Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][N:9]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C>O1CCCC1.ClCCl>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:19]([O:20][CH3:21])[CH3:18])=[O:13])=[CH:10][N:9]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
Oxalyl chloride 12.1 g (95.2 mmol) was added dropwise to a solution of 6-chloronicotinic acid 10.0 g (63.5 mmol) in 100 mL tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h, and then concentrated to give a residue, which was dissolved in 50 mL dichloromethane. The solution thus formed was added to a solution of N,O-dimethylhydroxylamine hydrochloride 12.4 g (126.9 mmol) and triethylamine 25.7 g (253.9 mmol) in 100 mL dichloromethane, stirred at room temperature for 1 h., concentrated, and purified by column chromatography to afford the desired product as colorless oil (9.4 g, 73.8% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([Cl:27])[N:19]=1>C1(C)C=CC=CC=1>[Cl:27][C:20]1[N:19]=[C:18]([NH:16][CH2:15][CH2:14][CH2:13][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: NCCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)nc1NCCCN1CCCCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Potassium carbonate (540 mg, 1.5 eq) and 3-piperidino-propylamine (420 mg, 1 eq) are added successively to 2,6-dichloro-3-nitropyridine (500 mg, 1 eq) in solution in toluene (10 ml). After stirring for 2 hours at a temperature of approximately 20° C., the mixture is concentrated under reduced pressure at 40° C. then water (20 ml) and dichloromethane (70 ml) are added. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the solid obtained, by flash chromatography on silica gel (eluent: heptane/ethyl acetate 3:7 to 100% ethyl acetate), produces the expected compound in the form of a yellow solid (473 mg; 61% yield).
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]2[N:11]([C:12]3[N:13]=[C:14]4[CH2:23][O:22][CH2:21][C:15]4=[CH:16][C:17]=3[CH2:18]2)[C@H:10]([CH3:24])[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O.[O-2].[O-2].[Mn+4]>[CH3:24][C@@H:10]1[CH2:9][NH:8][CH2:20][C:19]2[N:11]1[C:12]1[N:13]=[C:14]3[CH2:23][O:22][CH2:21][C:15]3=[CH:16][C:17]=1[CH:18]=2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc4c(nc3N21)COC4
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNCc2cc3cc4c(nc3n21)COC4
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a solution of 0.050 g (5R,8aR)-5-methyl-3,5,6,8,8a,9-hexahydro-1H-2-oxa-4,4b,7-triaza-cyclopenta[b]fluorene-7-carboxylic acid tert-butyl ester in 3 ml dichloromethane was added in 4 portions in intervals of 30 min 0.20 g manganese dioxide. The mixture was then stirred at room temperature for 18 h. The product was purified by chromatography on silica gel with heptane:ethyl acetate=1:1. to yield a yellow oil which was taken up in 1 ml trifluoroacetic acid and kept at room temperature for 30 min. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was neutralized to pH 12 by addition of 2N sodium hydroxide and extracted with dichloromethane. The dichloromethane phase was washed with half concentrated brine and purified by chromatography on silca gel with dichloromethane:methanol:ammonia=90:10:0.1. to yield 0.011 g of the title compound as slightly yellow oil. (MS 232.1 (M+H+))
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:51]=1.[NH2:60][C:61]1[CH:66]=[CH:65][C:64]([S:67]([N:70]2[CH2:75][CH2:74][CH:73]([NH:76][C:77](=[O:80])[CH:78]=[CH2:79])[CH2:72][CH2:71]2)(=[O:69])=[O:68])=[CH:63][CH:62]=1>O1CCOCC1.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]>[CH:52]1[C:57]2[C:58](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:59]=[C:50]([NH:60][C:61]2[CH:62]=[CH:63][C:64]([S:67]([N:70]3[CH2:71][CH2:72][CH:73]([NH:76][C:77](=[O:80])[CH:78]=[CH2:79])[CH2:74][CH2:75]3)(=[O:68])=[O:69])=[CH:65][CH:66]=2)[N:51]=1
Reactant: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(Nc3cc4ccccc4cn3)cc2)CC1
Temperature: 110 °C
