.0 ml) was added. The reaction was allowed to proceed at 0° C. for 6 hrs., and the solvent was then removed at 30° C. under reduced pressure. The residual solution was acidified to pH 2-3 using aqueous hydrochloric acid (3 M). The whole was extracted with ethyl acetate (50.0 ml), and the extract was dried (anhydrous sodium sulphate). The bulk of the ethyl acetate was removed under reduced pressure to leave a small volume of solution.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:18]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c(C)c1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2,4-dimethylphenylboronic acid (0.333 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 4 days to give 4-chloro-2-(2,4-dimethylphenyl)-5,7-difluoro-3-methylquinoline as a yellow oil. Mass Spectrum (ESI) m/e=325.0 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:12]([C:14]2[CH:24]=[CH:23][C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)[OH:13])=[N:8][C:9]=1[O:10][CH3:11].O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:12]([C:14]2[CH:24]=[CH:23][C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][O:21][C:16]=3[CH:15]=2)=[O:13])=[N:8][C:9]=1[O:10][CH3:11]
Reactant: COc1nc(C(O)c2ccc3c(c2)OCCN3C)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C(=O)c2ccc3c(c2)OCCN3C)ccc1Cl
Temperature: 25 °C
Yield: 77 %

Procedure:
Sodium hydride (purity: 63%, 75 mg) was added to a solution of (5-chloro-6-methoxypyridin-2-yl)(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanol (302 mg) in tetrahydrofuran (2 mL) under ice-cooling, and the mixture was stirred with warming to room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to give the title compound as a yellow solid (231 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([N+:10]([O-:12])=[O:11])=[N:3]1.[NH4+:13].[OH-]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH2:13])=[O:8])[C:4]([N+:10]([O-:12])=[O:11])=[N:3]1
Reactant: [NH4+]
Reactant: Cn1cc(C(=O)Cl)c([N+](=O)[O-])n1
Agent: [OH-]
Product: Cn1cc(C(N)=O)c([N+](=O)[O-])n1

Procedure:
Seven gm. of 1-methyl-3-nitro-4-pyrazolecarbonyl chloride was added in portions to 50 ml. of concentrated NH4OH. The mixture was heated at reflux for 15 to 20 minutes, evaporated to dryness, and cooled. The resultant crystallized product was identified as 1-methyl-3-nitro-4-pyrazolecarboxamide, m.p. 190°-192° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13](O)=[O:14])[CH:6]=[C:5]2[CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.[CH3:22][S:23]([NH2:26])(=[O:25])=[O:24].N1C=CN=C1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13](=[O:14])[NH:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:6]=[C:5]2[CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1
Reactant: O=C(O)CCn1cc(Cc2ncc[nH]2)c2cc(Br)ccc21
Reactant: CS(N)(=O)=O
Agent: c1c[nH]cn1
Solvent: CCO
Product: CS(=O)(=O)NC(=O)CCn1cc(Cc2ncc[nH]2)c2cc(Br)ccc21
Temperature: 120 °C
Yield: 29.2 %

Procedure:
A mixture of 5-bromo-1-(2-carboxyethyl)-3-(1-imidazolylmethyl) indole (0.87 g) and N,N'-carbonyldiimidazole (0.51 g) was heated on a steam bath for 1.5 hours to give a clear melt. Methanesulphonamide (0.47 g) was added and the mixture was heated at 120° C. for 2 hours and then cooled and dissolved in a small volume of ethanol. Some insoluble material was filtered off and the filtrate was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave initially some impurity. Further elution with a mixture of chloroform and methanol (9:1) gave a mixture of product and imidazole. The product containing fractions were evaporated and the residue was crystallised from a mixture of methanol and ether to give 5-bromo-1-[2-(N-methanesulphonylcarbamoyl)ethyl]-3-(1-imidazolylmethyl)indole (0.31 g,), m.p. 199°-201° C. Found: C, 45.21; H, 4.18; N, 12.95. C16H17BrN4O3S requires: C, 45.18; H, 4.03; N, 13.17%.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].N1C=CC=CC=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:1][CH:2]([OH:4])[CH3:3])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)O)cc1
Reaction time: 72 h

Procedure:
In 200 ml of methylene chloride were dissolved 38 g of 1,2-propanediol and 44 g of pyridine and, then, 95 g of p-toluenesulfonyl chloride was added gradually over a period of 15 minutes. The reaction was further conducted at room temperature for 72 hours. The reaction mixture was washed twice with one volume of water each, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was crystallized from toluene-hexane (100 ml-100 ml), filtered, and dried in vacuo to give colorless crystals of (RS)-1-p-toluenesulfonyloxy-2-propanol 2a ##STR21## (54 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[N+:13]([O-])=O.[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[NH2:13]
Reactant: [H][H]
Reactant: COc1ccc([Si](C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc([Si](C)(C)C)cc1N
Yield: 60.2 %

