Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:33][OH:34])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:11]2[C:16]([F:17])=[CH:15][C:14]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24]C4ON=C(C)C=4)[O:20][C:19]3=[O:31])=[CH:13][C:12]=2[F:32])=[CH:7][CH2:6]1)=[O:4].C(OC(N[C:43]1[N:47]=[CH:46][O:45][N:44]=1)=O)(C)(C)C.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[O:45]1[CH:46]=[N:47][C:43]([CH:23]([NH2:24])[C@H:21]2[O:20][C:19](=[O:31])[N:18]([C:14]3[CH:13]=[C:12]([F:32])[C:11]([C:8]4[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@@H:2]([OH:1])[CH2:33][OH:34])[CH2:6][CH:7]=4)=[C:16]([F:17])[CH:15]=3)[CH2:22]2)=[N:44]1
Reactant: Cc1cc(NC[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H](O)CO)CC4)c(F)c3)C(=O)O2)on1
Reactant: CC(C)(C)OC(=O)Nc1ncon1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: NC(c1ncon1)[C@@H]1CN(c2cc(F)c(C3=CCN(C(=O)[C@@H](O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
To a stirred solution of the appropriate intermediate of Example 20 (600 mg, 1.37 mmol) in anhydrous THF (30 ml) under an atmosphere of nitrogen was added 3-t-butyloxycarbonylamino-1,2,4-oxadiazole (304 mg, 1.64 mmol) and tri-n-butylphosphine (510 μL, 2.05 mmol). The mixture was cooled to 0° C. and 1,1′-(azodicarbonyl)-di-piperidine (518 mg, 2.05 mmol) was added portionwise. The reaction was allowed to warm to room temperature and stir for 18 hours. The THF was removed under reduced pressure and the resulting residue taken into dichloromethane (15 ml) and cooled to 0° C. A white solid precipitated and the solution was filtered and purified by MPLC (Merck 9385 silica, 40-60% ethyl acetate in iso-hexane). The solvent was removed under reduced pressure to give a clear, colourless oil which was triturated with ether to yield the title compound as a fine white powder (291 mg, 35%). 1H-NMR (300 MHz, DMSO-d6): δ=1.31 (d, 6H), 1.47 (s, 9H), 2.27-2.48 (m, 2H), 3.61-4.28 (m, 10H), 4.87-5.02 (m, 2H), 5.89 (broad s, 1H), 7.33 (d, 2H), 9.54 (s, 1H). MS: ESP+ (M+H)+606.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH:6]=1
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(OC)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.74 g, 0.002 mol) in DMF (10 mL), was added 3-methoxybenzyl bromide (0.47 g, 0.0023 mol) and powdered and potassium carbonate (1.93 g, 0.014 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.81 g in 77% yield. 1H NMR (CDCl3) δ 7.19 (s, 1H), 7.17 (m, 11H), 7.09 (t, 1H), 6.83 (d, 1H), 6.72 (t, 2H), 6.59 (m 2H), 4.19 (t, 1H), 3.72 (s, 6H), 3.61 (s, 4H), 3.55 (d, 2H), 3.07 (d, 2H), 2.62 (t, 2H), 1.82 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.9, 160.6, 144.9, 142.8, 136.6, 130.8, 130.3, 129.9, 129.7, 129.6, 127.6, 122.7, 122.6, 116.9, 115.2, 114.5, 114.3, 67.0, 61.2, 60.6, 56.4, 51.9, 51.2, 42.7, 28.2.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(O[CH2:28][CH:29]=[CH2:30])(=O)C>COCCOC.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:30]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])[CH:29]=[CH2:28]
Reactant: C=CCOC(C)=O
Reactant: O=C1CCCCC1c1ccccc1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: COCCOC
Product: C=CCC1(c2ccccc2)CCCCC1=O
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a solution of 2-phenylcyclohexanone (2 g, 11.48 mmol) in 50 ml of anhydrous DME in an ice bath was added 1M sodium bis(trimethylsilyl)amide (12.63 mL, 12.63 mmol) dropwise and the solution was stirred at the same temp for 20 minutes. In a separated flask allylpalladium chloride dimer (0.104 g, 0.287 mmol) was dissolved in 10 ml of anhydrous DME, and triphenylphosphine (0.151 g, 0.574 mmol) was added to the solution. It was stirred for 20 minutes at room temp and then allyl acetate (1.300 mL, 12.05 mmol) was added. This solution was added to the anion solution dropwise and the mixture was stirred at room temp for 2 hrs. The reaction was quenched with saturated NH4Cl and extracted with hexane. The organic layer was washed with brine. The combine aqueous layers were back-extracted with hexane once and combined. Dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with hexane followed by 1:9 EtOAc-hexane to give 2.24 g of 2-allyl-2-phenylcyclohexanone. 1H NMR (400 MHz, CDCl3) δ ppm 7.35 (2 H, t, J=7.58 Hz), 7.21-7.27 (1 H, m), 7.12-7.18 (2 H, m), 5.35-5.52 (1 H, m), 4.82-4.97 (2 H, m), 2.61-2.72 (1 H, m), 2.39-2.55 (2 H, m), 2.24-2.38 (2 H, m), 1.89-1.99 (1 H, m, J=9.39, 6.15, 2.88, 2.88 Hz), 1.62-1.81 (4 H, m).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[C:27]1([CH:33]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](O)([C:43]3[C:51]([OH:52])=[CH:50][C:46]4[CH2:47][CH2:48][O:49][C:45]=4[CH:44]=3)[C:35]2=[O:54])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:55]1([CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]([C:43]3[C:51]([OH:52])=[CH:50][C:46]4[CH2:47][CH2:48][O:49][C:45]=4[CH:44]=3)[C:35]2=[O:54])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCO2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1C(c2cc3c(cc2O)CCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1-benzofuran-6-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 434.4 (M+1).
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(I)ccc21
Product: COc1ccc(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)cc1OC
Yield: 72 %

