Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][S:6](=[O:41])(=[O:40])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([O:17][CH2:18][CH3:19])=[CH:10][C:9]=1[C@@H:20]1[CH2:24][N:23]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])C(=O)[N:21]1[C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)C.[OH-].[Li+].NO.CC[N:49](C(C)C)C(C)C>C(O)C.[Ni].C(O)(=O)C>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([NH:21][CH:20]([C:9]2[CH:10]=[C:11]([O:17][CH2:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=2[NH:7][S:6]([CH2:5][C:4]([OH:3])=[O:42])(=[O:40])=[O:41])[CH2:24][NH:23][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:33][CH:34]=1)(=[NH:39])[NH2:49]
Reactant: CCCS(=O)(=O)N1C[C@@H](c2cc(OCC)c(OCC)cc2NS(=O)(=O)CC(=O)OCC)N(c2ccc(C#N)cc2)C1=O
Reactant: CCN(C(C)C)C(C)C
Agent: [Ni]
Agent: NO
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCS(=O)(=O)NCC(Nc1ccc(C(=N)N)cc1)c1cc(OCC)c(OCC)cc1NS(=O)(=O)CC(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
(R)-{2-[3-(4-cyanophenyl)-2-oxo-1-(propane-1-sulfonyl)-imidazolidin-4-yl]-4,5-diethoxyphenylsulfamoyl}-acetic acid ethyl ester (0.160 g) was diluted with ethanol (5 mL) followed by lithium hydroxide (1 mL of a 10% aqueous solution, 10 Equiv.) and the solution was stirred for forty eight hours. The solution was purified by direct flash chromatography on silica gel (20% methanol/80% dichloromethane) to yield the product. This product was diluted with ethanol (1 mL) and hydroxylamine (0.035 g, 10 Equiv.) and Hunigs base (0.088 mL, 10 Equiv.) was added and the solution was heated to 60° C. for six hours. The reaction mixture was cooled to room temperature and stirred for twelve hours. Ethanol (3 mL) and acetic acid (0.5 mL), and Raney nickel (0.025 g) was added and the solution was hydrogenated for one hour. The reaction mixture was filtered through a pad of celite and the solvent was removed under reduced pressure. The product was purified by reverse-phase preparative chromatography to yield {2-[1-(4-carbamimidoylphenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4,5-diethoxyphenylsulfamoyl} acetic acid (52 mg). [α]Na −42.1 (c 1.01, methanol) MS (M+H)=587.
Reaction SMILES: ClN1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[N:17][OH:18])=[N:14][CH:15]=1.CN([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])C.C(N(CC)CC)C.Cl>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([C:23]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][N:14]=2)=[N:17][O:18][CH:22]=1)=[O:25])[CH3:28]
Reactant: ON=Cc1ccc(F)cn1
Reactant: CCOC(=O)C=CN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1conc1-c1ccc(F)cn1
Temperature: 60 °C
Reaction time: 64 h
Yield: 71.5 %

Procedure:
To a solution of N-chlorosuccinimide (17.34 g, 130 mmol) in DMF (128 mL) was added 5-fluoro-pyridine-2-carbaldehyde oxime (18.2 g, 130 mmol) portionwise over 2 h at room temperature and as the reaction warmed up to 60° C. the mixture was cooled back to room temperature with an ice-water bath and the resulting mixture was then stirred for 64 h at room temperature. To this solution was then added ethyl 3-(N,N-dimethylamino)acrylate (18.6 g, 130 mmol) and triethylamine (36.2 mL, 260 mmol) in chloroform (64 mL) and the resulting mixture was then stirred for 1 h at room temperature and poured onto a mixture of ice water and HCl (4 N, 1 L) and extracted with ethylacetate. The organic extract was then washed with water, saturated aqueous sodium hydrogen carbonate solution, brine, dried with sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethylacetate=100:0 to 1:1) afforded the title product (21.96 g, 72%) which was obtained as a yellow solid. MS: m/e=237.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.ClC1C=C(I)C=CN=1.[CH:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.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.O1CCOCC1>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([CH:27]=[O:28])=[CH:30][CH:31]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(-c2ccnc(Cl)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Clc1cc(I)ccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2cc(-c3ccc(OC(F)(F)F)cc3)ccn2)cc1
Yield: 63.6 %

Procedure:
2-Chloro-4-(4-trifluoromethoxyphenyl)-pyridine (0.55 mmol) starting from 2-chloro-4-iodopyridine, 4-formylphenyl boronic acid (0.82 mmol), tetrakis(triphenylphosphine)palladium(0) (0.005 mmol), 2 M potassium carbonate (0.55 mL) and dioxane (3 mL) were combined in a vial and irradiated by microwave for 15 min at 150° C. The reaction mixture was taken up in EtOAc and washed with brine. The organic layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded 120 mg of an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.81 (d, J=4.8 Hz, 1H), 8.24 (d, J=8.7 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.96 (m, 1H), 7.73 (d, J=9.0 Hz, 2H), 7.49 (dd, J=5.3, 1.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H); EIMS 343 m/z (M+).
