Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([NH2:26])=[O:25])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[F:15])=[CH:11][C:10]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:9][CH:8]=3.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[F:15][C:14]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:11]=3)[NH:6][C:5]=2[C:4]([C:24]([NH2:26])=[O:25])=[CH:3][C:2]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)c1cc(Br)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-c2ccccc2)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 105 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
3-Bromo-4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (25 mg, 0.059 mmol), phenylboronic acid (10.88 mg, 0.089 mmol), Pd(Ph3P)4 (6.87 mg, 5.95 μmol) and Na2CO3(2M) (0.074 mL, 0.149 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was stirred at 105° C. for 3 hrs. The mixture was filtered through a ACRODISC® PTFE membrane (0.45 um) and purified using preparative HPLC to give 9.7 mg of 4-fluoro-6-(morpholine-4-carbonyl)-3-phenyl-9H-carbazole-1-carboxamide. MS (ESI) m/z 418.06 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.9 (bs, 1H), 8.32 (bs, 1H), 8.19 (d, 1H, J=7.1), 8.15 (s, 1H), 7.84 (d, 1H, J=8.6), 7.72 (d, 2H, J=7.3), 7.62-7.53(m, 4H), 7.43 (t, 1H, J=7.3), 3.7-3.5 (bm, 8H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:15]=C([CH:19]=[CH:20][CH:21]=3)C#N)[CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:23]([OH:26])(=[O:25])[CH3:24]>>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:24]([CH:19]=[CH:20][CH:21]=3)[C:23]([OH:26])=[O:25])[CH:11]=[CH:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: N#Cc1cccc(-c2ccnc(Nc3ccccc3)n2)c1
Agent: Cl
Product: O=C(O)c1cccc(-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 100 °C
Yield: 84 %

Procedure:
To a suspension of 3-(2-phenylamino-pyrimidin-4-yl)-benzonitrile (10 g, 36.7 mmol) in acetic acid (20 mL) was added concentrated hydrochloric acid (30 mL) and the suspension was heated at 100° C. overnight. The starting material completely dissolved and then a solid precipitated. The reaction mixture was filtered and precipitate was washed with ether and methanol to afford 9 g (84%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:67])[C@:4]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[S:54]([C:57]1[S:61][C:60]([NH:62]C(=O)C)=[N:59][C:58]=1[CH3:66])(=[O:56])=[O:55])=[O:23])([CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.COC(=O)[C@](NC(C1CC2C=C3OC[C@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)OC3=CC=2CN1S(C1SC(N)=NC=1C)(=O)=O)=O)(C)CC1C=CC(C2C=CC(C#N)=CC=2)=CC=1>>[NH2:62][C:60]1[S:61][C:57]([S:54]([N:25]2[CH:24]([C:22]([NH:21][C@@:4]([CH3:20])([CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=4)=[CH:10][CH:11]=3)[C:3]([OH:67])=[O:2])=[O:23])[CH2:33][C:32]3[CH:31]=[C:30]4[O:34][CH2:35][C@H:36]([C:38]5[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]6[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=6)=[CH:40][CH:39]=5)[O:37][C:29]4=[CH:28][C:27]=3[CH2:26]2)(=[O:56])=[O:55])=[C:58]([CH3:66])[N:59]=1
Reactant: COC(=O)[C@](C)(Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: COC(=O)[C@](C)(Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: Cc1nc(N)sc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@](C)(Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methyl ester was converted to (S)-2-({(S)-7-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methyl ester according to General Procedure N. This ester, upon hydrolysis according to General Procedure B, gave the title compound. LCMS (m/z): 927.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)[CH3:3].[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26])#[N:21].CCN=C=NCCCN(C)C>ClCCl>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:13][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH2:2][CH3:3])=[N:5][N:6]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)=[O:26])#[N:21]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CCc1nn(-c2ccccc2)c2cc(N)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCc1nn(-c2ccccc2)c2cc(NC(=O)c3cccc(C#N)c3)ccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-1H-indazol-6-amine hydrochloride (1 g, 3.60 mmol, 1.00 equiv, 98%) in dichloromethane (50 mL), 3-cyanobenzoic acid (646.8 mg, 4.31 mmol, 1.20 equiv), TEA (445 mg, 4.31 mmol, 1.20 equiv), EDCI (845 mg, 4.31 mmol, 1.20 equiv). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). The collected fractions were combined and concentrated under vacuum to yield 3-cyano-N-(3-ethyl-1-phenyl-1H-indazol-6-yl)benzamide as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](#[N:22])[CH:20]=[CH2:21]>C(O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][NH:16][CH2:21][CH2:20][C:19]#[N:22])=[O:14])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: C=CC#N
Solvent: CCCO
Product: N#CCCNNC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 88 %