Procedure:
Prepared from 3-(7-iodo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 11 using the same conditions used to prepare Example 1 but using 3,4-dimethoxyphenyl boronic acid instead of benzene boronic acid. The title compound (110 mg) was obtained as a beige solid, (yield=72%).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH:32]C(=O)OC(C)(C)C)[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)=[N:12][C:9]=3[O:10][CH2:11][C:6]2=[N:5][N:4]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][CH2:2][C:3]1[N:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:13]([C:22]4[CH:23]=[CH:24][C:25]([C:28]5([NH2:32])[CH2:31][CH2:30][CH2:29]5)=[CH:26][CH:27]=4)=[N:12][C:9]=3[O:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(CF)nnc3CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(CF)nnc3CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 61.7 %

Procedure:
Tert-butyl (1-(4-(1-(fluoromethyl)-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (3 mg, 5.69 μmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (1.5 mg, 61% yield). LCMS (Method D) RT=0.774 min, M+1=428. 1H-NMR (500 MHz, CD3OD) δ 8.03 (1H, s), 7.41-7.35 (2H, d), 7.34-7.29 (2H, d), 7.27-7.23 (3H, m), 7.21-7.15 (2H, m), 5.86 (1H, s), 5.75 (1H, s), 5.64 (2H, s), 2.71-2.58 (2H, m), 2.49-2.37 (2H, m), 2.18-2.07 (1H, m), 1.91-1.79 (1H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:11]3[C:12]([CH3:20])=[CH:13][N:14]([CH:17]([CH3:19])[CH3:18])[C:15]=3[CH:16]=2)=[CH:4][CH:3]=1.[CH3:34][C@H:35]1[NH:40][CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]1.CC(C)([O-])C.[Na+]>[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCOCC1>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:10]1[C:11]2[C:12]([CH3:20])=[CH:13][N:14]([CH:17]([CH3:19])[CH3:18])[C:15]=2[CH:16]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([N:40]3[CH2:39][CH2:38][NH:37][CH2:36][C@H:35]3[CH3:34])=[CH:3][CH:4]=2)[CH:9]=1)=[O:22]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(Cl)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNC[C@H]4C)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Yield: 18.8 %