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[N:12]=[CH:11]1.[CH2:17]([N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35])[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32]([NH:16][CH2:15][C:13]3[N:12]=[CH:11][O:10][CH:14]=3)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35])[CH:18]([CH3:20])[CH3:19]
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Reactant: NCc1cocn1
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)NCc1cocn1
Yield: 17 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-4-ylmethanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 17% yield: mp 115-118° C.; 1H NMR (300 MHz, CDCl3) δ7.85 (s, 1H), 7.64 (s, 1H), 6.36-6.32 (m, 1H), 4.47 (d, J=5.5 Hz, 2H), 4.11-4.06 (m, 2H), 3.59-3.54 (m, 2H), 3.09 (d, J=7.4 Hz, 2H), 2.56 (s, 3H), 1.97-1.83 (m, 1H), 0.91 (d, J=7.4 Hz, 6H); MS (ES+) m/z 377.1 (M+1).
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].O[Li].O.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CO.O>[CH2:1]([O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH2:10][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCCCCCCCCO
Reactant: C=CCOC(C)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C=CCCCCCCCCOC(=O)C(C)OCC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
3,5 g of crude ethyl (RS)-2-allyloxy-propionate are introduced into 24 ml of MeOH/H2O=3:1, cooled to 0° C., and then 2.2 g (30 mmol) of LiOH·H2O are added in portions. The mixture is further stirred for 5 minutes before the ice cooling is removed and the mixture is stirred for a further 1 h at room temperature. Methanol is then removed on a rotary evaporator and the residue is taken up in water. The aqueous phase is firstly extracted with Et2O in order then to be acidified to pH 1 with 6N HCl. The aqueous phase is then saturated with NaCl and extracted three times with EtOAc. The combined organic phases are dried over Na2SO4, filtered and freed from solvent on a rotary evaporator. The resulting carboxylic acid is dissolved in 40 ml of toluene and treated with 4.7 g (30 mmol) of 9-decen-1-ol and 0.38 g (2 mmol) of p-toluenesulfonic acid. The mixture is then heated using a water separator until visible amounts of water no longer separate out. After cooling to room temperature, the reaction solution is once again wash ed with saturated NaHCO3 solution, then dried over Na2SO4, filtered and freed from solvent on a rotary evaporator. Flash chromatography (cyclohexane/EtOAc=20:1, Rf=0.31) over silica gel gives 2.8 g (52.2%) of dec-9-enyl (RS)-2-allyloxy-propionate as a colorless oil.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(C)C=CC=CC=1>B(F)(F)F>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:2][CH:3]=1
Reactant: Cc1ccccc1
Reactant: c1ccc2ncccc2c1
Agent: FB(F)F
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene was polymerized at a temperature of from 200° to 300° C. in the presence of a HF.BF3 catalyst. After the reaction, the catalyst was recovered in a gas state, and a low boiling point component was removed to obtain a pitch. The optically anisotropic phase was 2 volume % as observed under a polarization microscope, the softening point was 176° C., the quinoline-insoluble content was 1.6% by weight, and the toluene-insoluble content was 34% by weight.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:16][C@H:17]([NH:26][CH3:27])[C@@H:18]([OH:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[OH:25][CH:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:17]([N:26]([CH3:27])[C:13](=[O:15])[CH2:12][CH2:11][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[CH3:16]
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: O=C(O)CCC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C(O)c1ccccc1)N(C)C(=O)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (3.5 mL, 48 mmol) was added to a solution of cyclohexanepropionic acid (5.5 mL, 32 mmol) in CH2Cl2 (60 mL). The mixture was heated at reflux for 60 min and then allowed to cool to ambient temperature and the solvent removed. The residue was redissolved in THF (50 mL) and (1R,2R) pseudoephedrine (4.8 g, 29 mmol) in THF (60 mL) was added to the reaction mixture at 0° C. After stirring for 30 min, a solution of saturated NaHCO3 was added to the mixture which was then extracted with EtOAc. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes 1:1) to afford an oil which solidified when placed in the refrigerator over night (8.2 g, 94%). MS (CI/NH3) m/z: 304 (M+H)+.
