Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.O.[CH3:19][N:20]1CCCC1=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[CH:12]1([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:19]#[N:20])[CH:11]=3)[CH2:6][CH2:7][N:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN1CCCC1=O
Reactant: Brc1ccc2c(c1)C(C1CCCCC1)=NCC2
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ccc2c(c1)C(C1CCCCC1)=NCC2
Temperature: 120 °C
Reaction time: 18 h

Procedure:
7-bromo-1-cyclohexyl-3,4-dihydroisoquinoline (9.47 g) was dissolved in N-methyl-2-pyrrolidone (150 mL) to which tris(dibenzylideneacetone)dipalladium (2.97 g), 1,1′-bis(diphenylphosphino)ferrocene (7.19 g), and zinc cyanide (11.5 g) were then added, followed by stirring at 120° C. for 18 hours. Then, water was added to the reaction liquid which was then filtered through celite to separate the insoluble materials. The insoluble materials were extracted with EtOAc, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1-cyclohexyl-3,4-dihydroisoquinoline-7-carbonitrile (7.19 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:26][N:27](C=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Zn+2].C([O-])(=O)C.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:26]#[N:27])[CH:19]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nnn(-c2cccc(Br)c2)n1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nnn(-c2cccc(C#N)c2)n1
Yield: 43 %

Procedure:
The title compound of Example 13.1 (4.97 g, 12.61 mmol), dppf (0.042 g, 0.076 mmol), zinc cyanide (0.89, 7.57 mmol), Pd2(dba)3 (0.026 g, 0.025 mmol), zinc acetate (0.185 g, 1.01 mmol) and Zn dust (0.066 g, 1.01 mmol) were stirred in DMF (50 mL) and water (1.5 mL) for 12 h at 90° C. and a further 6 h at 120° C. The reaction mixture was partitioned between ethyl acetate and water. The organic extracts were dried over sodium sulphate, filtered and concentrated and purified by column chromatography to afford the title product (1.83 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:17])(=[O:16])[NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH3:27]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:17])(=[O:16])[NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:27])=[O:5]
Reactant: N
Reactant: O=C(O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Yield: 91 %

Procedure:
The title compound was prepared by following procedure as described for step-2 of Intermediate-26 by using 2-chloro-5-(N-cyclopropylsulfamoyl)benzoic acid (3.0 g, 10.0 mmol), DCM (30 mL), oxalyl chloride, ammonia gas (1.2 mL, 13.0 mmol), DMF (2-3 drop) and THF (40 mL) to afford 2.500 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.41 (m, 2H), 0.47-0.51 (m, 2H), 2.12 (m, 2H), 7.74-7.82 (m, 4H), 8.11 (br s, 2H); MS (m/z): 273.00 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27](OS(C(F)(F)F)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.[CH3:48][NH:49][C:50]([CH2:52][CH2:53][CH2:54][C:55]#C)=[O:51].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:25]=[CH:26][C:27]([C:55]#[C:54][CH2:53][CH2:52][C:50](=[O:51])[NH:49][CH3:48])=[CH:28][CH:29]=4)[CH2:22][CH2:21][N:20]([C:38]([O:40][CH2:41][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[O:39])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1
Reactant: C#CCCCC(=O)NC
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CCC#Cc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 45 °C
Reaction time: 36 h

Procedure:
The mixture of 0.124 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-(4-trifluoromethanesulphonyloxyphenyl)piperidine-1-carboxylate (Example 265b), 0.0305 g of N-methylpent-4-ynecarboxamide, 0.0797 g of N,N-diisopropylethylamine, 0.0136 g of bis(triphenylphosphine)palladium(II) chloride, 0.0038 g of copper(I) iodide and 1.0 ml of N,N-dimethylformamide is stirred under argon at 45° C. over 36 hours. The reaction mixture is cooled, poured onto saturated aqueous sodium hydrogencarbonate solution (20 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases are washed with brine (30 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (EtOAc); Rt=4.86.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[Cl:26][CH:27]([CH3:31])[C:28](Cl)=[O:29]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:26][CH:27]([CH3:31])[C:28]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23])=[O:29]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: CC(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(Cl)C(=O)Nc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
To a mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole (8.0 g, 19.0 mmol) in toluene was added 2-chloropropionyl chloride (3.62 g, 28.5 mmol), then zinc chloride (0.77 g, 5.7 mmol). The mixture was heated at reflux for 16 hours. After extractive workup and recrystallisation with heptane-ethyl acetate (1:1) the title product was obtained (7.02 g), 19F-NMR: −43.7; −64.2 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][CH:12](C)[CH3:13])[N:3]=1.ClC1N=C(N(OC)CCC)N=C(N(OC)CCC)N=1.COC1N=C(NC(C)C)N=C(NC(C)C)N=1.ClC1N=C(NCC)N=C(NCCCOC)N=1.CSC1N=C(NC(C)C)N=C(NC(C)C)N=1.CSC1N=C(NCC)N=C(NC(C)C)N=1.ClC1N=C(NC(C)C)N=C(NC(C)C)N=1.COC1N=C(NCC)N=C(NC(C)C)N=1.CSC1N=C(NCCOC)N=C(NC(C)C)N=1.NN1C(=O)C(C(C)(C)C)=NN=C1SC>>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH2:12][CH3:13])[N:5]=[C:6]([NH:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCNc1nc(Cl)nc(NC(C)C)n1
Agent: CC(C)Nc1nc(Cl)nc(NC(C)C)n1
Agent: CCCN(OC)c1nc(Cl)nc(N(CCC)OC)n1
Agent: CCNc1nc(Cl)nc(NCCCOC)n1
Product: CCNc1nc(Cl)nc(NCC)n1