Yield: 0.5 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (0) (0.05 g, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.015 g, 0.03 mmol), cesium carbonate (0.5 g, 2.0 mmol) and 2-chloroquinoline (0.085 g, 0.52 mmol) were added sequentially to a stirred solution of N-[1-(4-amino-benzenesulfonyl)-piperidin-4-yl]-acrylamide in dry dioxane (5 ml) under a nitrogen atmosphere. The mixture was heated to 110° C. for 12 hours. After this time the mixture was cooled to room temperature, filtered through a pad of celite, the celite was washed with EtOAc (50 ml) and the filtrate was washed sequentially with citric acid (10% solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by prep HPLC to give the title compound (0.002 g, 0.5% yield) as a white solid.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1>>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:33]2[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[CH2:35][CH2:34]2)=[O:17])=[CH:14][CH:13]=1)[C:8](=[O:11])[CH2:9][Cl:10])([CH3:3])[CH3:2]
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)Cl)cc1
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(F)cc3)CC2)cc1

Procedure:
Analogously to Example 55, 1.5 g of 4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl chloride are reacted with 0.9 g of [2-(4-fluorophenyl)ethyl]piperazine, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-fluorophenyl)ethyl]piperazine. The hydrochloride thereof melts at 166°-167°.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:15][C:16]#[N:17])=[CH:7][C:8]([N+:12]([O-])=O)=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni]>[C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[CH:7][C:6]=1[S:15][C:16]#[N:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(N)c([N+](=O)[O-])cc1SC#N
Agent: [Ni]
Product: CC(C)(C)c1cc(N)c(N)cc1SC#N

Procedure:
5-tert-Butyl-2-nitro-4-thiocyanato-phenylamine (prepared in Example QQ-2; 3 g, 12 mmol) was hydrogenated using Raney nickel (0.75 g) in the presence of hydrogen as described in General Method 3. MS(APCI): 222(M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:18]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCCBr
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of ethyl 4-bromobutyrate (2.0 g, 10.25 mmol), dibenzylamine (2.02 g, 10.25 mmol) and potassium carbonate (2.83 g, 20.5 mmol) in N,N-dimethylformamide (20 mL) was heated with stirring at 100° C. overnight. The resulting mixture was diluted with water (80 mL) and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (80 mL×2), and then dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc:PE=1:4) to afford ethyl 4-(dibenzylamino)butanoate as a white solid (2.0 g, yield: 64%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[C:4]([N+:20]([O-])=O)[C:3]=1[NH:23][C@@H:24]1[CH2:29][C@@H:28]2[CH2:30][C@@H:26]([C:27]2([CH3:32])[CH3:31])[C@H:25]1[CH3:33].[H][H]>CO.[C].[Pd]>[NH2:20][C:4]1[C:3]([NH:23][C@@H:24]2[CH2:29][C@@H:28]3[CH2:30][C@@H:26]([C:27]3([CH3:31])[CH3:32])[C@H:25]2[CH3:33])=[CH:2][C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[O:11])[N:5]=1
Reactant: [H][H]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1c([N+](=O)[O-])nn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cc(=O)n(CC(=O)NCc3ccncc3)nc1N)C2(C)C
Yield: 17.3 %

Procedure:
2-[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (11 mg, 0.0211 mmol) in methanol (1 mL) was stirred with 10 mass % palladium-carbon (about 5 mg) in a hydrogen atmosphere at room temperature for 2.5 hours. The reaction solution was filtered through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the desired product (1.5 mg, 17% yield).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[Br:15]Br.S([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[Br:15][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)Cc1ccccc1-2
Reaction time: 5 h
Yield: 78.6 %

Procedure:
In a three-liter flask having four openings equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, respectively, 237 g (1.4 mol) of fluorene, 1 L of water, three drops of a surfactant, and five drops of sulfuric acid were placed and stirred to mix. By adding 230 g (1.4 mol) of bromine into the mixture, a reaction was started. After the reaction had been conducted at room temperature for 5 hours, unreacted bromine was decomposed with an aqueous solution of sodium hydrogen sulfite. The reaction product, which was a light yellow solid, was filtered and thus 334 g of a crude product was obtained. The crude product was dissolved in toluene and was subsequently washed with water and a sodium hydrogencarbonate aqueous solution. The resulting organic liquid was dried using anhydrous magnesium sulfate. After filtration, the liquid was concentrated and then allowed to stand at 0° C., so that a white solid was precipitated. The precipitate was filtered and subsequently washed with toluene, followed by drying. Thus, 287 g (1.1 mol, yield of 82%) of a white solid product was obtained. This product was subjected to gas chromatography and the purity of the product was 98.