Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]2[C:6]=1[NH:7][CH:8]([O:18][CH3:19])[CH:9]([O:16][CH3:17])[NH:10]2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]2[C:6]=1[NH:7][CH:8]([O:18][CH3:19])[CH:9]([O:16][CH3:17])[NH:10]2
Reactant: COC1Nc2cc(Br)cc(CN=[N+]=[N-])c2NC1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC1Nc2cc(Br)cc(CN)c2NC1OC
Temperature: 20 °C
Reaction time: 4 h

Procedure:
4.47 g (13.8 mmol) of 5-azidomethyl-7-bromo-2,3-dimethoxy-1,2,3,4-tetrahydroquinoxaline are dissolved in 35 ml of tetrahydrofuran, and 3.98 g (1.1 equiv.) of triphenylphosphine are added. The mixture is stirred at 20° C. for 4 hours. 746 mg of water are added and the mixture is stirred for a further three hours. The solid is filtered off and the filtrate is extracted with ethyl acetate and sodium carbonate solution. The organic phases are combined, washed with brine, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/petroleum ether (1:1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:23])(=[O:22])[N:13]([CH3:21])[C:14]([C:17](OC)=[O:18])=[C:15]([OH:16])[C:4]1=2)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>C1(C)C(C)=CC=CC=1>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:23])(=[O:22])[N:13]([CH3:21])[C:14]([C:17]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:18])=[C:15]([OH:16])[C:4]1=2)[CH3:2]
Reactant: Nc1ccccn1
Reactant: CCn1c2c(c3ccccc31)S(=O)(=O)N(C)C(C(=O)OC)=C2O
Solvent: Cc1ccccc1C
Product: CCn1c2c(c3ccccc31)S(=O)(=O)N(C)C(C(=O)Nc1ccccn1)=C2O
Yield: 72 %

Procedure:
5-Ethyl-2,5-dihydro-4-hydroxy-2-methyl-N-(2-pyridyl)-1,2 thiazino[5,6-b]indole-3-carboxamide 1,1-dioxide was prepared analogous to Example 15 from methyl 5-ethyl-2,5-dihydro-4-hydroxy-2-methyl-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 2-amino-pyridine with a yield of 72% of theory. M.p.: 232° C. (decomposition, from xylene).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: Cn1cc(Cn2nc(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c3cc(OC(F)F)ccc32)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a solution of 2-[5-difluoromethoxy-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (56 mg, 0.09 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was dissolved in CH2Cl2 (2 mL) and ethylenediamine (0.2 mL, 2.96 mmol) was added. The reaction mixture was stirred at room temperature for 30 min then quenched with water and extracted with 5% MeOH/CH2Cl2. The organics were dried over MgSO4 and concentrated. The residue was triturated with EtOAc/Et2O and the product was collected via filtration to afford 29 mg (65%) of 2-[5-difluoromethoxy-1-(1-methyl-1H-pyrazol-4-ylmethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow solid. MS: (M+Na)+=517; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.62 (br. s., 1H), 8.97 (s, 1H), 8.26 (s, 1H), 8.06 (d, J=1.9 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.74 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.27 (dd, J=9.1, 1.9 Hz, 1H), 7.06 (7, J=75 Hz, 1H), 5.51 (s, 2H), 3.19 (s, 6H), 1.36 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22](=[O:23])[NH:13][CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:26]
Reactant: CCN(CC)CCC(CN)c1ccc(OC)c(OC)c1
Reactant: CCOC(N)=O
Product: CCOC(=O)NCC(CCN(CC)CC)c1ccc(OC)c(OC)c1

Procedure:
From 2-(3,4-dimethoxyphenyl)-4-diethylamino-butylamine in analogy to 3a. The urethane was further reacted in a crude state.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[C:35]([Cl:39])=[CH:36][CH:37]=[CH:38][C:33]=4[Cl:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(Cl)cccc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,6-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=80%.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=2)[CH:22]=[O:23])=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[BH4-].[Na+].O.Cl>CO>[F:1][C:2]([F:33])([F:34])[C:3]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH2:22][OH:23])[CH:24]=2)=[C:14]([CH2:30][CH2:31][CH3:32])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:5])([F:7])[F:6]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(CO)c1
Yield: 99.7 %