Procedure:
2-chloro-4-ethylamino-6-isopropylamino-s-triazine; 2-chloro-4,6-bis(methoxy-n-propylamino)-s-triazine; 2-methoxy-4,6-bis(isopropylamino)-s-triazine; 2-chloro-4-ethylamino-6-(3-methoxy-n-propylamino)-s-triazine; 2-methylmercapto-4,6-bis(isopropylamino)-s-triazine; 2-methylmercapto-4,6-bis(ethylamino)-2-triazine; 2-methylmercapto-4-ethylamino-6-isopropylamino-s-triazine; 2-chloro-4,6-bis(isopropylamino)-s-triazine; 2-methoxy-4-ethylamino-6-isopropylamino-s-triazine; 2-methylmercapto-4-(2-methoxyethylamino)-6-isopropylamino-s-triazine; 4-amino-6-(t-butyl)-3-(methylthio)-1,2,4-triazine-5(4H)-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Br[CH2:9][CH:10](OCC)OCC.Br>C(O)C>[N:7]1[CH:9]=[CH:10][N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: Nc1cnccn1
Reactant: CCOC(CBr)OCC
Agent: Br
Solvent: CCO
Product: c1cn2ccnc2cn1
Yield: 24 %

Procedure:
2-Pyrazinamine (9.51 g, 100 mmol) was dissolved in ethanol (300 ml) and 2-bromo-1,1-bis(ethyloxy)ethane (21.06 ml, 140 mmol) was added. 48% hydrobromic acid (33.3 ml) was added and the mixture heated at reflux for 24 hr. The solution was concentrated in vacuo to a crude solid that was basified with 10% ammonia-ice (300 ml). The solution was extracted in to ethyl acetate (3×300 ml), the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid, (4.76 g). The solid was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100% [25% 2M ammonmia/methanol in dichloromethane] in dichloromethane gradient) to afford imidazo[1,2-a]pyrazine (2.86 g, 24.01 mmol, 24.01% yield).).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([NH2:29])=[N:31][CH:32]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.49) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.174 g, 73%). MS (ISP) 475.1 [(M+H)+]; mp 207° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[NH:17][C:16](=[O:18])[C:15]([F:19])=[CH:14][N:13]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:12]1[NH:17][C:16](=[O:18])[C:15]([F:19])=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(Cl)ncc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(OCc2ccccc2)ncc1F
Yield: 78.2 %

Procedure:
A 100 ml quantity of benzyl alcohol and 7.2 g of sodium hydride are added to 100 ml of absolute toluene, and the mixture is refluxed for 1 hour. Subsequently 14.9 g of 2-chloro-5-fluoropyrimidin-4-one is added to the reaction mixture, and the resulting mixture is heated in a sealed tube at 140° to 150° C for 6 hours for reaction. The reaction mixture is further treated in the same manner as in Example 6 to give 17.2 g of white crystalline 2-benzyloxy-5-fluoropyrimidin-4-one in a yield of 78.2 %, m.p. 146°-147° C.
Reaction SMILES: [O:1]=[C:2]=[N:3][CH:4]1[CH2:13][C:12](C)(C)[CH2:11][C:6](C)([CH2:7][N:8]=[C:9]=[O:10])C1.[N-]=C=O.O>>[CH2:7]([N:8]=[C:9]=[O:10])[CH2:6][CH2:11][CH2:12][CH2:13][CH2:4][N:3]=[C:2]=[O:1]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: [N-]=C=O
Solvent: O
Product: O=C=NCCCCCCN=C=O
Temperature: 60 °C