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[OH:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=2)(=[O:31])=[O:30])=[C:3]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[OH:10])[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: COc1cccc(C(O)c2cc(Cl)ccc2N)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cccc(C(O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC)c(OC)c2)c1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To 1 g of (2-amino-5-chlorophenyl)(3-methoxyphenyl)methanol dissolved in 6 ml of pyridine are added, at room temperature, 1.08 g of 3,4-dimethoxybenzenesulfonyl chloride. After 18 hours, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 1.65 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:49]([O:51][CH3:52])=[O:50]>C(Cl)Cl>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:49](=[O:50])[O:51][CH3:52])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a 50 mL round bottom flask charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (380 mg, 0.705 mmol) in DCM (10 ml) was added pyridine (1 ml) followed by methyl chloroformate (65 μl, 0.847 mmol). The flask was capped and the contents stirred at room temperature for 16 h. An additional aliquot of methyl chloroformate (65 μL, 0.847 mmol) was added to push the reaction to completion. The volatiles were removed in vacuo, the resulting residue redissolved in DCM and washed with saturated copper sulfate solution (2×10 mL). The organics were separated using a phase separator cartridge and concentrated. The resulting residue was purified by flash column chromatography on silica gel (ISCO; 80 g prepacked) eluting with ethyl acetate/hexanes to give (R)-methyl (6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (371 mg, 0.622 mmol, 88%) as a white solid. MS ESI calc'd. For C36H33N6O3 [M+H]+ 597. found 597.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[C:19]12(C3C=CC(Br)=CC=3O)[CH2:28][CH:23]3CC(C[CH:21]([CH2:22]3)[CH2:20]1)C2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[C:15]12([C:4]3[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=3[O:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH2:18][CH:21]3[CH2:22][CH:23]([CH2:28][CH:19]([CH2:20]3)[CH2:16]1)[CH2:17]2
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc(OC2CCCCO2)c(C23CC4CC(CC(C4)C2)C3)c1

Procedure:
Using the same general procedure as for the preparation of of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 9.17 g (29.9 mmol) of 2-(1-adamantyl)-4-bromophenol (Compound F), 0.75 g (3.0 mmol) of pyridinium p-toluenesulfonate, 3.77 g (4.1 ml, 44.8 mmql) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane produced a bright yellow solid. Purification by flash chromatography (preabsorbed onto silica with chloroform, eluted with 2% ethyl acetate in hexane) yielded the title compound as a nearly white solid. PMR (CDCl3): d 1.6-2.2 (21H, m), 3.6-3.7 (1H, m), 3.8-3.9 (1H, m), 5.43 (1H, t, J=2.4 Hz), 7.05 (1H, d, J=8.7 Hz), 7.23 (1H, dd, J=8.7, 2.5 Hz), 7.30 (1H, d, J=2.5 Hz).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.C1(C)C=CC=CC=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)([CH3:24])[CH3:23])=[CH:18][CH:17]=1.C(O)(C)C>S(=O)(=O)(O)O.O>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([C:25]2[CH:26]=[CH:27][C:28]([N:31]3[C:1](=[O:7])[CH:2]=[CH:3][C:4]3=[O:6])=[CH:29][CH:30]=2)([CH3:24])[CH3:23])=[CH:20][CH:21]=1
Reactant: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(c1ccc(O)cc1)c1ccc(N2C(=O)C=CC2=O)cc1
Reaction time: 0.75 h
Yield: 478.3 %

Procedure:
