Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37]>C(#N)C>[CH3:34][C:35]([CH3:40])([CH3:39])[C:36]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH2:19]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])=[O:37]
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)C(C)(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 41.9 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (180 mg, 0.4 mmol) in acetonitrile (2 mL) was added 2,2-dimethyl-propionyl chloride (0.064 mL, 0.5 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (15 mL) and sodium hydrogen carbonate (15 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-(2,2-dimethyl-propionyloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (90 mg, 42% yield): mp, 146-148° C.; 1H NMR (DMSO-d6) δ 0.87-0.89 (m, 4H, 2CH2), 1.19 (s, 9H, 3CH3), 1.30 (t, J=7 Hz, 3H, CH3), 1.76-1.82 (m, 1H, CH), 3.04 (d, J=8 Hz, 2H, CH2), 3.73 (s, 3H, CH3), 3.97-4.05 (m, 2H, CH2), 4.19 (d, J=18 Hz, 1H, NCHH), 4.58 (d, J=18 Hz, 1H, NCHH), 5.66 (t, J=8 Hz, H, NCH), 6.87-6.94 (m, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.50 (d, J=8 Hz, 1H, Ar), 8.23(d, J=8 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.82 (s, 1H, NH); 13CNMR (DMSO-d6) δ 7.77, 14.69, 15.46, 26.71, 34.63, 37.63, 46.61, 51.03, 55.46, 63.78, 111.91, 112.07, 116.82, 117.32, 117.51, 119.24, 131.24, 132.76, 136.96, 142.24, 147.92, 148.55, 166.66, 168.00, 171.71, 175.41; Anal Calcd for C29H35N3O7: C, 64.79; H, 6.56; N, 7.82. Found: C, 64.91; H, 6.50; N, 7.84.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([I:20])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N+:8]([O-])=[CH:9]2)=[CH:4][N:3]=1.P(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([I:20])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:8]=[CH:9]2)=[CH:4][N:3]=1
Reactant: [O-][n+]1cc2cc(Cl)ncc2c(I)c1-c1ccccc1Cl
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: Clc1cc2cnc(-c3ccccc3Cl)c(I)c2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of 7-chloro-3-(2-chlorophenyl)-4-iodo-2,6-naphthyridine 2-oxide (870 mg, 2.1 mmol) in dichloromethane (13 mL) was added phosphorus trichloride (0.2 mL, 2.3 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford an orange residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-30% ethyl acetate in heptane) to afford the title compound as an orange solid (400 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 9.21 (s, 1H), 7.83 (s, 1H), 7.57-7.53 (m, 1H), 7.49-7.40 (m, 2H), 7.40-7.35 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.CN(C=O)C.C(Cl)[Cl:17]>[Cu](Cl)Cl>[Cl:17][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: ClCCl
Reactant: Brc1csc2ncccc12
Agent: Cl[Cu]Cl
Solvent: CN(C)C=O
Product: Clc1csc2ncccc12
Temperature: 130 °C
Yield: 71 %