Procedure:
Added 6-(6-chloropyridin-3-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (131 mg, 0.283 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (70.8 mg, 0.354 mmol), sodium tert-butoxide (59.8 mg, 0.623 mmol) and 1,4-Dioxane (2 mL) to a microwave vial and degassed for 10 minutes. Added Pd XPhos (10.45 mg, 0.014 mmol) and heated to 100° C. for 16 hours. Concentrated, added DCM and water. Filtered, separated phases. Extracted aqueous phase twice more with DCM. Combined DCM extracts and washed with water, brine, dried (MgSO4), filtered and rotovapped off DCM. The residue was purified via Biotage (0% to 5% MeOH:DCM; 10 g-HP-silica gel column) Obtained 28 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.32 Hz, 3H), 1.44-1.57 (m, 15H), 2.06 (s, 3H), 2.28 (s, 3H), 2.39 (s, 3H), 2.87-3.36 (m, 3H), 3.57 (s, 1H), 3.86-4.30 (m, 3H), 4.50 (d, J=9.35 Hz, 1H), 4.58-4.79 (m, 3H), 5.87 (s, 1H), 6.64 (d, J=8.59 Hz, 1H), 7.01 (s, 1H), 7.45 (s, 1H), 7.76 (d, J=8.08 Hz, 1H), 8.46 (d, J=2.27 Hz, 1H), 12.42 (br. s., 1H). LCMS: [M+H]+ 627.5.
Reaction SMILES: O[CH2:2][C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CC=CC=1.S(Cl)([Cl:18])=O>ClCCCl>[Cl:18][CH2:2][C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: CC1(CO)CCC(=O)N1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC1(CCl)CCC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 50 mL flask was charged with 5-(hydroxymethyl)-5-methylpyrrolidin-2-one (646 mg, 5 mmol), purged with nitrogen, and dry 1,2-dichloroethane (10 mL) and pyridine (1.8 mL, 22.5 mmol, 4.5 equiv.) were added. Neat thionyl chloride (1.8 mL, 25 mmol, 5 equiv.) was added dropwise over 10 min, during which the suspension clarified briefly before becoming a thick slurry. The mixture was stirred at room temperature for 30 min, then heated to reflux. After 3.5 h, the cooled mixture was concentrated to an orange semi-solid, which was absorbed on silica. Chromatography on silica (50-100% EtOAc/hexane) afforded the title compound as a colorless oil which solidified on standing (383 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 6.48 (br s, 1H), 3.52 (s, 2H), 2.56-2.41 (m, 2H), 2.15 (ddd, J=6.0, 9.4, 15.4 Hz, 1H), 1.98 (ddd, J=7.9, 9.4, 17.3 Hz, 1H), 1.42 (s, 3H); LRMS (ESI/APCI): 148 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(CC)CC)C.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>ClCCl>[CH3:1][S:2]([NH:5][C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)=[O:20])(=[O:4])=[O:3]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CS(N)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of methylsulphonamide (5.37 g, 57 mmol) in anhydrous dichloromethane (100 ml), cooled to 0° C. was treated with triethylamine (7.9 ml, 57 mmol) followed by a solution of 3-nitrobenzoyl chloride (10 g, 54 mmol) in anhydrous dichloromethane (100 ml) dropwise. After stirring for 2 h at 0° C., the reaction mixture was washed with 1M HCl (100 ml). The precipitate which formed was collected by filtration and triturated with diethyl ether and was then recrystallised from methanol to afford the title compound (4.3 g, 31%) as a colourless crystalline solid. mp 175°-178° C. 1H NMR (360 MHz, D6 -DMSO) δ 3.42 (3H, s), 7.82 (1H, dd, J=8.0 and 8.0 Hz), 8.38 (1H, d, J=8.0 Hz), 8.49 (1H, d, J=8.0 Hz), 8.80 (1 H,s).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1)[NH2:27]>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=2)[N:27]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: CC(=O)Nc1cccc(NN)c1
Product: CC(=O)Nc1cccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and N-(3-hydrazino-phenyl)-acetamide according to the method described for example 91. MS: M=456.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([CH:9]=[CH:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:8][C:4]=2[CH:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(COC)OC.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].O>[CH:11]1([CH:10]=[CH:9][C:7]2[NH:6][C:5]3[CH:17]=[CH:18][C:2]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]([F:19])([F:32])[F:31])=[CH:3][C:4]=3[N:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Brc1ccc2[nH]c(C=CC3CCCCC3)nc2c1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C=CC3CCCCC3)nc2c1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-(2-cyclohexyl-vinyl)-1H-benzimidazole (1.2 g, 3.9 mmol, prepared as in STEP B above), 2-trifluoromethoxyphenylboronic acid (1.6 g, 7.8 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.752 g, 0.92 mmol) in dimethoxyethane (32 mL) and 2M sodium carbonate (16 mL, 32 mmol) was stirred at 95° C. for 18 h. The resulting solution was cooled to room temperature and poured into a mixture of ethyl acetate and water (1:1, 50 mL). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica using 3:7 v/v ethyl acetate/hexanes to yield 2-(2-cyclohexyl-vinyl)-5-(2-trifluoromethoxy-phenyl)-1H-benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=2)[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester (3.60 g) in methanol (50 ml) was added 4-aminomethylbenzoic acid methyl ester (3.16 ml) and the mixture was stirred at room temperature for 18 hrs. The solvent was evaporated under reduced pressure and 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in methanol (100 ml). Conc. sulfuric acid (10 ml) was added, and the mixture was heated under reflux for 3 hr. The solvent was evaporated under reduced pressure, water was added under ice-cooling and the mixture was neutralized with potassium carbonate. The solution was extracted with ethyl acetate and the extract was washed with saturated brine. Sodium sulfate was added to dry the mixture. The obtained residue was recrystallized from methanol to give the title compound (3.39 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:47])=[C:21]([N:26]([C:33](=[O:46])[C@@H:34]([NH:38]C(=O)OC(C)(C)C)[CH:35]([CH3:37])[CH3:36])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[NH2:38][C@@H:34]([CH:35]([CH3:36])[CH3:37])[C:33]([N:26]([C:21]1[CH:22]=[CH:23][C:24]([F:25])=[C:19]([C:17]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=3)[NH:14][CH:15]=2)=[O:18])[C:20]=1[F:47])[S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])=[O:46]
Reactant: CCCS(=O)(=O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)N(C(=O)[C@@H](N)C(C)C)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 223.8 %