Procedure:
To a solution of 100 mmoles of (4-benzyloxy benzoyl) hydrazine in 200 ml of 1-propanol, 100 mmoles of acrylonitrile are added and the mixture is heated for 24 hours at reflux. Then 50 mmoles of acrylonitrile are added and the heating is continued at reflux for 24 hours. After cooling, the product is filtered and recrystallized in a water-ethanol mixture and 26 g (yield: 88%) of the expected product were obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1nc2ccccc2s1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4nc5ccccc5s4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-benzothiazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-benzothiazol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:20][C:21](=[O:31])[NH:22][O:23]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:20][C:21]([NH:22][OH:23])=[O:31])[C:8]([N:10]2[C@H:14]([C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)[C@@H]1CC=NN1C(=O)[C@@H](CC(=O)NOCc1ccccc1)CC1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)[C@@H]1CC=NN1C(=O)[C@@H](CC(=O)NO)CC1CCCC1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N,N-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxamide (120 mg, 0.28 mmol) in methanol (10 mL) was added Pearlman's catalyst (39 mg, 0.056 mmol). The resulting mixture was stirred under 1 atm of H2 for 1 hour. After 1 hour, the mixture was filtered, concentrated, and purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-[(2R)-2-(cyclopentylmethyl)-4-(hydroxyamino)-4-oxobutanoyl]-N,N-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxamide (78 mg, 0.23 mmol, 82% yield) as a yellow solid. MS: 389 ([M+H]+). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09-1.26 (m, 2H) 1.59 (br. s., 35H) 1.78-1.97 (m, 5H) 2.43-2.52 (m, 1H) 2.62-2.73 (m, 1H) 2.85-2.95 (m, 1H) 3.01 (s, 3H) 3.19 (s, 4H) 3.58-3.67 (m, 1H) 5.08-5.18 (m, 1H) 6.88-6.97 (m, 1H).
Reaction SMILES: [H][H].C([O:10][NH:11][C:12](=[O:33])[CH:13]([CH3:32])[C:14]1([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[OH:10][NH:11][C:12](=[O:33])[CH:13]([CH3:32])[C:14]1([CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27]
Reactant: [H][H]
Reactant: CC(C)CC1(C(C)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC1(C(C)C(=O)NO)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
An atmosphere of hydrogen is placed over a mixture of N-benzyloxy-α-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (80.0 mg, 0.189 mmol), MeOH (4.5 mL) and Pearlman's catalyst (15 mg). The mixture is stirred at room temperature for 4 hours. The mixture is filtered, the solids rinsed with MeOH (4×5 mL), and the filtrate concentrated to give 55.9 mg of an oil. Crystallization from hexane provided 46.9 mg (75%) of the title compound as a white solid (mp 107°-108° C.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10](O)[CH3:11].S(Cl)([Cl:15])=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([Cl:15])[CH3:11]
Reactant: CC(O)c1nc2ccccc2s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-benzothiazolyl)ethanol (2.5 g) prepared according to J. Indian Chem. Soc., 566 (1974) in methylene chloride (50 ml) was added thionyl chloride (3.32 g) and the resulting solution stirred at room temperature for 1 hour. The solution was poured onto ice-water (100 ml) and the organic extract separated. This extract was washed with aqueous bicarbonate (10 ml of a 5% solution) and then with water (50 ml). The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated to a light yellow oil (2.08 g).
Reaction SMILES: [CH3:1][S:2]SC.[CH:5]1[C:18]2[C:9](=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][S:2][C:17]1[C:18]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CSSC
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: CSc1c2ccccc2cc2ccccc12

Procedure:
For example, in acetonitrile, dimethyl disulfide shows an irreversible first oxidation peak at 1.05 V vs Ag/O.1M AgNO3 in acetonitrile reference electrode using the technique of cyclic voltimetry. The oxidation peak of anthracene is about 400 mV more positive than that for dimethyl disulfide. Consequently, pursuant to this invention, dimethyl disulfide can be selectively oxidized electrolytically in the presence of anthracene to produce the organothiated product, 9-methylthioanthracene, in very good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)=[O:10].[OH-].[Na+].C1COCC1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: CCOC(=O)Cc1ccc(NC(=O)N2CCc3ccccc32)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)N2CCc3ccccc32)c(Cl)c1
Yield: 60.4 %