Procedure:
500 mg of 3-Bromo-thieno[2,3-b]pyridine (2.3 mmol) and 136 mg of copper chloride (I) (2.78 mmol) are placed into reaction vial with 3.0 ml of dry DMF. The vial is capped with a Teflon cap and heated at 130° C. overnight. The reaction mixture is poured into CH2Cl2 and washed with NaHCO3, brine and dried over Na2SO4. The solvents are removed and the residue applied onto a chromatography silica-gel column (Hexane:AcOEt=10:1) to give 280 mg of the title compound (71%); mass spectrum (m/e): 170; 1H-NMR (CDCl3): 8.53 (m, 1H), 8.11 (m, 1H), 7.41 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl.O1CCOCC1>C1(C)C=CC=CC=1.CCOC(C)=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]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc(N[C@H]3CC[C@H](N)CC3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.150 g, 0.483 mmol, Example 228, Step 7), tert-butyl (trans-4-aminocyclohexyl)carbamate (0.41 g, 1.9 mmol, Combi-Blocks), NaOtBu (0.14 g, 1.4 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (70. mg, 0.12 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (53 mg, 0.058 mmol, Aldrich) in toluene (7.5 mL) was heated at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with water, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 1,4-dioxane (4.0 mL) and treated with 4.0 M HCl in dioxane (1.0 mL, 4.0 mmol). After stirring for one hour, solvent was removed in vacuo, and the product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (31 mg, 16%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:18]1[CH:37]=[CH:36][C:21]2[C:22]3[N:26]([CH2:27][CH2:28][O:29][C:20]=2[CH:19]=1)[CH:25]=[C:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[N:23]=3>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:18]2[CH:37]=[CH:36][C:21]3[C:22]4[N:26]([CH2:27][CH2:28][O:29][C:20]=3[CH:19]=2)[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:23]=4)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Brc1ccc2c(c1)OCCn1cc(-c3ccccn3)nc1-2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3c(c2)OCCn2cc(-c4ccccn4)nc2-3)C1
Temperature: 70 °C

Procedure:
To a solution of 3-hydroxypiperidine-1-carboxylic acid tertbutyl ester (176 mg, 0.88 mmol) in toluene (3 mL) was added NaH (60% in mineral oil, 35 mg, 0.88 mmol) and the mixture was heated at 70° C. for 15 min. After cooling to RT, 8-bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.58 mmol), Pd2 dba3 (11 mg, 0.001 mmol) and tertbutylXantphos (20 mg, 0.08 mmol) were added and the mixture was heated at 95° C. for 18 h. The reaction mixture was then partitioned between EtOAc and brine and the aqueous phase was further extracted with EtOAc (×3). The combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM followed by Si-PCC, gradient 0-10% 2M NH3/MeOH in EtOAc) affording 3-(2-Pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy)piperidine-1-carboxylic acid tertbutyl ester as a colorless oil, taken forward in the next step without further purification. LCMS: RT 2.68 min [M+H]+ 463.2
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].O[N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][C:29]([NH:31][CH2:32][C:33]([O:35][N:37]4[C:41](=[O:42])[CH2:40][CH2:39][C:38]4=[O:43])=[O:34])=[O:30])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(=O)ON5C(=O)CCC5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
To a solution of N-(cholest-5-en-3β-oxycarbonyl)glycine (2.92 g) in a mixture of dioxane (40 ml) and chloroform (6 ml) were added successively N-hydroxysuccinimide (0.69 g) and dicyclohexylcarbodiimide (1.236 g) at 0° C. and the reaction mixture was stood for 16 hours in a refrigerator. The resulting precipitate was collected by filtration and the filtrate was concentrated in vacuo to give succinimidyl N-(cholest5-en-3β-oxycarbonyl)glycinate (3.23 g).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]2[C:22]3[C:21]4[CH:20]=[C:19]([O:23][CH3:24])[C:18]([O:25][CH3:26])=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[K+].[CH:37](B1OC(C)(C)C(C)(C)O1)=[CH2:38]>CN(C)C=O.O.COCCOC>[CH3:26][O:25][C:18]1[C:19]([O:23][CH3:24])=[CH:20][C:21]2[C:22]3[C:10]([C:8]4[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH:37]=[CH2:38])[CH:9]=4)=[N:11][NH:12][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)c(Br)c4)c3c2cc1OC
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: C=Cc1cc(-c2n[nH]c3cnc4cc(OC)c(OC)cc4c23)ccc1C#N
Temperature: 150 °C
Yield: 52.5 %

