Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[NH:15][C:14]([C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:13]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C1COCC1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:15]([C:1]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[O:2])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:13]2)=[CH:10][CH:11]=1
Reactant: C1CNCCN1
Reactant: CCOc1cc(N(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1cc(N(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
Phosgene (0.47 mL, 0.91 mmol, 1.93 M in toluene) was added to a stirred solution of {4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-dimethyl-amine (83 mg, 0.18 mmol) and triethylamine (0.14 mL, 1 mmol) in THF (3 mL) at 0° C. over a period of 5 min. The mixture was stirred for 1 h and evaporated. The residue was dissolved in methylene chloride (2 mL) and added dropwise to a stirred solution of piperazine (0.239 g, 2.77 mmol) in methylene chloride (2 mL) at room temperature for 1 h. The mixture was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 0-10% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(4-dimethylamino-2-ethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone as a white foam (68 mg, 66%). HR-MS (ES, m/z) calculated for C30H34N5O2Cl2[(M+H)+]566.2084, observed 566.2088.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=2[NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[N:6][CH:7]=1.[B-][N+](C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=2[NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(CO)ccc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: [B-][N+](C)(C)C
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(CO)cc1NCC1CCNCC1
Yield: 78.2 %

Procedure:
Using a similar procedure to that described in Example 47-D, N-(5-chloropyridin-2-yl)-4-hydroxymethyl-2-[(1-Boc-piperidin-4-ylmethyl)amino]benzamide (1.45 g, 3.07 mmol) and borane trimethylamine complex (672 mg, 9.22mmol) afforded 900 mg (79%) of the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH3:11])=[CH:5][CH:4]=1.[CH:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([N:12]([CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH2:27][CH2:28][CH3:29])[CH3:11])=[CH:5][CH:4]=1
Reactant: CCC=O
Reactant: COc1ccc(CC(C)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(C)Cc1ccc(OC)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of N-[2-(4-methoxyphenyl)-1-methylethyl]-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine (0.87 grams, 2.4 mmole), propionaldehyde (0.2 ml, 2.5 mmole) and sodium triacetoxyborohydride (0.763 grams, 3.6 mmole) in 1,2-dichloroethane (25 ml) was stirred at 22° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between 100 ml ethyl ether and 25 ml 10% aqueous sodium carbonate. The dried (anhydrous magnesium sulfate) and concentrated organic phase was subjected to flash chromatography over silica gel 230-400 mesh eluting with 10% ethyl acetate/hexane. Product fractions were concentrated under reduced pressure to give N-[2-(4-methoxyphenyl)-1-methylethyl]-N-propyl-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)amine as a syrup (0.93 grams, 95%), M+H 405.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:16]([C:17]4[C:22]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:14]=[C:13]1[C:8]=3[CH:9]=[CH:10][CH:11]=[CH:12]1.CN(C)C=O.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:14]1[CH:15]=[C:16]2[C:7](=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)[C:6]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=1[C:22]1[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)ccc1c3ccccc3c3ccccc3c21
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2c3ccccc3c3ccccc3c2c2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
5.21 g of benzo[g]chrysene and 50 mL of N,N-dimethylformamide were placed in a flask. 10 mL of N,N-dimethylformamide solution of 4.00 g of N-bromosuccinimide were added. The resulting solution was heated with stirring at 80° C. for 8 hours. After cooling to room temperature, the reaction solution was poured to 200 mL of water. Deposited solids were filtered off, and washed with water and methanol. The resulting solids were purified by silica gel column chromatography, whereby 5.87 g (yield 88%) of 10-bromobenzo[g]chrysene was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1>CN(C)P(N(C)C)(N(C)C)=O.O>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccc(Cl)cc2Cl)cc1

Procedure:
A solution of 22.8 g of β-bromo-2,4-dichlorophenetole and 29.8 g of ethyl 4-aminobenzoate in 100 ml of hexamethylphosphoramide is heated at 125° C. for 16 hours. The solution is chilled, diluted with water (80 ml) and filtered. The solid is washed with 50% ethanol to give the product. Recrystallization from ethanol gives crystals, mp 111°-113° C.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl>[N+:1]1([O-:20])[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2ncccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1CCCc2c1ccc[n+]2[O-]
Reaction time: 4 h
Yield: 83.7 %