Procedure:
To a solution of 5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrobenzaldehyde (576 mg, 1.16 mmol) in methanol (5.8 mL), sodium borohydride (46 mg, 1.22 mmol) was added under ice-cold conditions, and the resultant mixture was stirred under ice-cold conditions for 20 minutes. The reaction solution was added with water and 5% aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. (5-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-nitrophenyl) methanol (575 mg, yield 99%) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:14][CH2:15][CH3:16])[C:11]([OH:13])=O.Cl.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:11](=[O:13])[CH:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[F:1])[O:14][CH2:15][CH3:16])=[CH:22][CH:21]=1)#[N:18]
Reactant: CCOC(C(=O)O)c1c(F)ccc(O)c1F
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F
Temperature: 0 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
To an ice cooled mixture under Ar of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid, 4-aminomethyl-benzonitrile hydrochloride (10.6 g) and 1-hydroxybenzotriazole (9.8 g) in DMF (140 ml) was added EDC (13.9 g) and triethylamine (55 ml). The mixture was stirred 2.5 h at 0° C. and 2 d at rt. The solvent was evaporated and H2O (250 ml) was added. The product was extracted with AcOEt (2×200 ml). The organic layers were washed with 5% NaHCO3 aq. sol. (100 ml), brine 100 ml). After drying (Na2SO4) the solvent was evaporated. CC (AcOEt/Hept 2:3) afforded 7.66 g (49%) of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-ethoxy-acetamide. White solid. MS 364.1 ([M+NH4]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([Cl:18])=[O:13])[S:10][C:3]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 100 mL round bottom flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.500 g, 2.28 mmol), methylene chloride (15 ml), and 6 drops of DMF. Oxalyl chloride (0.248 ml, 2.85 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours then concentrated in vacuo to yield 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride as a brown solid. This material was suspended in chloroform (5 mL). N′-hydroxyacetamidine (0.186 g, 2.50 mmol), triethylamine (0.347 ml, 2.50 mmol), and chloroform (15 mL) were stirred together in a 50 mL flask to form a slurry, which was slowly added to the 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride suspension, then stirred for 1.5 hours at room temperature. The reaction mixture was diluted with chloroform (50 mL) and washed with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown solid was triturated with toluene, and the precipitate collected to obtain the title compound (0.282 g, 46% yield) as a tan solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:10]2[NH:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[O:24][CH3:25])[CH2:7]1)=O)[CH3:2].[O-]S([O-])(=O)=O.[Na+].[Na+].CS(O)(=O)=O>C1COCC1.CC(C)=O>[CH2:39]([N:3]([CH2:4][CH:6]1[CH2:7][N:8]2[CH2:13][CH2:12][CH:11]1[CH:10]([NH:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])[CH:9]2[CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:1][CH3:2])[CH3:40]
Reactant: CCN(CC)C(=O)C1CN2CCC1C(NCc1cc(OC)ccc1OC)C2C(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CC1CN2CCC1C(NCc1cc(OC)ccc1OC)C2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A solution of 19 (300 mg, 0.55 mmole) in dry THF (2 ml) was added to a suspension of LiAIH4 (105 mg, 2.75 mmole) in 5 ml of dry THF at 5° C. and stirred at room temperature for 1 hour. Na2SO4 /10H2O (2 g) was added to the reaction mixture and stirred for 15 hours at room temperature. The suspension was filtrated, and the solids were washed with dry THF. The filtrate was concentrated under reduced pressure. The resulting oil was dissolved in 2 ml of acetone, and CH3SO3H (159 mg, 1.65 mmole) was added to the solution of the crude oil in acetone (2 ml). The resulting precipitate was collected by filtration and dried in vacuo to give 20 (254 mg, 0.31 mmole, 57%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([S:24]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:19][CH2:18]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([S:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:19][CH2:18]3)=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)nc4)ccc32)cc1
Temperature: 90 °C
Yield: 62.9 %