Procedure:
A mixture of (S)-tert-butyl (1-(N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propylsulfonamido)-3-methyl-1-oxobutan-2-yl)carbamate (50 mg, 0.07 mmol) and a saturated solution of HCl in EtOAc (2 mL) was stirred at rt for 2 h. The mixture was concentrated in vacuo to afford the title compound as a white solid (49 mg, 99%). The title compound was characterized by LC-MS as shown below:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([Cl:21])=[O:18])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1cccc(C(=O)c2ccccc2)c1

Procedure:
20 g of m-benzoyl-phenyl acetic acid (prepared by process of French patent No. 1,546,478) and 100 ml of thionyl chloride were refluxed for 3 hours and then evaporated to dryness. Excess thionyl chloride was removed by entrainment with benzene to obtain 21.74 g of m-benzoyl-phenyl-acetic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([C:30]([NH2:32])=O)[N:29]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([C:30]#[N:32])[N:29]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(C(N)=O)cs3)ccc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(C#N)cs3)ccc2c1=O
Yield: 90.7 %

Procedure:
A solution of tert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.32 g, 0.6 mmol) and cyanuric chloride (0.33 g, 1.8 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(4-cyano-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.28 g, 90.3%) as crystals.
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH:9][C:10]#[N:11])=[NH:8])[CH2:2][CH2:3][CH2:4][CH3:5].C(NCC)C.[SH2:17]>CO>[CH2:1]([NH:6][C:7]([NH:9][C:10]([NH2:11])=[S:17])=[NH:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S
Reactant: CCCCCNC(=N)NC#N
Solvent: CO
Solvent: CCNCC
Product: CCCCCNC(=N)NC(N)=S
Yield: 59.9 %

Procedure:
N-Pentyl-N'-cyanoguanidine (30.0 g, 0.195 mol) and diethylamine (3 ml) were combined in methanol (550 ml). This solution was cooled to -40°, saturated with hydrogen sulfide gas, transferred to a stainless steel bomb and heated at 85° for 40 hours. The excess hydrogen sulfide was purged from the reaction mixture with nitrogen and the solution was then concentrated in vacuo. The residue was flash chromatographed (140 mm column, 5% methanol in chloroform). The fractions containing pure product were combined and evaporated yielding 22.01 g (59.9%) of white solid. A portion was recrystallized from chloroform to furnish material with mp 98°-100°, mass spec.: M+ 188.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20]>O1CCCC1>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2])=[O:20]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CCc1nc(C)c[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(C)cn1C(=O)c1c(Cl)cccc1Cl
Yield: 64.3 %

Procedure:
22.02 g of 2-ethyl-4-methyl-imidazole and 20.85 g of triethylamine are dissolved in 250 ml of tetrahydrofuran. There are then added dropwise, at reflux temperature within 20 minutes, 41.88 g of 2,6-dichlorobenzoyl chloride, dissolved in 100 ml of tetrahydrofuran, and the mixture is refluxed for 30 minutes, and subsequently further processed as described in Example 1. Recrystallisation of the crude product from 120 ml of acetonitrile yields 36.4 g of product (64.3% of theory), m.p. 112°-113.5° C.