Procedure:
5,6,7,8-Tetrahydroquinolin-5-one (7.12 g) was dissolved in dichloromethane (138 mL), added with 3-chloroperbenzoic acid (14.5 g) under ice cooling, and stirred for 4 hours at the same temperature. After adding a saturated aqueous solution of sodium hydrogen carbonate and diluting with chloroform, insoluble was removed by filtration through Celite. After adding 1 mol/L aqueous solution of sodium hydroxide, it was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residues were suspended in diethyl ether and collected by filtration to obtain the title compound (6.61 g) as a yellow powder.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.C(N(CC)C(C)C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2C(=O)[CH2:46][CH2:45][CH2:44][C:43]=2[OH:49])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:42]2[C:43](=[O:49])[CH2:44][CH2:45][CH2:46][C:6]=2[O:7][CH3:9])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[CH:34][N:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cc(C(F)(F)F)ccn2)C2=C(O)CCCC2=O)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2cc(C(F)(F)F)ccn2)c2ccc(C#N)cc2)C(=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyloxonium tetrafluoroborate (185 mg, 1.25 mmol) is added to a solution of N,N-diisopropylethylamine (210 μL, 1.21 mmol) and 1-((4-cyanophenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(4-(trifluoromethyl)pyridin-2-yl)urea (intermediate 24, 264 mg, 0.613 mmol). The mixture is stirred at room temperature for 1 h and extracted with water. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 200 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.08 min (V011_S01).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[N:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)[OH:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:38])[C:39]4[N:40]([CH3:44])[CH:41]=[CH:42][CH:43]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: CNCC(O)c1cccn1C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1cccn1C
Temperature: 90 °C
Yield: 63.5 %

Procedure:
N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of rac-2-(methylamino)-1-(1-methyl-1H-pyrrol-2-yl)ethanol (Preparation 48, 0.126 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature, poured into water (25 mL), and was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography (CH2Cl2/methanol, 98/2) followed by recrystallization from ethyl acetate to yield 0.126 g the title compound as a white solid. Physical characteristics. M.p. 122-124° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.55, 7.41-7.32, 6.89, 6.61-6.60, 5.85-5.83, 4.84, 4.74-4.69, 4.55, 3.91, 3.79-3.71, 3.58, 2.79-2.70, 2.31; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.7, 153.2, 150.6, 141.1, 137.3, 132.8, 131.4, 128.9, 128.6, 123.4, 116.8, 114.8, 106.8, 106.6, 106.0, 61.9, 60.8, 54.3, 42.5, 41.9, 37.8, 34.1; MS (ESI+) m/z 483 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26]4[N:27]=[CH:28][CH:29]=[CH:30][N:31]=4)[CH2:21][CH2:22]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: c1cnc(N2CCNCC2)nc1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(c4ncccn4)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 18 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-(piperazin-1-yl)pyrimidine as described in Step 5, Example 24 to give the title compound as a yellow solid (18% yield). LC/MS: RT 2.98 min; m/e 446 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH3:22])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.CO.[Pt](=O)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH3:22])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN
Agent: O=[Pt]=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCn1nc2c(N)nc3c(c2c1CCCCN)CCCC3
Reaction time: 24 h

Procedure:
A solution of 1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (2.40 g, 8.06 mmol) in trifluoroacetic acid (20 mL) was treated with platinum (IV) oxide. The mixture was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) for 1 day, and then was diluted with chloroform (50 mL) and methanol (25 mL). The mixture was filtered through CELITE filter agent. The filtrate was concentrated under reduced pressure to yield 6.0 g the bis-trifluoroacetic acid salt of 1-(4-aminobutyl)-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine in residual trifluoroacetic acid as a yellow liquid.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[CH:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=O.[OH-].[K+].C1CCCCC1>O1CCCC1.C(O)C>[O:4]=[C:3]1[CH2:5][CH2:6][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:2]=[CH:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C=CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Temperature: -5 °C
Reaction time: 16 h

Procedure:
Methyl vinyl ketone (146 mL) was added to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (375 g) in tetrahydrofuran (18 L). The reaction mixture was cooled to −5° C. and a solution of potassium hydroxide in ethanol (3N, 0.243 L) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Cyclohexane (10 L) was added and the solution was washed with saturated sodium chloride (3×10 L). The organic layer was concentrated to an oil. This oil was dissolved in 2 L of 80:20 cyclohexane/ethyl acetate and filtered through Celite® to remove insoluble material. The filtrate was purified via flash column chromatography (70:30 hexane/ethyl acetate) to afford the product as an oil. The oil was triturated in hexanes to afford the desired product as a white solid (131 g, 28%).
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=1)=[O:4])[NH2:2].[CH:17](OCC)(OCC)OCC>>[CH3:11][C:9]1[N:10]=[C:6]([N:5]2[C:3](=[O:4])[NH:1][N:2]=[CH:17]2)[S:7][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1sc(NC(=O)NN)nc1C
Product: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Temperature: 95 °C
Yield: 80 %