Reaction SMILES: [CH2:1]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].[CH3:20][CH:21]1[CH2:26][C:25](=[O:27])[O:24][C:23](=[O:28])[CH2:22]1.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH3:20][CH:21]([CH2:26][C:25]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:27])[CH2:22][C:23]([OH:28])=[O:24]
Reactant: CCCCCCCCc1cc2ccccc2[nH]1
Reactant: CC1CC(=O)OC(=O)C1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCc1cc2ccccc2n1C(=O)CC(C)CC(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 2-octyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture 4-methyl-dihydro-pyran-2,6-dione was added and stirred for 3 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]2[S:24][CH:25]=[CH:26][C:22]=2[CH:21]=1.C([O-])(O)=O.[Na+]>ClCCl>[S:24]1[CH:25]=[CH:26][C:22]2[CH:21]=[C:20]([NH:19][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH3:12])(=[O:10])=[O:9])[CH:28]=[CH:27][C:23]1=2
Reactant: Nc1ccc2sccc2c1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2sccc2c1
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (47 mg, 0.21 mmol) in dichloromethane (2 mL) was added pyridine (40 μL, 0.50 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-benzo[b]thiophene [20] (30 mg, 0.20 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a dark brown solid (50 mg, 74%), single spot at Rf 0.58 (3:1 hexane:ethyl acetate). mp 108.5-109.0° C., HPLC purity 99% (tR 2.20 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.87 (1H, d, J=7.9 Hz), 7.70 (1H, d, J=8.7 Hz), 7.54-7.51 (2H, m), 7.44 (1H, d, J=5.4 Hz), 7.21 (1H, d, J=5.4 Hz), 7.16 (1H, t, J=7.9 Hz), 6.98 (1H, dd, J=8.7, 2.2 Hz), 6.73 (1H, s, N—H), 2.74 (3H, s). LCMS: 336.07. FAB-MS (MH+, C15H12ClNO2S2): calcd 336.9998, found 337.0004.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C1CCN2C(=NCCC2)CC1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: COC(=O)CBr
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.1 %

Procedure:
Into a solution of 5-iodo-1H-indole-2,3dione (10.0 g, 36.6 mmol) in anhydrous DMF (180 ml) were added DBU (8.2 mL, 54.9 mmol) and methyl bromoacetate (5.1 mL, 54.9 mmol). After stirring at rt for 45 min, the reaction mixture was quenched with water (600 mL) and HCl (1N, 100 mL). Extraction with EtOAc (3×500 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Recrystallization from AcOEt 150 mL) gave the title compound as an orange powder (6.45 g, 51%) in 99.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([N:5]=[C:1]=[O:2])[S:7][C:8]=2[CH:14]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2ccc(Cl)cc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-6-chlorobenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 6-chlorobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:3]=1.[ClH:39].O1CCOCC1>C(OCC)(=O)C.CCOCC>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([C:4]2[CH:5]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([CH:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:34]1.[ClH:39]
Reactant: CC1Cc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
tert-Butyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidine-1-carboxylate (0.26 g, 0.50 mmol) in ethyl acetate (1 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.00 mL, 4.00 mmol) at r.t. for 1 h. The mixture was diluted with ether (3 mL), and centrifugalized. The solvents were decanted. The residue was dried in-vacuo to afford the desired product as HCl salt which was directly used in next step reaction without further purification. (M+H)+: m/z=422.2.