Procedure:
236.5 mg 2-(Trifluormethyl)pyridin-5-ylboronic acid, 300.0 mg 4-(5-Bromo-2,3-dihydro-indole-1-sulfonyl)-benzonitrile and 807.4 mg cesium carbonate were dissolved in a mixture of 3 ml water and 10 ml dimethylformamide. The reaction mixture was degassed with argon and then 47.7 mg tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 90° C. for two hours. The cooled reaction mixture was diluted with 100 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 223 mg 4-[5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(Cl)(=O)=[O:35])=CC=1.[O-][O-].[Na+].[Na+]>C(#N)C.O>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35]
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [O-][O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Yield: 55.9 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mmol) is dissolved with stirring in acetonitrile (40 ml). The resulting solution is stirred while p-toluene- sulphonyl chloride (2.38 g, 12.5 mmol) added. The reaction mixture is cooled in an ice-water bath. A solution of sodium peroxide (2.42 g, 31 mmol) in water (30 ml) is added dropwise over 20 minutes. After a further 2 hours the reaction mixture is filtered under vacuum and the filtrate evaporated in vacuo. Water is added and the resulting solid collected, and washed with water and ether to give (tolyl)diphenylsulphoxonium hexafluorophosphate (0.63 g, 56%) with spectra identical to authentic material.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=O.C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([O:30][CH3:31])[C:22]=3[O:21][CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COc1ccc(CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 1.27 g of the compound (9) synthesized in Example 2 and 0.8 g of 2,3,4-trimethoxybenzaldehyde was stirred at 120° C., then, 0.18 ml of formic acid was added dropwise. This was stirred for one hour at the same temperature, then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added and the results were shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the above-referenced compound (29) in an amount of 1.46 g (yield 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]1=2>C(O)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[N:1]1[C:13](=[O:14])[C:12]2[CH2:16][CH2:17][CH2:18][CH2:19][C:11]=2[C:10]1=[O:15]
Reactant: Nc1cc(O)ccc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Yield: 80.3 %

Procedure:
3-Amino-4-fluorophenol (V) (2 g) and 3,4,5,6-tetrahydrophthalic anhydride (2.4 g) were dissolved in acetic acid (50 ml), and the resultant solution was heated under reflux for lhour, followed by extraction with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration and washed with a small amount of ether to give 3.3 g of N-(2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI). M.P. 164.6° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2=[N:6][C:7]=1[CH2:8][OH:9]>C1(C)C=CC=CC=1>[CH2:13]([C:11]1[N:10]([CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2=[N:6][C:7]([CH2:8][OH:9])=[C:2]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=3)[CH:3]=[C:4]2[N:12]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc2cc(Br)c(CO)nc2n1CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cc(-c3ccccn3)c(CO)nc2n1CC(=O)c1ccccc1
Temperature: 25 °C
Yield: 141.4 %

Procedure:
1 g(0.00249 mole) of the compound obtained in step 7 of Example 1 was dissolved in 10 ml of toluene and to the resulting solution were 1 g(0.00274 mole) of 2-tributyltin pyridine and 0.058 g(0.00005 mole) of tetrakistriphenyl-phosphine palladium. The resultant was refluxed for 24 hours, and cooled to room temperature after the completion of the reaction. The reaction solution was extracted with 100 ml of ethyl acetate and washed with 100 ml of water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure, and the residue was purified with column chromatography (ethyl acetate) to obtain 0.705 g of the title compound(yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH3:25][O:26][C:27](OC)(OC)OC.[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:25]([O:26][CH3:27])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Reactant: COC(OC)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)CCCCCOc1ccc2nc(OC)n(-c3ccccc3)c2c1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was mixed with 0.12 ml of tetramethylorthocarbonate and 40 μl of acetic acid, and the mixture was heated for 4 hours to 80° C. After cooling, it was mixed with 1N sodium hydroxide solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 104 mg was obtained.
Reaction SMILES: [CH:1]1[CH2:7][CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([Br:11])(Br)Br.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[Br:11][CH:8]1[C:6]2=[CH:5][CH:4]=[CH:3][CH:2]=[C:7]2[CH2:1]1
Reactant: BrC(Br)Br
Reactant: C1=CC=CCC=C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrC1Cc2ccccc21
Temperature: 145 °C
Reaction time: 9.5 h

