Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]3[NH:19][C:18]4[CH2:17][CH2:16][C:15](=[O:20])[CH2:14][C:13]=4[C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:20][CH:15]1[CH2:16][CH2:17][C:18]2[NH:19][C:10]3[CH:9]=[N:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:12][C:11]=3[C:13]=2[CH2:14]1
Reactant: O=C1CCc2[nH]c3cnc(-c4ccccc4)nc3c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCc2[nH]c3cnc(-c4ccccc4)nc3c2C1

Procedure:
To a mixture of 2-Phenyl-5,6,7,9-tetrahydro-8H-indolo[3,2-d]-pyrimidin-8-one (200 mg) and dry tetrahydrofuran (5 mL) was added lithium aluminum hydride (100 mg) in one portion. After 1 h at room temperature the reaction was quenched with 1N NaOH, the reaction was filtered through celite and the solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel with 10% methanol in methylene chloride as the eluent to afford 8-Hydroxy-2-phenyl-6,7,8,9-tetrahydro-5H-indolo[3,2-d]-pyrimidine (Compound 31) melting at 211°-212° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (3.80 g, 18.2 mmol) in carbon tetrachloride (50 ml) were added N-bromosuccinimide (3.54 g, 19.9 mmol) and 2,2′-azobis(isobutyronitrile) (136 mg, 0.83 mmol), and the mixture was heated under reflux for 4 hrs. After cooling, the reaction solution was filtered, and the filtrate was concentrated to give ethyl 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(2-fluoropyridin-4-yl)-3-oxopropionate (3.5 g, 16.6 mmol) in 1,2-dimethoxyethane (35 ml) was added sodium hydride (60% in oil, 0.66 g, 16.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1) to give ethyl 3-(2-fluoropyridin-4-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (4.78 g, 69%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 116.8 %

Procedure:
A solution of nickel (II) chloride hexahydrate (180 mg, 0.8 mmol) and (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylic acid methyl ester (695 mg, 2.0 mmol) in methanol (15 mL) was cooled to 0° C. and then treated with sodium borohydride (454 mg, 12 mmol) in five portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 d. The reaction mixture was concentrated in vacuo, and the residue was diluted with a 3N aqueous hydrochloric acid solution (50 mL) and ethyl acetate (75 mL). The two layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid methyl ester (815 mg, 99%) as a viscous oil: EI-HRMS m/e calcd for C17H21ClN4O2 (M+) 348.1353, found 348.1359.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH2:16]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH2:16]([N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[Br:1])=[O:6])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: Cc1cccc(C(=O)O)c1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1cccc(C(=O)c2nccn2Cc2ccccc2)c1Br
Temperature: 60 °C
Yield: 102.3 %

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (2.0 g, 9.3 mmol) in thionyl chloride (4.75 ml, 65.1 mmol) was heated at 65° C., under nitrogen, for 3 h. The mixture was concentrated in vacuo and to the residue was added acetonitrile (25 ml). This solution was concentrated in vacuo and the process was repeated. To the final residue was added acetonitrile (25 ml), 1-benzylimidazole (1.62 g, 10.2 mmol) and triethylamine (1.44 ml, 10.2 mmol) and the reaction mixture was heated at 60° C., under nitrogen, for 18 h. The mixture was concentrated in vacuo and to the residue was added ethyl acetate (80 ml). The solution was washed with water (40 ml) and saturated aqueous sodium hydrogen carbonate solution (40 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (3.38 g).
Reaction SMILES: CC(N1CCN(CC(O)=O)CCN(C(C)C(O)=O)CCN(C(C)C(O)=O)CC1)C(O)=O.C1(C[O:39][CH2:40][CH:41]([N:45]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]([OH:60])=[O:59])[CH2:53][CH2:52][N:51]([CH:61]([CH2:65][O:66]CC3C=CC=CC=3)[C:62]([OH:64])=[O:63])[CH2:50][CH2:49][N:48]([CH:74]([CH2:78][O:79]CC3C=CC=CC=3)[C:75]([OH:77])=[O:76])[CH2:47][CH2:46]2)[C:42]([OH:44])=[O:43])C=CC=CC=1>>[OH:66][CH2:65][CH:61]([N:51]1[CH2:52][CH2:53][N:54]([CH2:57][C:58]([OH:60])=[O:59])[CH2:55][CH2:56][N:45]([CH:41]([CH2:40][OH:39])[C:42]([OH:44])=[O:43])[CH2:46][CH2:47][N:48]([CH:74]([CH2:78][OH:79])[C:75]([OH:77])=[O:76])[CH2:49][CH2:50]1)[C:62]([OH:64])=[O:63]
Reactant: O=C(O)CN1CCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CC1
Agent: CC(C(=O)O)N1CCN(CC(=O)O)CCN(C(C)C(=O)O)CCN(C(C)C(=O)O)CC1
Product: O=C(O)CN1CCN(C(CO)C(=O)O)CCN(C(CO)C(=O)O)CCN(C(CO)C(=O)O)CC1