Procedure:
2-Bromo-4-(7,8-dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (540 mg, 1.32 mmol) is dissolved in N,N-dimethylformamide (4.0 ml) under an argon protective-gas atmosphere. Tripotassium phosphate (578 mg, 2.64 mmol), KOH (67 mg, 1.19 mmol), 1,2-dimethoxyethane (9.0 ml) and water (50 μl), vinylboronic acid pinacol ester (942 μl, 5.28 mmol) and trans-bis(tricyclohexylphosphine)palladium(II)dichloride (98 mg, 132 μmol) are subsequently added. The suspension obtained is heated at 150° C. (microwave) for 30 min. For work-up, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness in vacuo. The residue is purified over flash silica gel (solvent gradient cyclohexane/0-80% by vol. of ethyl acetate), giving 4-(7,8-dimethoxy-3H-pyrazolo[3,4-c]-quinolin-1-yl)-2-vinylbenzonitrile (247 mg, 693 μmol) as a solid. MS: 357.2 (M+H+), TLC (HPTLC): Rf=0.47 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [N+:1]([C:4]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[N+:1]([C:4]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:5]=1[C:6]([Cl:20])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.7 g (28 mmoles) of 2-nitro-3,4,5,6-tetrafluorobenzoic acid [Tetrahedron, 23, 4719, (1967)], 3.8 g (30 mmoles) of oxalyl chloride and 50 ml of dichloromethane was treated with four drops of N,N-dimethylformamide and stirred at room temperature overnight. The solvent was removed and the residue was used as is without further purification.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4]1.[F:11][C:12]([F:21])([F:20])[CH2:13][CH2:14][CH:15]([C:18]#[N:19])[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:15]([CH2:14][CH2:13][C:12]([F:11])([F:20])[F:21])([C:16]#[N:17])[C:18]#[N:19])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccn(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
0.61 g of 1-chloromethyl-3-nitro-1H-pyrole and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 0.28 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.80 g of [(3-nitro-1H-pyrole-1-yl) methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (45), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Br.[Br:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:35]2[CH2:36][CH2:37][CH:32]([Br:31])[CH2:33][CH2:34]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: BrC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCC(Br)CC3)ccc21
Yield: 133 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (42.7 mg, 0.104 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-bromopiperidine hydrobromide (105 mg, 0.428 mmol), acetic acid (0.120 mL, 2.10 mmol) and sodium triacetoxyborohydride (51.1 mg, 0.241 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-bromopiperidinomethyl)indol-2-yl]isoindolinone (77.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:39][CH3:40])[C:20]3[C:21]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CO>CO.O.C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:39][CH3:40])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCN(c1ncnc2[nH]ccc12)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 60 °C
Yield: 50.8 %

Procedure:
To a solution of (S)-2-(3,5-dichlorophenylamino)-1-(3-(ethyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl) ethanone (70 mg, 0.11 mmol) in MeOH:H2O (4:1, 10 mL), K2CO3 (48 mg, 0.35 mmol) was added and the reaction mixture was heated at 60° C. for 1 h, the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under vacuo to give a residue. The residue triturated with 10% MeOH in EtOAc (15 mL), the suspension was filtrated, the filtrate was evaporated under vacuo to give the crude compound that was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (25 mg, 45%) of the titled compound. 1H NMR (400 MHz, DMSO-d6): δ 11.79 and 11.6 (2s, 1H), 8.106 (d, J=6.8 Hz, 1H), 7.18 and 7.13 (2s, 1H), 6.76 (s, 1H), 6.69 (s, 1H), 6.62 (s, 1H), 6.49 and 6.43 (2s, 1H), 6.37 and 6.33 (2t, J=2.3 Hz, 1H), 4.74-4.69 (m, 1H), 4.46-4.39 (m, 1H), 4.13-3.88 (m, 4H), 3.76-3.70 (m, 2H), 3.20-3.16 (m, 1H), 3.00 (t, J=12.0 Hz, 1H), 2.86 (t, J=12.0 Hz, 1H), 2.62 (t, J=13.6 Hz, 1H), 1.98-1.81 (m, 3H), 1.65-1.49 (m, 1H), 1.19 (t, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=447. HPLC (254 nm): 97.68%. HPLC (210 nm): 98.20%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Mg].O(CC)CC.[CH3:15][N:16]1[C:20]2[C:21]([CH:25]=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1>O>[F:8][C:4]1[CH:3]=[C:2]([CH:25]([C:21]2[C:20]3[N:16]([CH3:15])[N:17]=[N:18][C:19]=3[CH:24]=[CH:23][CH:22]=2)[OH:26])[CH:7]=[CH:6][CH:5]=1
Reactant: Cn1nnc2cccc(C=O)c21
Reactant: Fc1cccc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: Cn1nnc2cccc(C(O)c3cccc(F)c3)c21
Yield: 95.2 %