Procedure:
The above trimethyl-silane (760 mg, 3.4 mmol) was dissolved in 25 mL of EtOH. To this was added 10% Pd/C (128 mg). The reaction was stirred for 12 h under a 1 atm balloon of hydrogen gas. The reaction was then filtered through diatomaceous earth and concentrated in vacuo to provide 400 mg (60%) of 2-methoxy-5-trimethylsilanyl-phenylamine as an amber oil which was used without further purification.
Reaction SMILES: [CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]#[CH:27])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCOCCn1c(CCCCCCCC)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Product: CCCCCCCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.75 h
Yield: 71.7 %

Procedure:
Using the general method of Example 12 Part A, 2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (4.84 g, 13.32 mmol) was reacted with iodobenzene (1.7 mL, 14.65 mmol) at 40° C. After 45 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil purified by chromatography over silica gel (98/2 (dichloromethane/methanol) to provide 4.2 g of 2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][CH:15]=2)=[N:6]1.O[CH:27]1[CH:32](O)OCCO1>C(O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[CH:15]=[CH:16][C:17]3[C:18]([N:19]=2)=[N:20][CH:27]=[CH:32][N:21]=3)=[N:6]1
Reactant: OC1OCCOC1O
Reactant: Nc1ccc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: CCO
Product: Fc1ccccc1Cn1nc(-c2ccc3nccnc3n2)c2cccnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
200 mg (0.598 mmol) of the compound from example 43A were initially charged in ethanol (10 ml), then 144 mg (1.20 mmol) of 2,3-dihydroxy-1,4-dioxane were added and the reaction mixture was stirred at RT for 5 h. The solid formed was filtered off, washed with ethanol and dried under high vacuum. This gave 90 mg (41% of theory) of the title compound in solid form.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:20]1COC[CH2:21]1>O>[CH2:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[CH3:21]
Reactant: C1CCOC1
Reactant: O=C1OCc2ccc(Br)cc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1ccc2c(c1)C(=O)OC2
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-3H-isobenzofuran-1-one (Intermediate 72, 0.7 g) and potassium phosphate (1.9 g) in THF (7.3 ml) and water (3.7 ml) was degassed and palladium chloride dppf adduct with DCM (0.134 g) and triethyl borane (1M solution in THF, 4.3 ml) were added. The resultant mixture was stirred and heated at 100° C. for 1.5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine then dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give 6-ethyl-3H-isobenzofuran-1-one (0.435 g) as a colourless oil.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]2[CH:10]=[CH:11][N:12]=[C:6]2[N:5]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>Cl.O>[N:12]1[CH:11]=[CH:10][N:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[N:5][C:6]=12
Reactant: COC(OC)c1ccn2ccnc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccn2ccnc2n1
Temperature: 48 °C
Yield: 98.3 %

Procedure:
7-Dimethoxymethylimidazo[1,2-a]pyrimidine (1.00 g, 5.18 mmol) was dissolved in 3N hydrochloric acid and heated at 48° C. for 14 h. The solution was layered with ethyl acetate (30 ml) and solid sodium hydrogencarbonate (1.06 g, 12.6 mmol) was added in portions over 5 min. The mixture was diluted with water (6 ml) and extracted with dichloromethane (5×50 ml). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to give imidazo[1,2-a]pyrimidine-7-carbaldehyde (749 mg, 99%) as a yellow solid: δH (360 MHz, CDCl3) 7.53 (1H, d, J 7), 7.77 (1H, d, J 1), 8.10 (1H, d, J 1), 8.60 (1H, d, J 7), 10.05 (1H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]Cl.[SH:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][SH:20].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:10]1[CH2:11][CH2:12][S:20][CH2:19][CH2:18][S:17][CH2:16][CH2:15][S:14][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: ClCCOCCOCCOCCCl
Reactant: SCCSCCS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C1COCCSCCSCCSCCOCCO1

Procedure:
This compound is obtained by reacting 1,11-dichloro-3,6,9-trioxaundecane with 1,5-dimercapto-3-thiapentane in the presence of sodium carbonate in aqueous ethanol: ##STR8##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:28]3[C:14](=[CH:15][C:16]4[O:17][CH2:18][CH2:19][CH2:20]S[CH2:22][CH2:23][CH2:24][O:25][C:26]=4[CH:27]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].O[O:30][S:31]([O-:33])=O.[K+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:28]3[C:14](=[CH:15][C:16]4[O:17][CH2:18][CH2:19][CH2:20][S:31](=[O:33])(=[O:30])[CH2:22][CH2:23][CH2:24][O:25][C:26]=4[CH:27]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S([O-])OO
Reactant: Fc1ccc(Nc2ncnc3cc4c(cc23)OCCCSCCCO4)cc1Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=S1(=O)CCCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2OCCC1
Reaction time: 4 h