Procedure:
By way of example of the huge potentialities given by this synthetic route, the synthesis of the novel compound, α,α',α"-tris(methyl)-1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid, is reported in Experimental section: ##STR12## as well as that of α,α',α"-tris [(phenylmethoxy)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ##STR13## which, by catalytic hydrogenation, as described in example 6 of the cited Patent, yields α,α',α"-tris(hydroxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. ##STR14##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:15]1[C:20]([C:21]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=2)=[CH:19][C:18]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:17][N:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl>CN(C=O)C.O>[NH2:28][C:23]1[N:24]=[C:25]([CH3:27])[N:26]=[C:21]([C:20]2[C:15]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:16][CH:17]=[C:18]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:19]=2)[N:22]=1
Reactant: Cc1nc(N)nc(-c2cc(C3CCOCC3)cnc2F)n1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N)nc(-c2cc(C3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Reaction time: 1.5 h

Procedure:
To a solution of N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (60 mg, 0.271 mmol) and 4-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (55 mg, 0.190 mmol) in anhydrous DMF (1 mL) cooled in an ice bath was added solid NaHMDS (210 mg, 1.088 mmol) under nitrogen. The resulting orange mixture was stirred with cooling. After 1.5 h, HCl (5N, 0.25 mL, 1.25 mmol) was added to the mixture. The resulting mixture was diluted with water (5 mL) and acidified with HCl, 5N) to about pH 5. The resulting slurry was filtered and washed with water (3×3 mL). The solid was washed with EtOAc to afford the product as a brown solid. The mother liquid was chromatographed on silica gel (0-5% MeOH in EtOAc) to give additional product. The combined product was about mg (32%). m/z (ESI, positive ion): 491.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.82 (m, 4H) 2.46 (s, 3H) 2.84 (t, J=11.35 Hz, 1H) 3.12 (s, 3H) 3.46 (t, J=10.76 Hz, 2H) 3.97 (d, J=12.13 Hz, 2H) 7.78 (br. s., 1H) 7.92 (br. s., 1H) 8.33 (s, 1H) 8.64 (d, J=3.33Hz, 2H) 8.72 (s, 1H) 9.64 (br. s., 1H) 12.17 (s, 1H).
Reaction SMILES: C(O)(=O)C(O)=O.[O:7]1[CH:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:8]1[CH2:9][NH:10][CH2:11]2.[OH-].[Na+]>>[N:10]1[C:9]2[CH:8]=[CH:14][CH:15]=[CH:16][C:17]=2[CH:18]=[CH:13][CH:12]2[O:7][C:11]=12
Reactant: c1ccc2c(c1)C1CNCC2O1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C1=CC2OC2=Nc2ccccc21
Yield: 103.8 %