Procedure:
To a stirred and refluxed Grignard complex, previously prepared starting from 8.15 parts of 1-bromo-3-fluorobenzene, 1.2 parts of magnesium and a small amount of 1,1'-oxybisethane was added a solution of 5 parts of 1-methyl-1H-benzotriazole-7-carboxaldehyde in 80 parts of 1,1'-oxybisethane. After stirring for 2 hours at room temperature, the reaction mixture was poured into 300 parts of water. The product was extracted three times with 65 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was stirred for 15 minutes in 100 parts of water and 13 parts of petroleum ether at room temperature. The product was filtered off and dried, yielding 7.6 parts (95.2%) of α-(3-fluorophenyl)-1-methyl-1H-benzotriazole-7-methanol; mp. 152° C. (int. 19).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:6]=1[CH3:16])(=[O:3])[CH3:2].[OH-].[NH4+:18]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12](=[O:14])(=[O:13])[NH2:18])=[CH:7][C:6]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(=O)Nc1cc(F)c(S(=O)(=O)Cl)cc1C
Agent: [OH-]
Product: CC(=O)Nc1cc(F)c(S(N)(=O)=O)cc1C

Procedure:
The moist 2-acetamido-4-fluoro-5-chlorosulphonyltoluene (3) was heated in 650 ml of concentrated ammonium hydroxide until it reached 50°. The resulting solution was cooled and extracted with ethyl acetate, (10×1000 ml). The extracts were combined and concentrated in vacuo, to give a solid. The latter was purified by dissolving the solid in 350 ml of a 20% aqueous solution of sodium hydroxide, filtering this mixture and acidifying the filtrate with concentrated hydrochloric acid. The precipitate, which separated out, was recovered, then dried; yield: 32.9 g (23.4%); m.p.: 205-207°; literature:1 m.p.: 206-208°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([F:36])[CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A mixture of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (10.26 g, 20 mmol), 3-fluorophenylboronic acid (3.36 g, 24 mmol) and sodium carbonate (5.30 g, 50 mmol) in toluene (50 mL), ethanol (10 mL) and water (10 mL) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and the mixture was refluxed under heating under an argon atmosphere for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (6.31 g, 68.7%) as crystals.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[NH:24][C:23](=[O:28])[C:22]3[NH:29][CH:30]=[CH:31][C:21]=3[C:20]=2[CH:19]=1.[CH2:32]([C:34]([O-:36])=[O:35])[CH3:33]>CN(C)C=O>[C:8]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[NH:24][C:23](=[O:28])[C:22]3[NH:29][CH:30]=[CH:31][C:21]=3[C:20]=2[CH:19]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:32]([C:34]([O-:36])=[O:35])[CH3:33]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1)c1ccccc1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 53.1 %

Procedure:
52 μL (0.37 mmol) of triethylamine and then 24 μL (0.20 mmol) of benzoyl chloride are added to 50 mg (0.18 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) suspended in anhydrous dimethylformamide (1 mL). The solution is stirred for 2.5 h at 40° C. The solvent is evaporated and the residue obtained is purified by recrystallization from methanol to give 36 mg (52%) of 8-benzoylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.