Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[CH3:12][S:13]([NH2:16])(=[O:15])=[O:14].[OH-].[Na+].[CH2:19](O)C.CI>CC(C)=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[N:16][S:13]([CH3:12])(=[O:15])=[O:14])[S:11][CH3:19])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: CS(N)(=O)=O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NS(C)(=O)=O)Nc1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
A mixture of 5 g (0.31 mol) of 4-cyanophenyl isothiocyanate, of 3.8 g (0.04 mol) of methylsulfonamide in 50 cm3 of acetone and of 1.6 g (0.04 mol) of sodium hydroxide in 3 cm3 of water is maintained for two hours at room temperature. The precipitate obtained is filtered, washed with acetone and ethyl ether (2×20 cm3). The final solid is then placed in 50 cm3 of 95% ethanol containing 2.75 cm3 (0.044 mol) of methyl iodide. After 24 hours at room temperature, the solution is concentrated to dryness and the residue is washed with ethyl ether (3×20 cm3) and dried in vacuo to produce N-(4-cyanophenyl)-N'-methylsulfonyl-S-methylisothiourea.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:33]=[CH:32][C:31]4[NH:30][C:29](=[O:34])[C:28]5[NH:35][CH:36]=[CH:37][C:27]=5[C:26]=4[CH:25]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=O)(C)(C)C.[CH2:38]([C:40]([O-:42])=[O:41])[CH3:39]>ClC(Cl)C>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:33]=[CH:32][C:31]4[NH:30][C:29](=[O:34])[C:28]5[NH:35][CH:36]=[CH:37][C:27]=5[C:26]=4[CH:25]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.[CH2:38]([C:40]([O-:42])=[O:41])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(-c3ccc4[nH]c(=O)c5[nH]ccc5c4c3)ccc21
Agent: CCC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccc(-c3ccc4[nH]ccc4c3)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
1 mL of trifluoroacetic acid is added to a solution of 70 mg (0.15 mmol) 8-(1-tert-butoxycarbonyl-1H-indol-5-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 4 mL of dichloroethane. The solution is stirred for 2 hours at room temperature then the precipitate that forms is filtered and washed with diethyl ether to give 26 mg (45%) of 8-(1H -indol-5-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:17][OH:18].Cl.C(O)(=O)C>C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:17][OH:18])[CH2:12][N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(=O)C[N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(C[N+](=O)[O-])=NO)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-methanesulfonyl-phenyl)-2-nitro-ethanone (12.5 g, 51.4 mmol) in ethanol (100 mL), was added NH2OH.HCl (3.57 g, 51.4 mmol) and acetic acid (33 mL) at room temperature. The reaction was refluxed for 3 h and cooled to room temperature. The reaction was concentrated under vacuum and extracted with ethyl acetate (200 mL). The reaction was concentrated to afford the crude compound which was recrystallized from petroleum ether/hexane (1/3) as white crystals (10.3 g, 83.4%). 1H NMR (400Mz, DMSO-d6) δ 12.81 (s, 1H), 8.03 (m, 4H), 5.93 (s, 2H), 3.28 (s, 3H). LCMS 259.2[M+H].
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]#[C:23][NH2:24].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(NC2CCCCC2)=S)CCCCC1>C(#N)C.C(N(CC)CC)C>[C:23]([NH:24][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[N:22]
Reactant: N#CN
Reactant: S=C(NCCCCOc1ccccc1)Nc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: S=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CNC(=Nc1cccnc1)NCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(4-Phenoxybutyl)-N'-3-pyridylthiourea (1.41 g) was dissolved in acetonitrile (10 ml), and cyanamide (400 mg), N,N'dicyclohexylcarbodiimide (1.95 g) and triethylamine (0.08 ml) were added. The mixture was stirred for 3 days at room temperature, when it was filtered, washed with acetonitrile, and ether to yield a solid mixture of the crude product and N,N'-dicyclohexylthiourea. The pure compound was obtained by extracting the mixture with 0.5N hydrochloric acid (16 ml), filtering and re-precipitation by addition of 9N sodium hydroxide to the filtrate.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.Cl[C:15]1[C:20]([S:21]([N:24]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[C:25]2[C:30]([O:31][CH3:32])=[N:29][C:28]([CH3:33])=[CH:27][N:26]=2)(=[O:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C>[CH:1]1([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([C:15]3[C:20]([S:21]([N:24]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[C:25]4[C:30]([O:31][CH3:32])=[N:29][C:28]([CH3:33])=[CH:27][N:26]=4)(=[O:22])=[O:23])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(CC2CC2)cc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC2CC2)cc1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