Procedure:
The product prepared in Example 19 (3.85 g, 0.15M) was made basic with NaOH, partitioned between H2O and CH2Cl2, and the organic layer dried (Na2SO4) and evaporated to give the 3-H-epoxybenzazepin (2.50 g, 0.015M). This compound was treated with propionic anhydride (10 ml) and allowed to stir for two hours. Excess propionic anhydride was removed in vacuo to give 3-propoxy-epoxybenzazepin as a white solid (3.3 g, 98% yield).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:39][C@@H:40]1[CH2:45][CH2:44][C@H:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C@@H:42]([F:54])[CH2:41]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:54][C@H:42]1[CH2:41][C@H:40]([OH:39])[CH2:45][CH2:44][C@@H:43]1[NH:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:50])[CH3:52]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C[C@@H]1F
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (11.9 g; 36.7 mmol) is added to a solution of tert-butyl [(1S*,2S*,4R*)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-fluorocyclohexyl]carbamate (example C18; 8.7 g; 18.3 mmol). The reaction mixture is stirred over night at ambient temperature. The solvent is removed under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt—60:40 to 40:60) to yield 4.2 g of the title compound as colourless oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.Cl[CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][N:26]([CH3:28])[C:24](=[O:25])[CH2:23][N:2]([CH3:1])[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(C)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (90 mg, 0.30 mmol, 1.00 equiv) in DMF (10 mL) was added 2-chloro-N,N-dimethylacetamide (54.45 mg, 0.45 mmol, 1.50 equiv) and potassium carbonate (83 mg, 0.60 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (5.0% CH3CN up to 49.0% in 13 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired N,N-dimethyl-2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]acetamide (31.8 mg) as a white solid. MS (ES, m/z): 388 (M+H+). 1H NMR (400 MHz, DMSO): δ 8.25 (s, 1H), 5.98 (d, 1H), 4.01-4.04 (m, 1H), 3.22 (s, 2H), 3.08 (t, 2H), 3.03 (s, 3H), 2.93 (t, 2H), 2.80 (s, 3H), 2.42-2.44 (m, 3H), 2.20 (s, 3H), 1.97-2.00 (m, 2H), 1.78-1.81 (m, 2H), 1.24-1.48 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CO
Product: O=C1CCN(C(=O)c2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 89.4 %

Procedure:
After 6-bromopicolinic acid (600 mg, 2.97 mmol) was suspended in acetonitrile (25 ml), 4-piperidone monohydrate hydrochloride (500 mg, 3.27 mmol), N,N-diisopropylethylamine (1 ml, 7.43 mmol), and HBTU (1.1 g, 3.56 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 13 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of MC (50 ml), and then washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (3% MeOH/MC), to obtain 752 mg of yellow solid (89%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][OH:12].[OH-].[K+]>C(O)C>[OH:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCl
Reactant: C1CCCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCCN1CCCCCC1
Yield: 88 %

