Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH3:24])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>>[CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:24])[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:34])[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)OCC
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C)cc3)c2)cc1)OCC
Temperature: 50 °C
Yield: 87.2 %

Procedure:
A mixture of 1 g (3 mmol) of ethyl (Z)-2-ethoxy-3-(3′-methylaminobiphenyl-4-yl)acrylate (prepared according to Example 41b) and 0.8 mL (6 mmol) of 4-methylphenyl isocyanate is placed in a sealed tube and heated at 50° C. for 15 hours. The reaction medium is cooled and the residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1.2 g (85%) of ethyl (Z)-2-ethoxy-3-[3′-(1-methyl-3-p-tolylureido)biphenyl-4-yl]acrylate are obtained in the form of a white paste.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C(=O)C.COC(C)(C)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
At room temperature, to a 3-L pear-shaped evaporating flask was added methyl(4-hydroxyphenyl)acetate (202 g) and potassium carbonate (233 g) which were dissolved in N,N-dimethylacetamide (DMA) (1 L). To the solution was added benzyl chloride (117 mL) at room temperature and stirred. The solution was then heated to 60° C. and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with methyl tert-butylether (MTBE) (1.3 L) and added with water (3 L) and an organic layer was extracted. The resulting organic layer was washed three times with a 1 N sodium hydroxide aqueous solution, then with water and a saturated sodium chloride solution and then dried over anhydrous magnesium sulphate. The solvent was distilled off at reduced pressure to give the titled compound (245 g) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[C:20]([NH2:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl.CCOC(C)=O>[NH2:21][C:20]1[C:9]([C:4]2[C:3]([Cl:22])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[CH:7]=[CH:6][C:5]=2[Cl:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([S:17][CH3:18])=[N:13][C:12]=2[N:19]=1
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(N)c3Cl)c(N)nc2n1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
To a solution of 6-(3-amino-2,6-dichloro-phenyl)-2-methylsulfanyl-pyrido[2,3-d]-pyrimidin-7-ylamine (0.5 g, 1.42 mmol) in CH2Cl2 (40 mL) is added 3-(trifluoromethyl)benzoyl chloride (1.07 mL, 7.1 mmol). After the mixture is stirred for 24 hours at room temperature, the mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by a flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N)(95/5%), to give the title intermediate as a solid (0.591 g, 79.4 %).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8]>ClCCl.[Zn+2].[I-].[I-].C1(P(CC)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][Si:7]([CH3:9])([CH3:8])[C:10]1[CH2:11][CH:5]=[C:3]([CH3:4])[CH2:2][CH:1]=1
Reactant: C#C[Si](C)(C)C
Reactant: C=CC(=C)C
Agent: CCP(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1=CCC([Si](C)(C)C)=CC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
In a four-necked flask, 1.12 g (5.1 mmol) of CoBr2, 5.43 g (17 mmol) of ZnI2, and 2.24 g (5.6 mmol) of diphenylphosphinoethane were dissolved in 250 ml of dichloromethane, and the solution was stirred for 30 minutes at 30° C. Subsequently, 50 ml (500 mmol) of isoprene, 63.5 ml (450 mmol) of trimethylsilylacetylene, and 1.45 g (5.6 mmol) of Bu4NBH4 were added thereto, and the mixture was allowed to react for one hour at 30° C. After completion of the reaction, dichloromethane was evaporated, and then the residue was distilled under reduced pressure. Thus, 68.6 g of the title compound, trimethyl (4-methyl-1,4-cyclohexadienyl) silane, was obtained at a yield of 91.7% (GC purity 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].C(O)(=O)C>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][O:9][C:4]2[CH:3]=[C:2]([NH:1][CH:21]([CH3:22])[C:20]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: Cc1cc(N)cc(OCCc2ccc(C#N)cc2)c1
Reactant: C=CC(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)C(C)Nc1cc(C)cc(OCCc2ccc(C#N)cc2)c1
Yield: 28.9 %