4-(cyclopropylmethyl)benzeneboronic acid (1.5 g), 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (2.99 g) and sodium carbonate (912 mg) were added to a mixture of toluene (66 ml), ethanol (33 ml) and water (24 ml). The mixture was deoxygenated by alternatively bubbling argon through and evacuating (3 cycles) and tetrakis(triphenylphosphine) palladium(0) (347 mgs) was added. The reaction mixture was heated to 80° C. for 18 hours with efficient stirring and, after cooling, ethyl acetate (50 ml) and water (30 ml) were added. The organic phase was separated and the aqueous layer extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with brine (15 ml), dried (MgSO4) and evaporated. The residue was purified by chromatography on a Mega Bond Elut column, eluting with a gradient of ethyl acetate in hexane (0-100%) to give 2-(4-cyclopropylmethylphenyl)-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.85 g); 1H NMR (d6 -DMSO): 0.25 (q, 2H), 0.54 (m, 2H), 1.03 (M, 1H), 1.64 (m, 1H), 2.55 (s, 3H), 2.60 (d, 2H), 3.83 (d, 2H), 3.98 (s, 3H), 7.33 (d, 2H), 7.46 (d, 2H), 7.77 (dd, 1H), 8.15 (s, 1H), 8.10-8.95 (m, 2H); mass spectrum (+ve ESP) 511 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl.O>[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([C:20]([C@H:17]2[CH2:16][CH2:15][C@H:14]([CH2:13][NH:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[CH2:19][CH2:18]2)=[O:22])[CH2:46][CH2:45]1
Reactant: CN1CCNCC1
Reactant: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)CC1
Reaction time: 1 h

Procedure:
200 mg (0.54 mmol) of trans-4-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid, 210 mg (1.09 mmol, 2 eq) of EDCI, 221 mg (2.2 mmol, 4 eq) of Et3N and 274 mg (2.74 mmol, 5 eq) of 1-methyl-piperazine were dissolved in 5 mL of CH2Cl2. After 70 h reaction at RT, 1 mL of H2O was added and the reaction mixture was stirred vigorously for 1 h. The organic phase was separated, the aqueous phase was extracted with 10 mL of CH2Cl2 and the combined organic phases were washed with H2O and brine. After drying over anhydrous Na2SO4, the organic phase was evaporated. The residue was chromatographed on silicagel with CH2Cl2:MeOH:25% NH4OH (9:1:0.1) as eluent. 120 mg (49%) of trans-N-[4-(4-methyl-piperazine-1-carbonyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide were obtained as colorless amorphous solid, MS: 448 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14].C(O)(C(F)(F)F)=O>C(OC(C)=O)(C)C>[Cl:9][C:5]1[CH:6]=[C:7]([NH:8][CH:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CCC(=O)CC
Reactant: Nc1cc(Cl)cnc1N
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)Nc1cc(Cl)cnc1N
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 2,3-diamino-5-chloropyridine (7.0 g, 48.6 mmol, 1.0 equiv) and 3-pentanone (6.16 mL, 58.3 mmol, 1.2 equiv) in iPrOAc (100 mL) was added TFA (7.2 mL, 97.2 mmol, 2.0 equiv) by syringe. After stirring for 10 min, NaHB(OAc)3 (20 g, 97.2 mmol, 2.0 equiv) was added as a solid in several portions over ˜5 min. The reaction was allowed to stir overnight. The reaction mixture was then washed with satd. aq. NaHCO3 and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (10%-40% EtOAc/Hexanes) provided 5-chloro-N3-(pentan-3-yl)pyridine-2,3-diamine as a beige solid (2.6 g, 25%). m/z=214.1 [M+H]+
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[CH2:22]([C:24]([C:33]1[CH:46]=[CH:45][C:36]([O:37][CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[C:35]([CH3:47])[CH:34]=1)([C:27]1[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:25][CH3:26])[CH3:23].CO.Cl>C1COCC1>[CH2:22]([C:24]([C:33]1[CH:46]=[CH:45][C:36]([O:37][CH2:38][CH:39]([OH:44])[C:40]([CH3:41])([CH3:43])[CH3:42])=[C:35]([CH3:47])[CH:34]=1)([C:27]1[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a mixture of (R)-2-methyl-CBS-oxazaborolidine (0.1 ml, 0.1 mmol, 1M in toluene), borane-N,N-dimethyl aniline complex (0.18 ml, 1 mmol) in THF (5 ml) is added a solution of 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (372 mg, 1 mmol) in THF (5 ml) over a period of m. The reaction is stirred at RT for 2 h and MeOH (2 ml) is added followed by 1N hydrochloric acid. The mixture is extracted with EtOAc and the organic phase is concentrated and chromatographed (Hex to 25% EtOAc/Hex) to give the title compound (305 mg, 82%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]3[N:27]4[CH2:28][CH2:29][NH:30][CH2:31][C:26]4=[N:25][C:19]=3[C:20]([NH2:24])=[N:21]2)=[CH:16][CH:15]=1>CN(C=O)C>[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]3[N:27]4[CH2:28][CH2:29][N:30]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:31][C:26]4=[N:25][C:19]=3[C:20]([NH2:24])=[N:21]2)=[CH:16][CH:15]=1