Procedure:
A solution of 1 mole of azepane and 0.5 mole of 3-chloro-1-propanol in 500 ml of ethanol was refluxed for 18 hours. The reaction mixture was treated with 0.55 mole of KOH and refluxed for 0.75 hour. Cooling, filtration and distillation yielded 88% of N-(3-hydroxypropyl)azepane (b.p.=136° C. at 21 mm; analysis for C9H19NO, calculated: %N=8.91; found: %N=8.30).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([N:31]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]>>[C:28]([N:31]([C:32]1[CH:37]=[CH:36][C:35]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:34][CH:33]=1)[CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])(=[O:30])[CH3:29]
Reactant: CC(=O)N(CCCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(CCCN(C)C)C(C)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-acetyl-N-(3-dimethylamino-propyl)-p-phenylenediamine
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:14]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([NH:28][C:29]3[N:34]=[C:33]([N:35]([CH:45]4[CH2:47][CH2:46]4)[CH2:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=4)[C:32]4=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]4[N:30]=3)[C:21]=2[Cl:53])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:18][CH2:17][C:16]([NH:15][C@@H:14]1[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([NH:28][C:29]3[N:34]=[C:33]([N:35]([CH:45]4[CH2:47][CH2:46]4)[CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[C:32]4=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]4[N:30]=3)[C:21]=2[Cl:53])[CH2:10][C@H:9]1[OH:8])=[O:19]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)CCl)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)CCl)[C@H](O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To (+/−)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)-2-chloroacetamide (43 mg, 0.055 mmol) in THF (1 mL) was added TBAF (1M in THF, 0.112 mL, 0.112 mmol) and the reaction solution was stirred at room temperature overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0.5-4% methanol/dichloromethane) to give (+/−)-2-chloro-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)acetamide (22 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH2:32][CH3:33])[N:10]=[C:9]2[CH3:34])[CH:5]=[CH:6][CH:7]=1.[CH:35]([Sn](CCCC)(CCCC)CCCC)=[CH2:36].[Cl-].[Li+].[F-].[K+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:30]([C:11]1[N:10]=[C:9]([CH3:34])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:35]=[CH2:36])[CH:3]=2)[C:13](=[O:14])[C:12]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH2:31][CH2:32][CH3:33]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCc1nc(C)n(-c2cccc(Br)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cccc(-n2c(C)nc(CCCC)c(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A suspension of 4′-{[1-(3-bromophenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g), vinyltributyltin (0.86 mL), dichlorobis(triphenylphosphine)palladium(II) and lithium chloride (0.25 g) in N,N-dimethylformamide (10 mL) was stirred at 90° C. for 3 hr under an argon atmosphere. The mixture was allowed to cool to room temperature, 20% aqueous potassium fluoride solution was added, and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.45 g, 50%).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:10][N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2-c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2nn(-c3ccccc3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 4-(4-methoxy-1-phenyl-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (82.0 mg) in acetonitrile (10 mL) were added sodium iodide (64.6 mg) and chloro(trimethyl)silane (0.218 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate to give the title compound (79.0 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])C=C>C(Cl)Cl>[F:14][C:11]([F:12])([F:13])[O:10][C:8]1[CH:7]=[CH:6][C:5]2[NH:15][C:16](=[O:19])[CH:17]=[CH:18][CH2:1][C:4]=2[CH:9]=1
Reactant: C=CCc1cc(OC(F)(F)F)ccc1NC(=O)C=C
Solvent: ClCCl
Product: O=C1C=CCc2cc(OC(F)(F)F)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-allyl-4-(trifluoromethoxy)phenyl)acrylamide (15 g, 55.3 mmol) in DCM (800 ml) was added Zhan catalyst I (2.0 g, 2.77 mmol) and the mixture was stirred at room temperature for 3 hrs. The resulting mixture was concentrated under reduced pressure to give a crude solid that was recrystallized from ethyl acetate to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].F[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26]>CCO>[CH2:12]([C:4]1[S:3][C:2]([NH:1][C:15]2[C:16]([N+:25]([O-:27])=[O:26])=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]([F:22])([F:24])[F:23])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1F
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1c([N+](=O)[O-])cccc1C(F)(F)F

Procedure:
Ethyl 2-amino-5-ethylthiophene-3-carboxylate and 2-fluoro-3-trifluoromethylnitrobenzene, m.p. 72°-73° C. (EtOH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:20](Cl)(=[O:32])[O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[C:25]([Cl:31])[CH:24]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[C:25]([Cl:31])[CH:24]=2)=[O:32])[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: N#Cc1cc(Cl)cc(COC(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (1.045 g, 5.22 mmol) in DCM (25 mL) at RT was added a saturated solution of sodium bicarbonate (5.6 ml). 3-Chloro-5-cyanobenzyl carbonochloridate (Example 36, step 4) (1.2 g, 5.22 mmol) was then added in DCM (2 ml) and the reaction mixture stirred at RT for 2 hours. The layers were separated and the organic portion was washed with a saturated solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product;