Procedure:
Amino-3-[2-(4-cyanophenyl)ethoxy]-5-methylbenzene (0.252 g; 1.00 mmol; from Example 17(iii) above), ethyl acrylate (130 μL; 1.2 mmol) and acetic acid (9 μL; 0.15 mmol) were refluxed together for 8 hours. After evaporation in vacuo, the resultant black oil was purified by flash chromatography (SiO2; EtOAc:heptane (3:7)) to give 0.102 g (29%) of the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cc(F)cc2cc[nH]c12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a mixture of 7-Bromo-5-fluoro-1H-indole [which was prepared according to the known method (Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (400 mg, 1.87 mmol) and methyl acrylate (241 mg, 2.8 mmol) in triethylamine (1.5 ml), palladium(II) acetate (43 mg, 0.19 mmol) and tri-o-tolylphosphine (170 mg, 0.56 mmol) was added under argon at rt The reaction mixture was stirred at 100° C. for 4 hrs in a sealed pressure tube and then cooled to rt The reaction mixture was diluted with CH2Cl2 (50 ml), washed with water (3×30 ml), brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel with EtOAc/hexane as an eluent to give 300 mg of compound I-30 as a yellow solid. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: C[O:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C[Si](C)(C)[Cl:18]>C(Cl)Cl>[Cl:18][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1(c2ccccc2)OC2CCC2O1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Product: O=C(O[C@@H]1CC[C@H]1Cl)c1ccccc1
Yield: 97.6 %

Procedure:
26.0 g (0.126 mol) of 3-methoxy-3-phenyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 17.1 g (0.16 mol) of trimethylchlorosilane in 70 ml of methylene chloride are heated to the reflux for 14 hours. Evaporation and fractional distillation in vacuo gives 25.9 g (98%) of trans-1-chloro-2-benzoyloxy-cyclobutane. Boiling point0.35 94°-95°, melting point 20°.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[CH:13][C:8]=2[O:7][C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:4].[CH2:26](N(CC)CC)C.COS(OC)(=O)=O.O>C(OCC)C>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:14][CH3:26])=[CH:13][C:8]=2[O:7][C:6]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[O:4]
Reactant: CCN(CC)CC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC(C)C)cc12
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCOCC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC)c(OC(C)C)cc12
Yield: 56 %

Procedure:
6-Amino-2-(4-fluoro-phenyl)-5-isopropoxy-benzofuran-3-carboxylic acid methylamide, prepared according to Example 16 (55 mg, 161 μmol) was dissolved in anhydrous diethyl ether (2 mL). Triethylamine (25 μL, 193 μmol) was added to the reaction mixture, followed by the slow addition of dimethylsulfate (17 μL, 177 μmol). Water (1 mL) was added after 2 hours. The reaction was concentrated to dryness, and the crude product was purified on HPLC (reverse phase) to provide 32 mg (56%) of pure product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[C:13]([O:21][CH2:22][CH:23]([O:34][CH2:35]Br)[CH2:24][O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:10]([CH2:35][O:34][CH:23]([CH2:22][O:21][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:24][O:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(OCC(COC(=O)c1ccccc1)OCBr)c1ccccc1
Reactant: Nc1ncnc2pc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2pcn(COC(COC(=O)c3ccccc3)COC(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.5 %