Procedure:
In a 250 mL round bottomed flask equipped with a drying tube and a condenser, a solution of cycloheptatriene (30.7 g, 300 mmol), bromoform (25.3 g, 100 mmol), anhydrous K2CO3 (15.0 g, 109 mmol), and 18-crown-6 (0.75 g) was heated with stirring at 145° C. for 9-10 h. The solution was allowed to cool and diluted with an equal volume of acetone. Silica gel (15.0 g) was added to reaction mixture and the insoluble solid residue was separated via vacuum filtration and the filter cake washed with acetone until the washings were colorless. The filtrate was concentrated and distilled to remove residual cycloheptatriene. The viscous, brown residue was precipitated into hot petroleum ether. After filtration to remove the precipitate, the filtrate was concentrated and distilled in vacuo through a Vigreaux column to give slightly impure product. Pure 1-bromobenzocyclobutene was obtained as a light yellow liquid by redistillation yield (2.95 g, 5.94%). 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 1H, ArH), 7.16 (d, 1H, J=7.0 Hz, ArH), 7.07 (d, 1H, J=6.4 Hz, ArH), 5.39 (m, 1H, CH), 3.85 (dd, 1H, J=4.4 Hz, J=14.7 Hz, CH2), 3.45 (d, 1H, J=14.7 Hz, CH2).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][C:28]1=[O:42]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:30]4[CH:31]=[CH:32][N:27]([CH3:26])[C:28](=[O:42])[CH:29]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)cc1=O
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccn(C)c(=O)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. LCMS (M+H)+: m/z=432.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]1[O:21][CH2:22][O:23][C:10]=1[CH:9]=2)=[O:5])[CH3:2].[Se](=O)=[O:25]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]1[O:21][CH2:22][O:23][C:10]=1[CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)C1=C(c2ccccc2)c2cc3c(cc2C1)OCO3
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccccc2)c2cc3c(cc2C1=O)OCO3
Reaction time: 24 h
Yield: 69.5 %

Procedure:
5,6-Methylenedioxy-3-phenyl-1H-indene-2-carboxylate ethyl ester (3 g, 9.73 mmol) was dissolved in 1,4-dioxane. Selenium dioxide (10.8 g, 97.3 mmol) was added thereto and the reaction mixture was refluxed while stirring for 1 day, followed by cooling. The solution obtained after filtering residual solid selenium dioxide was combined with 1M sodium bicarbonate, and extracted with ether/water. The extract was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 5,6-methylenedioxy-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester (2.18 g, yield 70%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH2:11])[CH3:8])([CH3:4])[CH3:3].Cl[C:14]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[K+].[K+]>>[CH3:4][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][NH:11][C:14]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)[CH3:8])([CH3:1])[CH3:3]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNc1ncc(Br)cn1)C(=O)OC(C)(C)C
Yield: 72.5 %

Procedure:
The title compound (2.40 g, 73%) was prepared from (2-amino-ethyl)-methyl-carbamic acid dimethyl-ethyl ester (1.74 g, 10 mmol), 2-chloro-5-bromo-pyrimidine (1.93 g, 10 mmol), N,N-diisopropylethylamine (3.87 g, 30 mmol) and K2CO3 (2.76 g, 20 mmol) according to the procedure described for Description 1.