Procedure:
(3-Chloro-4-fluoro-phenyl)-(2,10-dioxa-6-thia-14,16-diaza-tricyclo[9.8.0.013,18]nonadeca-1-(11),12,14,16,18-pentaen-17-yl)-amine (16, 140 mg, 0.33 mmol) was suspended in MeOH, to which was added a cloudy aqueous solution of oxone (monopersulfate compound) (820 mg, 1.33 mmol) at room temperature. The suspension was stirred and monitored by TLC which indicated that the reaction was completed in 4 h. The reaction mixture was poured into H2O (10 mL), and extracted with EtOAc (3×15 mL). The organic layers were collected, dried and concentrated to give a pale yellow residue which was flash chromatographed to give the product as a white solid: 140 mg (93%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 8.00 (d, 1H), 7.24 (s, 1H), 7.26 (s, 1H), 7.42 (s, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 4.40 (t, 4H), 4.75 (t, 2H), 3.40 (t, 2H), 2.55 (m, 2H), 2.23 (m, 2H); ES-MS m/z: 452 (MH+).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].O.[C:16]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>C(O)C.O>[C:16]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][S:1][C:2]3[N:3]([CH3:12])[C:4](=[O:11])[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:32][CH:33]=2)=[O:25])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cn1c(S)nc2ccsc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4ccsc4c(=O)n3C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.98 g) and 1N-sodium hydroxide/water (10 ml) in ethanol (30 ml) was added 4-(4-acetoxybenzoyl)benzyl bromide (3.95 g) and the mixture was stirred at 60° C. for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as colorless solid (3.87 g).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O.C(Cl)(Cl)Cl>CO.[Pt]=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:14][C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CNc2ccccc2Oc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
In 60 ml of methanol were dissolved 3.70 g of 2-aminodiphenyl ether and 3.70 g of 2,4-dimethoxybenzaldehyde, and then 70 mg of platinum oxide was added, followed by stirring at room temperature under a hydrogen stream overnight. To the reaction mixture was added 30 ml of chloroform for dissolving the precipitate, and the catalyst was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to give 5.06 g of N-(2,4-dimethoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccccc2c1Cl
Temperature: 25 °C

Procedure:
5.5 g (29 mmol) 3-nitro-quinolin-4-ol (Example 1a) in 25 ml POCl3 are heated for 2 h to keep at 130° C. The mixture is cooled to rt and poured into ice-water. The precipitate is filtered off, washed with ice-cold water, and dissolved in CH2Cl2. The organic phase is washed with cold 0.1N NaOH (1×) and with cold water (2×). After drying over MgSO4, the solvent is evaporated to dryness. The residue is stirred in hexane. The title compound is isolated as a powder and is dried at 60° C. under vacuum. mp: 121-122° C.; NMR (CDCl3): 9.26/s (1H), 8.44/d and 8.21/d (2H), 7.95/t and 7.82/t (2H); HPLC: tret=1 1.64 min (Grad 1).
Reaction SMILES: [I-].[K+].[CH2:3]([S:5][C:6]1[C:11]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[N:13][CH2:14][C:15]3[N:16]([C:17]([CH2:20]Cl)=[N:18][N:19]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:4].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>O1CCCC1>[CH2:3]([S:5][C:6]1[C:11]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[N:13][CH2:14][C:15]3[N:16]([C:17]([CH2:20][NH:32][CH:29]4[CH2:31][CH2:30]4)=[N:18][N:19]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:4]
Reactant: NC1CC1
Reactant: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, a potassium iodide and 7-(ethylthio)-1-(chloromethyl)-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 7-(ethylthio)-1-[(cyclopropylamino)methyl]-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[N:60]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[N:60]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1[N+](=O)[O-]
Yield: 13.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 32, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 2-aminoquinoline (95 mg, 0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C. overnight. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-quinolin-2-yl-propionamide (28 mg, 13.6%) as a white foam: mp 102-106° C. (foam to gel); EI-HRMS m/e calcd for C24H25N3O5S (M+) 467.1515, found 467.1513.
Reaction SMILES: [CH3:1][C@H:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]#[CH:4].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].C(N(C(C)C)C(C)C)C>C(#N)C.[Cu]I>[C:8]([O:7][C:6](=[O:12])[NH:5][C@H:2]([C:3]1[N:15]=[N:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:4]=1)[CH3:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1
Reactant: C#C[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)c1cn(-c2ccc(Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of (S)-tert-butyl but-3-yn-2-ylcarbamate (250 mg, 1.48 mmol), 1-azido-4-chlorobenzene (227 mg, 1.48 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.77 mL, 4.43 mmol, 3.0 equiv) in anhydrous acetonitrile (14.8 mL) was stirred at room temperature for 10 min. Copper(I) iodide (563 mg, 2.95 mmol, 2.0 equiv) was then added in portions. The mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic extracts were washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (S)-tert-butyl(1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (0.428 g, white solid) in 90% yield. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 5.02 (m, 1H), 1.63 (d, J=6.8 Hz, 3H), 1.46 (s, 9H). MS m/z 323.1 (M+H)+; Rt-0.92 min.