Procedure:
To a suspension of 7-amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.5 g, 3.29 mmol) in DMF (20 mL) was added NaH (0.16 g, 4 mmol) under an argon atmosphere. After stirring the mixture at room temperature for 40 min, (1,3-dibenzoyloxy-2-propoxy)methyl bromide (109) (1.38 g, 3.5 mmol) was added and the reaction was continued for 18 h. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (150 mL) and the organic solution was washed with water (30 mL). Aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic extracts were dried (Na2SO4) and evaporated. The residue was purified by silica gel column (2×15 cm) chromatography. The column was flash eluted with dichloromethane containing 0-2.5% methanol. The appropriate fractions containing the desired product were evaporated to yield 0.68 g (44%) of the title compound, mp 148-150° C. 1H nmr (DMSO-d6): δ 4.35 (m, 3 H, CH, CH2), 4.52 (m, 2 H, CH2), 5.79 (s, 2 H, CH2), 7.45-7.75 (m, 10 H, 2 Bz), 8.33 (s, 2 H, NH2), 8.66 (d, 1 H, C5H), and 8.81 (d, 1 H, J =57.9 Hz, C2H ). Anal. Calcd. for C23H21N4O5P: C, 59.48; H, 4.56; N, 12.07. Found: C, 59.08; H, 4.56; N, 12.02.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:14]([CH:15]=[CH2:16])[CH2:13][CH2:12][O:11][CH:10]2[OH:17])[CH:5]=[CH:6][C:7]=1[F:8].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([C@H:30](O)[CH3:31])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>ClCCl>[F:18][C:19]([F:33])([F:34])[C:20]1[CH:21]=[C:22]([C@H:30]([O:17][C@@H:10]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C@H:14]([CH:15]=[CH2:16])[CH2:13][CH2:12][O:11]2)[CH3:31])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: C=CC1CCOC(O)C1c1ccc(F)c(Br)c1
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: C=C[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)c(Br)c1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
(±) 3-(3-Bromo-4-fluorophenyl)-4-vinyltetrahydropyran-2-ol (from step f) above; 10.32 g, 0.034 mol), (1R)-3,5-bis(trifluoromethyl)phenylethanol (11 g, 0.042 mol), Amberlyst™ (5 g) and molecular sieves (8 g) were suspended in dichloromethane (20 mL) and the mixture was shaken at 40° C. for 3 days. The resulting yellow solution was filtered, concentrated in vacuo and was purified by chromatography on silica using 1-5% ethyl acetate in hexane as eluant to give a mixture of isomers 1-3 (which were retained) and the desired isomer 4 (3.6 g, 20%) as a colourless oil.
Reaction SMILES: C([N:4]([C@@H:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:5]([CH:14]=[CH:15][CH3:16])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.[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>[CH3:24][C@H:17]([NH:4][C@@H:5]([CH:14]=[CH:15][CH3:16])[CH2:6][C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CCN([C@@H](C=CC)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC=C[C@@H](CC(=O)OC(C)(C)C)N[C@@H](C)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of compound (12) from Example 4 (1.080 g, 3.28 mmol) in anhydrous dichloromethane (20 ml) was added tetrakis-(triphenylphosphine)-palladium (0) (0.040 g, 1 mol %) and N,N'-dimethylbarbituric acid (0.536, 9.85 mmol). This mixture was stirred at 40° C. for 2 hours, after which the dichloromethane was removed under reduced pressure. The residue was dissolved in diethyl ether (50 ml) and washed with saturated sodium bicarbonate solution (2×20 ml) and brine (20 ml) and dried (magnesium sulphate) and the solvent was removed under reduced pressure to yield a pale yellow oil. Purification by flash chromatography on silica gel [ethyl acetate/petroleum ether (4:9)] afforded the title compound (Rf 0.30) as a colourless oil (0.950 g, 100%). δH (300 MHz; CDCl3) 7.32-7.18 (5H, m, Ph), 5.55 (1H, dq, J=15.2 and 6.4, CH3CH=CH), 5.26 (1H, ddq, J=15.2, 8.0 and 1.6, trans CH2CH=CH), 3.84 (1H, q, J=6.5, PhCHCH3), 3.45 (1H, m, NCHCH2), 2.41 (1H, dd, J=14.5 and 6.6, CH2CO2), 2.35 (1H, dd, J=14.5 and 6.5, CH2CO2), 1.65 (3H, dd, J=6.4 and 1.6, CH3C=C), 1.45 (9H, s, (CH3)3C), 1.33 (3H, d, J=6.5, PhCHCH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[CH3:25][NH:26][O:27][CH3:28].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH3:28][O:27][N:26]([CH3:25])[C:15](=[O:17])[CH:14]=[CH:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNOC
Reactant: COc1ccc2cccc(C=CC(=O)O)c2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cccc(C=CC(=O)N(C)OC)c2c1

Procedure:
The acid chloride obtained starting from 6.5 g (28.5 mmol) of the acid obtained in Step E and 5 ml of oxalyl chloride are added dropwise to a suspension of N,O-dimethylhydroxylamine chloride (5.6 g) in a mixture of CH2Cl2/H2O in the presence of 3 g of Na2CO3. The protected acid is obtained in the form of a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[N:24][N:25]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1.O.C(=O)(O)[O-].[Na+]>O1CCOCC1.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]>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([C:21]4[O:22][C:23]([CH3:26])=[N:24][N:25]=4)[CH:3]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(C)o4)cc(Br)cc32)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 150 °C
Yield: 52.9 %