Reactant: Nc1nc2cc(Br)ccc2c2c1nc1n2CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCn2c(nc3c(N)nc4cc(Br)ccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
Triethylamine (3.82 g, 37.7 mmol) and methanesulfonyl chloride (2.38 g, 20.7 mmol) were sequentially added to a solution of 3-bromo-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine (6.00 g, 18.9 mmol) in DMF (50 mL), and the mixture was stirred at ambient temperature overnight. A precipitate formed and was isolated by filtration, washed with dichloromethane, and dried to provide 600 mg of 3-bromo-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, mp 315-317° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:11]3[N:16]=[C:15]([CH:17]=O)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2].[CH3:29][C:30]1([CH3:40])[NH:35][CH2:34][CH2:33][N:32]([CH:36]2[CH2:39][O:38][CH2:37]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][C:30]1([CH3:40])[CH2:31][N:32]([CH:36]2[CH2:37][O:38][CH2:39]2)[CH2:33][CH2:34][N:35]1[CH2:17][C:15]1[S:14][C:12]2[N:13]=[C:8]([N:7]3[C:6]4[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=4[N:4]=[C:3]3[CH2:1][CH3:2])[N:9]=[C:10]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:11]=2[N:16]=1
Reactant: CC1(C)CN(C2COC2)CCN1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)sc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4COC4)CC3(C)C)sc2n1
Reaction time: 5 h
Yield: 39.7 %

Procedure:
A mixture of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (200 mg, 0.51 mmol), 3,3-dimethyl-1-oxetan-3-ylpiperazine (100 mg, 0.65 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (10 mL) was allowed to stir at r.t. for 1 h before the addition of sodium triacetoxyborohydride (150 mg, 0.71 mmol). The resulting mixture was allowed to stir for 5 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-1%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 813 (111 mg, 40%). LCMS (method G): RT 6.17 min [M+H]+ 549.3. 1H NMR (CDCl3, 400 MHz): δ 8.01-8.00 (1 H, m), 7.75-7.74 (1 H, m), 7.32-7.22 (2 H, m), 4.67 (2 H, t, J=6.47 Hz), 4.59 (2 H, t, J=6.08 Hz), 4.40 (4 H, brd s), 3.87 (6 H, t, J=4.72 Hz), 3.47-3.46 (1 H, m), 3.34 (2 H, q, J=7.47 Hz), 2.75 (2 H, t, J=4.94 Hz), 2.37 (2 H, brd s), 2.15 (2 H, brd s), 1.43 (3 H, t, J=7.47 Hz), 1.20 (6 H, s)
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]1[C:49]([CH3:50])=[CH:48][C:47]([OH:51])=[CH:46][C:45]=1[CH3:52])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@@H:19]([CH2:43][C:44]1[C:49]([CH3:50])=[CH:48][C:47]([OH:51])=[CH:46][C:45]=1[CH3:52])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1c(C)cc(O)cc1C
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
To the solution of 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 299 mg (1.26 mmol) and (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-3-(4-hydroxy-2,6-dimethylphenyl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-9) 404 mg (0.84 mmol) in dichloromethane 5 ml and dimethylformamide 5 ml, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 305 mg (1.26 mmol) was added and stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on Buch silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain the title compound 298 mg (50%).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=[O:34]>ClCCl.C(Cl)(Cl)Cl>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH2:32][Cl:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Dissolve 2-[(triphenylmethyl)thio]ethylamine (5.24 g, 16.4 mmol) and triethylamine (2.76 mL, 19.6 mmol) in 150 mL dichloromethane. Chloroacetyl chloride (1.56 mL, 19.6 mmol) is dissolved in 20 mL chloroform. Being cooled down with an ice bath, slowly drop chloroacetyl chloride into the solution. Then stir the solution at room temperature for 2 hours. Next wash organic phase with followings in turn: 2N hydrochloric acid solution (120 mL), and saturated sodium bicarbonate aqueous solution (100 mL). The organic phase is dehydrated by anhydrous sodium sulfate (Na2SO4) and then is concentrated in vacuo to yield yellow oily N-[2-((Triphenylmethyl)thio) ethyl]-chloroacetamide (5.62 g, 86.6%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.COC1C=CC(C[C:22]2([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28](OCC)=[S:29])=CC=1.[C:42]([O:45]C(=O)C)(=[O:44])[CH3:43]>O1CCCC1>[C:42]([O:45][C:22]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:28]=2[S:29][C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:44])[CH3:43]