Procedure:
The mixture was heated to be at 70° C., and a mixture of 178 parts by mass of isophorone diisocyanate and 244 parts of hexamethylene-1,6-diisocyanate was added thereto, and a resultant mixture was stirred at 80° C. to 90° C. until a content of isocyanate thereof became 5.6% by mass. The prepolymer was cooled to 60° C., and 56 parts by mass of biuret polyisocyanate obtained from 3 mol of hexamethylene diisocyanate and 1 mol of water and 175 parts by mass of bisketimine obtained from isophorone diamine and acetone were sequentially added to obtain an aqueous dispersion of polyurethane.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)=[O:4].[OH-].[Na+]>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)Nc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Nc1ccc(C(=O)O)cc1
Yield: 53.9 %

Procedure:
To a suspension of methyl 4-(methoxycarbonyl)aminobenzoate (1.5 g, 7.17 mmol) in 10 mL of deionized water was added 1N sodium hydroxide (7 mL, aqueous) and the mixture was heated to 60°-70° C. for 8 h. The reaction mixture was filtered and the filtrate was neutralized with 6N HCl. The precipitated solid was separated through filtration, dried in air followed by drying in a pistol at acetone reflux in vacuo to give 754 mg (54%) of the title compound as a white solid, mp 195°-196° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)#[N:12].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:8]/[N:7]=[CH:6]/[C:5]1[CH:9]=[CH:10][C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:11]#[N:12])[CH:18]=2)=[CH:3][CH:4]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: ON=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccc(/C=N/O)cc2)c1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To a stirred solution of 4-bromobenzaldehyde (3.0 g, 16.2 mmol) in ethanol (100 mL) and water (25 mL) was added sodium acetate (1.7 g, 21.0 mmol) and hydroxylamine hydrochloride (1.4 g, 19.5 mmol). The resulting mixture was heated to reflux for 2 hours. The solution was allowed to cool to room temperature, concentrated, and filtered to give 4-bromobenzaldehyde oxime (3.02 g, 93%). 4-Bromobenzaldehyde oxime (0.25 g, 1.25 mmol) was added to a stirred solution of 3-cyanophenyl boronic acid (0.28 g, 1.87 mmol) in glyme (13 mL). Sodium carbonate (0.39 g, 3.75 mmol) in water (2 mL) and tetrakis(triphenylphosphine) palladium (0) (0.07 g, 0.06 mmol) was added and the resulting solution was heated to reflux for 3 hours. The solution was cooled to room temperature and partitioned between a saturated ammonium chloride solution (100 mL) and ethyl acetate (150 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 4′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-3-carbonitrile as a white solid (0.17 g, 61%). MS m/z 223; HRMS: calcd for C14H10N2O+H+, 223.08659; found (ESI, [M+H]+), 223.087; Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.49; H, 4.98; N, 12.51.
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].C(SCl)C.[CH3:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][CH:21]=3)[N:17]([CH2:31][CH2:32][CH3:33])[CH2:16]1>ClCCl>[CH3:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][C:21]=3[S:8][CH3:9])[N:17]([CH2:31][CH2:32][CH3:33])[CH2:16]1
Reactant: CCCN1C[C@H](C)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CSSC
Agent: CCSCl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCN1C[C@H](C)C[C@@H]2c3cccc4[nH]c(SC)c(c34)C[C@H]21
Reaction time: 8 h

Procedure:
A solution of sulphuryl chloride (0.74 g) in dichloromethane (15 ml) was added dropwise over 15 minutes at -20° C. to a stirred solution of dimethyl disulphide (0.46 g) in dichloromethane (15 ml). After allowing it to reach room temperature the solution of ethyl sulphenyl chloride was added dropwise to a suspension of 8β-methyl-6-propylergoline (2.4 g), in dichloromethane (150 ml) at -70° C. The reaction mixture was stirred and allowed to reach room temperature overnight. Ice cold ammonia solution was added and the mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated to dryness. Chromatography on neutral alumina (CH2CH2) and crystallisation from ethanol gave the title compound. The free base was converted to its maleate salt and crystallised from ethanol, m.p. 216°-219° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])/[CH:6]=[CH:7]\[C:8]([O:10]CC)=O>C(O)CC>[O:10]=[C:8]1[NH:4][CH2:1][CH2:2][NH:3][CH:7]1[CH2:6][C:5]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NCCN
Solvent: CCCO
Product: CCOC(=O)CC1NCCNC1=O