Procedure:
6-Bromo-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazole (70 mg, 0.162 mmol) was dissolved in 1,4-dioxane (1.2 ml) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (47.1 mg, 0.194 mmol, available from Frontier Scientific Europe), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (5.91 mg, 8.08 μmol), water (0.8 ml) and 2M aqueous sodium bicarbonate (0.242 ml, 0.485 mmol) were added. The reaction mixture was heated under microwave irradiation at 150° C. for 15 mins. The solution was loaded onto a silica cartridge (0.5 g) and eluted with methanol. The eluant was concentrated, the residue dissolved in methanol and absorbed onto Florisil. This was placed on top of a silica cartridge (10 g) and eluted with 25-50% ethyl acetate/cyclohexane. Appropriate fractions were evaporated to give the title compound as a yellow solid (27 mg).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][CH:5]=1.[CH:12](Br)=[CH2:13].CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:10][C:7]1[N:6]=[CH:5][C:4]([C:3]2[CH:13]=[CH:12][O:1][N:2]=2)=[CH:9][CH:8]=1
Reactant: C=CBr
Reactant: Cc1ccc(C(Cl)=NO)cn1
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccon2)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To crude N-hydroxy-6-methylnicotinimidoyl chloride in 10 mL toluene was added vinyl bromide (1 M in THF, 11 mL, 11.0 mmol), followed by bis(tributyltin)oxide (2.12 g, 1.87 mL, 3.67 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to isolate 155 mg (26%, for two steps) of the title compound as a white solid. HPLC/MS: retention time=0.39 min, [M+H]+=161.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[O:6].[CH3:18][N:19](C=O)C>[Cu]>[C:18]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[O:6])#[N:19]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)C(=O)c1ccc(F)c(Br)c1
Agent: [Cu]
Product: CCCN(CCC)C(=O)c1ccc(F)c(C#N)c1
Temperature: 25 °C

Procedure:
Combine 3-bromo-4-fluoro-N,N-dipropylbenzamide (1.0 g, 3.3 mmol) with copper cyamide (0.45 g, 5.0 mmol) in DMF (5 mL) and heat at reflux until all starting material is consumed. Cool to room temperature and partition between ethyl acetate and saturated aqueous sodium bicarbonate. Separate the organic layer and wash with saturated aqueous sodium bicarbonate, saturated sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](Cl)(Cl)=[S:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:9]=[S:10]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1ccccc1N=C=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
Into a solution of 2-fluoroaniline (1.0 g, 9.0 mmol) in 30 mL of toluene at room temperature, thiophosgene (1.06 mL, 13.5 mmol) and triethylamine (1.55 mL, 13.5 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (1.05 g, 76%). 1H NMR (CDCl3) δ 7.1-7.3 (m, 4H).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17]([CH:21]2[S:25][C:24](=[O:26])[NH:23][CH:22]2[C:27](O)=[O:28])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:27]([CH:22]1[CH:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[S:25][C:24](=[O:26])[NH:23]1)=[O:28])([O-:7])=[O:6]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2cccc([N+](=O)[O-])c2)S1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)S1
Yield: 67.8 %

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 380 mg of N-(2-nitrooxyethyl)-amine nitrate and 500 mg of 5-(3-nitrophenyl)-2-oxothiazolidine-4-carboxylic acid, to obtain 450 mg of the title compound as a pale yellow powder.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[N:9][CH:10]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[Cl:29][C:30]1[CH:38]=[CH:37][C:36]2[NH:35][C:34]3[CH2:39][CH2:40][N:41]([CH3:43])[CH2:42][C:33]=3[C:32]=2[CH:31]=1>CN(C=O)C.[Cu]I>[Cl:29][C:30]1[CH:38]=[CH:37][C:36]2[N:35](/[CH:2]=[C:3](/[C:5]3[CH:10]=[N:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=3)\[CH3:4])[C:34]3[CH2:39][CH2:40][N:41]([CH3:43])[CH2:42][C:33]=3[C:32]=2[CH:31]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: COc1ccc(C(C)=CBr)cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
5-(1-Bromoprop-1-en-2-yl)-2-methoxypyridine (113 mg, 0.5 mmol) was dissolved in DMF (2 mL) and potassium phosphate (212 mg, 1 mmol) was added followed by copper (I) iodide (9 mg, 0.05 mmol) and L-proline (11.5 mg, 0.1 mmol). 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (110 mg, 0.5 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica gel (100-200 mesh) using 0-4% MeOH:DCM as eluent. The compound was further purified through reverse phase HPLC. Yield: 15 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.40 (s, 1H), 7.98 (d, 1H), 7.56 (s, 1H), 7.22 (s, 2H), 7.0 (s, 1H), 6.84 (d, 1H), 4.50 (s, 2H), 3.96 (s, 3H), 3.70 (m, 2H), 3.18 (m, 2H), 3.12 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]4[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=4)=[CH:30][CH:29]=3)[CH2:17][CH2:16]2)=[O:19])=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Solvent: O=CO
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 40.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide formate (0.77 g, 1.85 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.671 g, 1.66 mmol) according to Procedure G to give the title compound (0.53 g, 0.67 mmol).