Reaction SMILES: Br[C:2]1[N:22](S(C2C=CC=CC=2)(=O)=O)[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)[CH2:35][CH2:34]1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])[O-].[K+].[K+]>O.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.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([C:42]4[CH:41]=[CH:40][C:39]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)=[CH:44][CH:43]=4)[NH:22][C:5]3=[N:6][CH:7]=2)[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)cc3n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 336 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (30.0 mg, 59.7 μmol), 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (from Alfa Aesar, cat# H51659, 19.8 mg, 6.57 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloro-methane (1:1) (4.9 mg, 5.97 μmol), and potassium phosphate (25.4 mg, 119 μmol) in water (0.2 mL)/1,4-dioxane (1 mL) was heated at 88° C. After 1 hour, the volatiles were removed under vacuum and the residue was dissolved in methanol (1 mL). Potassium carbonate (16.5 mg, 119 μmol) was added and the reaction mixture was warmed up to 60° C. After 1 hour, the reaction mixture was cooled to ambient temperature and was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (10.1 mg, 44%) as its (trifluoroacetic acid) TFA salt. LCMS calculated for C27H32N5O2 (M+H)+: m/z=458.2. Found: 458.2; 1H NMR (400 MHz, DMSO-d6): δ 12.21 (s, 1H), 9.73 (s, 1H), 8.01 (s, 1H), 7.89 (d, J=9.2 Hz, 2H), 7.12 (d, J=9.2 Hz, 2H), 6.93 (d, J=2.0 Hz, 1H), 6.38 (d, J=2.4 Hz, 2H), 6.28 (t, J=2.4 Hz, 1H), 4.01 (d, J=14.0 Hz, 2H), 3.67 (s, 6H), 3.52 (d, J=12.8 Hz, 2H), 3.19-2.93 (m, 8H), 2.86 (d, J=4.0 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+].[NH4+].[Cl-]>O1CCOCC1.O>[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])=[CH:6][CH:7]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
To a stirred solution of 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (400 mg), (4-methoxycarbonylphenyl)boronic acid (275 mg), dichlor(1,1′-bis(diphenyl-phosphino)-ferrocene)palladium (II) dichloromethane adduct (41 mg) in dioxane (3 mL) and water (2.6 mL) was added a 2 M aqueous sodium carbonate solution (1.52 mL). The mixture was stirred at 80° C. for 1.5 h. A saturated solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:1) to yield the title compound as a yellow foam (400 mg, 88%), MS (ESI+): m/z=450.2063 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].[H-].[Na+]>CC1CCCO1.O.C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][C:15]2=[O:16])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(NCCO)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCOC2=O)ccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 2-((6-methyl-5-nitropyridin-2-yl)amino)ethanol (223 mg, 1.131 mmol) in 2-methyltetrahydrofuran (20 mL) was added 1,1′-carbonyldiimidazole (CDI) (220 mg, 1.357 mmol) and the reaction mixture stirred under nitrogen for 4 hours. The mixture was then left to stand for 20 hours. To this was added sodium hydride (60% wt in mineral oil) (100 mg, 2.488 mmol) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was then diluted with water and ethyl acetate and the organic phase separated, washed with brine, then dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient) to give the title compound (0.213 g) as an off-white solid. LCMS (2 min, formic) Rt 0.85 min, m/z (ES+) 224 (M+H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:25]=2[CH:42]=1>CC(N(C)C)=O>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:25]=2[CH:42]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-bromo-6-(2-pyridyl)-1-(chloromethyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine to give 8-bromo-6-(2-pyridyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.