To a reaction vessel equipped with a stirrer, thermometer and an azeotropic distillation trap, 60 g (0.1 mole) of maleic anhydride, 480 g of toluene and 2.6 g of 95% sulfuric acid were charged and heated to a reflux temperature. A solution containing 114 g (0.5 mole) of 2-(4-hydroxyphenyl)-2-(4-aminophenyl)propane in 160 g of N,N'-dimethylacetamide was dropwise added from a dropping funnel over 4 to 5 hours and reacted for 5 hours at the same temperature. Generated water by the reaction was removed by azeotropic distillation. After completing the reaction, the reaction mixture was cooled to 80° to 90° C. and the solvent was successively removed under reduced pressure. The organic layer thus obtained was mixed with 100 ml of isopropyl alcohol and then 300 ml of water was added and stirred for 0.5 to 1 hour to precipitate crystals. The crystals were filtered and dried to obtain 147 g of 2-(4-hydroxyphenyl)-2-(4-maleimidophenyl)propane as yellow crystals. The yield was 96%.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:17]=[C:18]([C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:19]=2)=[O:14])=[CH:9][C:8]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=O.[OH-].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:48](I)[CH2:49][CH:50](C)C>O1CCCC1.CN(C)C=O.O.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(O)C>[CH2:26]([N:16]1[CH:17]=[C:18]([C:20](=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])[CH:19]=[C:15]1[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:4][CH2:3][CH:2]([CH3:1])[CH3:38])=[C:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH2:37][CH:49]([CH3:50])[CH3:48])=[O:34])[CH:9]=1)=[O:14])[CH2:27][CH:28]([CH3:29])[CH3:30]
Reactant: CC(C)CCI
Reactant: CCOC(=O)CCc1cc(C(=O)c2cc(C(=O)CC(C)C)cn2CCC(C)C)ccc1OC(=O)CC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCOC(=O)CCc1cc(C(=O)c2cc(C(=O)CC(C)C)cn2CCC(C)C)ccc1OCCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.68 g of 2-(3-ethoxy-3-oxopropyl)-4-{[1-isopentyl-4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}phenyl 3-methylbutanoate in 4 ml of tetrahydrofuran is dropwise added to a mixture of 14 ml of ethanol and 13 ml of 1 mol/L sodium hydroxide solution at 40-50° C., and the mixture thus obtained is stirred at the same temperature as above for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is dissolved in 14 ml of N,N-dimethylformamide, 0.89 g of potassium carbonate and 0.9 ml of isopentyl iodide are added, and the mixture thus obtained is stirred at 100° C. for 15 minutes. The reaction mixture cooled to ambient temperature is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.69 g of isopentyl 3-[5-{[1-isopentyl-4-(3-methylbutanoyl)-1H-pyrrol-2-yl]carbonyl}-2-(isopentyloxy)phenyl]propanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.BrC1C=C(NC2C=CC(N3CCN(C4COC4)C[C@@H]3C)=CN=2)C(=O)N(C)C=1.[C:55]([O:58][CH2:59][C:60]1[C:61]([N:75]2[CH2:87][CH2:86][N:78]3[C:79]4[CH2:80][CH2:81][CH2:82][CH2:83][C:84]=4[CH:85]=[C:77]3[C:76]2=[O:88])=[N:62][CH:63]=[CH:64][C:65]=1B1OC(C)(C)C(C)(C)O1)(=[O:57])[CH3:56].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].C(#N)C.O>[C:55]([O:58][CH2:59][C:60]1[C:61]([N:75]2[CH2:87][CH2:86][N:78]3[C:79]4[CH2:80][CH2:81][CH2:82][CH2:83][C:84]=4[CH:85]=[C:77]3[C:76]2=[O:88])=[N:62][CH:63]=[CH:64][C:65]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:57])[CH3:56]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[C@H]1CN(C2COC2)CCN1c1cnc(Nc2cc(Br)cn(C)c2=O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (S)-5-bromo-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrazin-2-ylamino)pyridin-2(1H)-one (90 mg, 0.21 mmol) 191i, 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (80.4 mg, 0.21 mmol), Pd(dppf)Cl2 (17.2 mg, 0.021 mmol), K3PO4 (89 mg, 0.42 mmol), sodium acetate (57.1 mg, 0.42 mmol), water (0.5 mL), and acetonitrile (30 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 228a as brown solid (60 mg, 42%). MS-ESI: [M+H]+ 694.3.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][CH:8]=[C:9]2[C:14](=[O:15])OC(C)(C)OC2=O)=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][O:24][CH3:25])#[N:2].C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[C:1]([C:3]1[CH:20]=[C:19]2[C:6](=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][O:24][CH3:25])[NH:7][CH:8]=[CH:9][C:14]2=[O:15])#[N:2]
Reactant: COCCOc1cc(NC=C2C(=O)OC(C)(C)OC2=O)ccc1C#N
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COCCOc1cc2[nH]ccc(=O)c2cc1C#N
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
5-((4-Cyano-3-(2-methoxyethoxy)anilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (840 mg, 2.4 mmol) was added in portions to a mixture of biphenyl (8 ml) and phenyl ether (22 ml) at 250° C. and the mixture stirred at that temperature for 30 minutes. The mixture was allowed to cool, hexane was added and the solid product collected by filtration and recrystallised from methylene chloride/methanol/hexane to give 6-cyano-7-(2-methoxyethoxy)-1,4-dihydroquinolin-4-one (230 mg, 38%).