Reactant: CCOC(=S)C1CCCCC1(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2sc3c(c2OC(C)=O)CCCC3)cc1
Reaction time: 0.25 h
Yield: 43.4 %

Procedure:
A solution of 1.5 mL (10.7 mmol) of diisopropylamine in 10 mL of dry tetrahydrofuran was cooled to -78° under nitrogen. To this was added 4 mL of 2.5M n-butyllithium (in hexane) and after 15 minutes, a solution of 1.36 g (3 mmol) of ethyl 2,2-bis-(4-methoxyphenyl)methylthiocyclohexanecarboxylate in 5 mL of dry tetrahydrofuran was added and the solution was stirred under N2 for 2 hours. Then 1.5 mL (15 mmol) of acetic anhydride was added and the solution was stirred at room temperature for 1 hour. The solution was partitioned between ether and NaHCO3 and the ether layer was washed with NaHCO3, then brine, and dried over MgSO4. The solution was concentrated and the residue chromatographed on silica gel (20% ethyl acetate-hexane) to afford a colorless oil. This was crystallized from ethyl acetate-hexane to afford 0.394 g (47%) of title compound as a white crystalline solid, m.p. 81° C. NMR (CDCl3, (CH3)4Si) δ1.81 (4H, m), 2.25 (3H, s, CH3CO), 2.35 (2H, t, J=6Hz), 2.71 (2H, t J=6Hz), 3.80 (3H, s, OCH3), 6.90 (2H, AB), 7.39 (2H, AB).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH:18]=[CH:19][N+:20]([O-:22])=[O:21])[C:7]=2[N:23]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.C(Cl)(Cl)Cl.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]3[CH2:11][C:12]4[C:17]([C:9]3=[C:8]([CH2:18][CH2:19][N+:20]([O-:22])=[O:21])[C:7]=2[N:23]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2Cc2ccccc2-1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2Cc2ccccc2-1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 660 mg (2.15 mmol) of the compound obtained in Step F are suspended in 10 ml of isopropanol and 30 ml of chloroform in the presence of 1.5 g of 230-400 mesh silica; 408 mg (10.75 mmol) of sodium borohydride are added slowly. After 30 minutes' stirring at room temperature, acetic acid is added and the reaction mixture is filtered through a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered and concentrated to yield the title compound in the form of a yellow solid.
Reaction SMILES: O[CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:3].N1C=CC=CC=1.P(Br)(Br)[Br:20]>CCOCC>[Br:20][CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:3]
Reactant: CC(O)C#Cc1ccc(Cl)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(Br)C#Cc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
The product prepared in step (d) above (0.05 mol) and dry pyridine (1 ml) are dissolved in dry ether (20 ml) and cooled to 0° C. Phosphorous tribromide (0.025 mol) in 20 ml dry ether is added dropwise with stirring. The reaction mixture is then refluxed for 3 hours. After cooling the mixture to 0°, the excess PBr3 is destroyed by adding crushed ice. The ether layer is washed and dried. The ether is removed and the title product is obtained by distillation.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26]>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:25][OH:26])[CH2:27][CH3:28])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Reactant: CC[C@H](N)CO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 130 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester (9.000 g, 26.45 mmol) and (S)-2-amino-1-butanol (12.7 ml) in 1-methyl-2-pyrrolidinone was heated at 130° C. for 2 hr. then at 100° C. overnight. The mixture cooled to rt and poured into ice-water and diluted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 13.6 g of crude product as a light yellow oil. The oil was purified through silica gel column chromatography using chloroform to 2% MeOH in chloroform as eluent to give 6.6839 g (64%) of the title compound as a white glass foam. The glass foam was triturated with hexane to give a white solid. The solid was recrystallized from di-iso-propyl ether to give a white crystals, mp 122.5-124° C. Anal. calc. for C20H25ClN2O4: C, 61.14; H, 6.41; N, 7.13; found: C, 60.98; H, 6.43; N, 6.95.