Procedure:
To ethyl 3-chloro-4-(1-indolinylcarbonylamino)phenylacetate (3.07 g, 8.56 mmol) were added 0.25N NaOH (68.4 ml, 17.1 mmol) and THF (70 ml). The mixture was heated and refluxed for 4 hours. After cooling, the reaction mixture was poured in 1N hydrochloric acid (50 ml). The crystals thus precipitated were collected by filtration, and dried under reduced pressure for 12 hours, whereby 3-chloro-4-(1-indolinylcarbonylamino)phenylacetic acid (1.71 g, 60%) was obtained as a colorless crystalline powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][O:21][CH:22]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:23]([O:25][CH3:26])=[O:24])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41]>>[ClH:41].[C:14]1([C:11]2([CH2:20][O:21][CH:22]([C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[C:23]([O:25][CH3:26])=[O:24])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: COC(=O)C(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 24 h

Procedure:
The product of step (c) above was dissolved in saturated methanolic hydrogen chloride, and allowed to stand at room temperature for 24 hours. The solvents were evaporated at reduced pressure then toluene was added to the residue and evaporated at reduced pressure to afford the title compound as a colourless foam. Analysis Calcd. for C23H23 F6NO3.HCl. 0.5(H2O): C, 53.03; H, 4.84; N, 2.69; Found: C, 52.78; H, 4.75; N, 2.75%. MS (Cl+) 476 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11](CS(N)(=O)=O)[CH:12]=[CH:13][CH:14]=2)[N:3]=1.ClC1N=C(Cl)N=CN=1.NC1C=C([S:35]([NH2:38])(=[O:37])=[O:36])C=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: Clc1ncnc(Cl)n1
Product: NS(=O)(=O)c1cccc(Nc2ncnc(Cl)n2)c1
Yield: 35 %

Procedure:
A2 was prepared following the general procedure reported for A1 using 2,4-dichloro-1,3,5-triazine and 3-aminobenzenesulfonamide as reacting agents. The crude product was purified by flash chromatography on silica gel (cHex/EtOAc=20:1 to 1:20) to yield the desired product A2 as a white solid (35%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 7.41 (s, 2H), 7.59 (m, 2H), 7.85 (d, J=6.9 Hz, 1H), 8.21 (br.s, 1H), 8.69 (s, 1H), 11.02 (s, 1H). MS (ES) C9H8ClN5O2S requires: 285. found: 286 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:18][C:12]=3[N:11]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)[C:10](=[O:39])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1>[OH-].[Na+].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:18][C:12]=3[N:11]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)[C:10](=[O:39])[CH2:9]2)=[O:7])=[CH:40][CH:41]=1
Reactant: COC(=O)CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10 mg (0.017 mmol) of methyl 3-[4-(4-chlorobenzoyl)-2-oxo-1-(4-(1-pyrrolidinecarbonyl)benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl]propionate was dissolved in a mixture of 5 ml of 1 N sodium hydroxide and 5 ml of ethanol. The obtained solution was stirred at room temperature for 5 hours. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@@H:22]3[O:31][C@H:25]4[O:26]C(C)(C)[O:28][C@H:24]4[C@H:23]3[CH2:32][CH2:33][N:34]3[C:39](=[O:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=[N:35]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(#N)C.C(OCC)(=O)C.O>[OH:28][C@@H:24]1[C@H:25]([OH:26])[O:31][C@@H:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)=[CH:15][CH:16]=2)[C@@H:23]1[CH2:32][CH2:33][N:34]1[C:39](=[O:40])[C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[N:36]=[N:35]1
Reactant: COc1ccc(-c2ccc(CC[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(CC[C@@H]3O[C@@H](O)[C@@H](O)[C@H]3CCn3nnc4ccccc4c3=O)cc2)cc1
Temperature: 55 °C

Procedure:
Perchloric acid (0.2 mL) was added to a solution of the compound obtained from step f above (0.6 g) in acetonitrile (50 mL) and water (10 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using a sodium hydrogen carbonate solution. The solvents were evaporated at reduced pressure. The residue thus obtained was taken in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.6 g).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[F:5][C:6]([F:10])([F:9])[CH:7]=[O:8]>O1CCCC1.[Zn]>[F:5][C:6]([F:10])([F:9])[CH:7]([OH:8])[CH2:3][C:2]#[CH:1]
Reactant: O=CC(F)(F)F
Reactant: C#CCBr
Agent: [Zn]
Solvent: C1CCOC1
Product: C#CCC(O)C(F)(F)F
Yield: 65 %