Procedure:
Ethylenediamine (1.17 ml, 17.42 mmol) and diethyl maleate (3 g, 17.42 mmol) were stirred for 16 h at 55° C. in propanol (30 ml). The solvent was removed in vacuo and the residue was dried in vacuo. The product was used in the next stage without being purified further.
Reaction SMILES: C(O)=O.[C:4]1([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[N:22][N:23]=[C:13]3[CH:12]([NH2:24])[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:24][CH:12]2[N:11]=[C:10]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[N:22][N:23]=[C:13]23)=[O:34])=[CH:28][CH:27]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2-n2cnnc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2-n2cnnc21
Reaction time: 8 h

Procedure:
6-Phenyl-4H-[1,2,4]triazolo-[4,3-a][1,4]benzodiazepin-4-ylamine formate salt (200 mg, 0.38 mmole) was combined with 4-chlorophenylisocyanate (57 mg, 0.37 mmole) and triethylamine (57 μL) in 10 mL of dry tetrahydrofuran. The mixture was allowed to stand at room temperature overnight. The analytically pure product, which crystallized from solution was collected and dried: m.p. 294°-296° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH2:20][C:19]2[N+:18]([O-])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([O:26][CH:20]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:21]1)(=[O:25])[CH3:24]
Reactant: O=C(NC1CCc2c(ccc[n+]2[O-])C1)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC1CC(NC(=O)OCc2ccccc2)Cc2cccnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
6-Benzyloxycarbonylamino-5,6,7,8-tetrahydroquinoline 1-oxide (1.62 g, 5.44 mmol) was dissolved in acetic anhydride (7.7 mL, 81.6 mmol), and the reaction mixture was stirred at 60° C. for 2 h under nitrogen. After this time, the solvent was removed under vacuum to yield a residue, which was dissolved in methylene chloride. The resulting solution was washed sequentially with water, saturated aqueous sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to obtain the title compound (1.73 g, 93%) as a brown oil. HPLC/MS [M+H]+, 341.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])[CH3:3]>CO.[H][H]>[CH3:4][C:2]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O

Procedure:
Boc-Orn--OH (0.51 g) (obtained by catalytically reducing Boc-Orn(Z)--OH in methanol in a stream of hydrogen using 10% Pd-carbon as a catalyst) was dissolved in DMF, and the solution was cooled with ice. TEA (0.61 ml) and PhCOONB (prepared from PhCOOH (0.30 g), HONB (0.47 g) and DCC (0.54 g)) were added thereto, followed by stirring overnight. The reaction solution was concentrated, and the residue was dissolved in AcOEt. The resulting solution was washed with 10% aqueous citric acid. After washing with water, the solution was dried with Na2SO4 and concentrated. Then, ether and dicyclohexylamine (438 μl) were added to the residue to separate out a precipitate, which was collected by filtration.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:20][OH:21])=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.Br.C(O)(=O)C>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:19](=[CH:20][OH:21])[C:18]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=2)=[O:29])=[CH:27][CH:26]=1
Reactant: COc1cc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)ccc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
1.60 g (3.66 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl)acrylamide, 925 mg (5.49 mmol) of 48% hydrobromic acid and 15 ml of acetic acid were mixed and stirred at 80° C. for 1.5 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 600 mg of 2-(4-chlorophenyl)-3-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]acrylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[H-].[Na+].Cl[S:19]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=2[C:23]=1[CH3:32])(=[O:21])=[O:20]>C1COCC1>[F:31][C:29]1[CH:28]=[CH:27][C:25]2[S:26][C:22]([S:19]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:20])=[O:21])=[C:23]([CH3:32])[C:24]=2[CH:30]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(F)cc3c2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Into 300 mL of THF was dissolved 14.0 g of methyl 4-amino-3-methanesulfonylbenzoate, followed by addition of 6.10 g of sodium hydride (oily, 60%) at 0° C. After 40 minutes of stirring at the same temperature, 16.0 g of 2-chlorosulfonyl-5-fluoro-3-methylbenzo[b]thiophene was added at 0° C. followed by 3 hours of stirring at room temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding 2 mol/L hydrochloric acid at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was diluted with ethyl acetate. After the solution was treated with active carbon, purification by recrystallization (ethyl acetate/ether) afforded 24.8 g of the title compound as colorless powder.