Procedure:
In a mixture of propargyl bromide (3.46 g, 29 mmol), zinc powder (2.3 g, 0.035 gram-atom) in tetrahydrofuran (60 ml), trifluoroacetaldehyde (1.9 g, 19 mmol) was added under bubbling. An hour later, the reaction mixture was poured into aqueous 2% HCl solution for a similar treatment to the one used in the above Examples. Distillation gave 1,1,1-trifluoro-4-pentyne-2-ol (b.p.: 95°-96° C.) at a yield of 65%. The above product gave the following analytical data:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[N:10]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][CH:13]=1)=[O:8].CN.O.C(OCC)(=O)C>CN(C=O)C>[NH2:14][N:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:8]
Reactant: Cc1ccsc1C(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccsc1C(=O)c1cccn1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 79.4 %

Procedure:
To a solution consisting of 2-[2-[(3-methyl-2-thienyl)carbonyl]-1H-pyrrol-1-yl]-1H-isoindole-1,3(2H)dione (11.5 g) in DMF (30 ml) was added 40% methylamine (aq., 34.0 ml) solution at room temperature. The reaction mixture was stirred at ambient temperature for 3.5 hours, then poured into water and ethyl acetate. The layers were separated and the aqueous phase was extracted thrice with EtOAc. The combined organics were washed with water, brine, and dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, 2:1 heptane/EtOAc), followed by crystallization from ether/pentane afforded 5.6 g of the product as a solid, m.p. 42°-44° C.
Reaction SMILES: [CH2:1]([C:5]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:11]([O:13]CC)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH:3]=[CH2:4].[OH-].[Na+]>C(O)C>[C:20]([O:19][C:17]([NH:16][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH2:1][CH2:2][CH:3]=[CH2:4])[C:11]([OH:13])=[O:12])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: C=CCCC(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCC(NC(=O)OC(C)(C)C)(C(=O)O)C(=O)OCC
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A solution of the diethyl 2-(but-3-enyl)-2-(tert-butoxycarbonylamino)malonate (10.0 g, 30.4 mmol) in ethanol (100 mL) was cooled to 0° C. and treated with aqueous sodium hydroxide (1 N, 31 mL). After stirring for 30 minutes, the cooling bath was removed and stirring was continued for an additional 19 h. The solvent was removed by evaporation and the resulting residue was diluted with water (150 mL) and washed with ethyl acetate (2×100 mL). The aqueous layer was acidified with concentrated hydrochloric acid to pH 2 and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1×100 mL), dried over MgSO4, filtered and concentrated to give 2-(tert-butoxycarbonylamino)-2-(ethoxycarbonyl)hex-5-enoic acid (8.2 g, 82%). 1H NMR (CDCl3) δ 5.87-5.75 (m, 1H), 5.06-5.02 (m, 2H), 4.26 (m, 2H), 2.34 (m, 2H), 1.96-1.93 (m, 2H), 1.43 (s, 9H), 1.29 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([NH:20][C:21]1[S:22][C:23]([C:27]2[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[C:30]([Cl:33])=[N:31][CH:32]=2)=[C:24]([CH3:26])[N:25]=1)(=[O:19])[CH3:18]>C1COCC1>[Cl:33][C:30]1[N:31]=[CH:32][C:27]([C:23]2[S:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[N:25][C:24]=2[CH3:26])=[CH:28][C:29]=1[S:34](=[O:35])(=[O:36])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(S(=O)(=O)Cl)c2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(S(=O)(=O)NCc3ccc(Cl)cc3)c2)s1
Temperature: 0 °C

Procedure:
4-Chlorobenzylamine (0.17 mL) and triethylamine (0.12 mL) were added in turn to a stirred slurry of 5-(2-acetamido-4-methyl-1,3-thiazol-5-yl)-2-chloropyridine-3-sulfonyl chloride (250 mg) in THF (20 mL) that had been cooled to 0° C. The resultant mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic solution was washed with a saturated aqueous sodium chloride solution, filtered, dried over magnesium sulfate and evaporated. The material so obtained was purified by ‘basic reversed-phase chromatography’ (Waters ‘Xterra’ C18 reversed-phase silica, 150×21 mm, solvent gradient of 5-50% acetonitrile in water (containing 1% aqueous ammonium hydroxide (d=0.88) solution). The material so obtained was triturated under diethyl ether, isolated and dried at 55° C. under vacuum. There was thus obtained the title compound as a white solid (155 mg); 1H NMR Spectrum: (DMSOd6) 2.22 (s, 3H), 2.40 (s, 3H), 4.24 (s, 2H), 7.25 (s, 4H), 8.06 (m, 1H), 8.63 (m, 1H), 9.06 (br s, 1H), 12.54 (br s, 11H); Mass Spectrum: M+H+ 471 and 473.