Procedure:
To a 2-neck round bottom flask (1 L) equipped with a mechanical stirrer was added ethyl 2-(hydrazinecarboxamido)-4-methylthiazole-5-carboxylate (42.00 g, 172.00 mmol) in anhydrous triethyl orthoformate (393 mL). The yellow reaction mixture was heated at 95° C. for 2 h, and then cooled to ambient temperature. The precipitate was filtered and washed with cold methanol (100 mL) to afford the title compound as a colourless solid (34.9 g, 80%): mp 165-167° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br, 1H), 9.09 (s, 1H), 4.64 (t, J=7.1 Hz, 2H), 2.98 (s, 3H), 1.67 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.3, 157.1, 154.5, 152.3, 133.6, 118.4, 61.9, 17.7, 14.9; MS (ES+) m/z 255.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.[C:37]([O:41][C:42](=[O:52])[C@H:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[NH2:44])([CH3:40])([CH3:39])[CH3:38]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:44][C@H:43]([C:42]([O:41][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:52])[CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@@H](Cc3ccccc3)C(=O)OC(C)(C)C)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-phenylalanine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 7.46-7.21 (5H, m), 6.95 (1H, s), 6.34 (1H, s), 4.32-4.09 (3H, m), 3.27-2.88 (6H, m), 1.84-1.63 (5H, m), 1.34 (9H, s), 1.19 (6H, d, J=7.0 Hz). LC/MS: purity 97.5%, m/z 511 [M+H]+
Reaction SMILES: CS(O[CH:6]([CH2:16][CH2:17][O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:7][O:8][Si:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])(=O)=O.[C-:26]#[N:27].[Na+].O>CS(C)=O>[CH3:23][C:20]([Si:19]([CH3:24])([CH3:25])[O:18][CH2:17][CH2:16][CH:6]([CH2:7][O:8][Si:9]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:14])[CH3:15])[C:26]#[N:27])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(C#N)CO[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
A mixture of 6-methylsulfonyloxy-2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disiladodecane (i.e. the product of Step B) (59.29 g, 0.144 mol) and sodium cyanide (15.55 g, 0.317 mol) in DMSO was heated at 90° C. (using an oil bath) for 2 h. The reaction mixture was cooled to room temperature, water (500 mL) was added and the mixture was extracted with diethyl ether (4×250 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to a dark-yellow oil (48.86 g). The oil was purified by silica gel chromatography (eluting with petroleum ether, followed 1-4% gradient of ethyl acetate in petroleum ether) to provide the title compound (150 mg), a compound of the present invention, as a dark foam. Mixed fractions were combined with mixtures from a previous experiment (total weight 19 g) and purified by silica gel chromatography to provide the title compound (about 11 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[C:18]([O:37][CH3:38])=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[C:18]([O:37][CH3:38])=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1cc2c(c(CN3CCN(C(=O)OC(C)(C)C)CC3)c1OC)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2c(c(CN3CCNCC3)c1OC)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-5,6-dimethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.026 g, 0.050 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-5,6-dimethoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.016 g, 76%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]([Si:12]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:13][C:14]([C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH2:15])([CH3:11])[CH3:10].CCOCC.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.CCCCCC>[Cl:1][CH:15]=[C:14]([C:16]1[N:17]=[CH:18][CH:19]=[CH:20][N:21]=1)[O:13][Si:12]([CH:9]([CH3:10])[CH3:11])([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(O[Si](C(C)C)(C(C)C)C(C)C)c1ncccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)[Si](OC(=CCl)c1ncccn1)(C(C)C)C(C)C

Procedure:
N-chlorosuccinimide (9.97 g, 74.7 mmol) was added to a solution of 2-{1-[(Triisopropylsilyl)oxy]vinyl}pyrimidine (17.3 g, 62.2 mmol) in dry THF (120 ml) under N2 then heated at 65° for 5 hr. After cooling, ether (275 ml) was added and then washed with sat. sodium bicarbonate solution (2×100 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to leave an amber oil. This oil was dissolved in hexane (250 ml), treated with MgSO4 and filtered. Evaporation afforded the product as a yellow oil in quantitative yield.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:12]3[CH:13]=[CH:14][C:15]4[C:19](=[O:20])[O:18][CH2:17][C:16]=4[C:11]=3[CH2:10][CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[CH:32]1[CH2:34][O:33]1>CCO>[OH:33][CH:32]([C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[O:31])[O:28][CH2:29][C:30]=2[C:22]=1[CH3:21])[CH2:34][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH:8]2[C:12]3[CH:13]=[CH:14][C:15]4[C:19](=[O:20])[O:18][CH2:17][C:16]=4[C:11]=3[CH2:10][CH2:9]2)[CH2:2][CH2:3]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: O=C1OCc2c1ccc1c2CCC1CN1CCNCC1
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(CC3CCc4c3ccc3c4COC3=O)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
6-(Piperazin-1-ylmethyl)-1,6,7,8-tetrahydro-3H-indeno[4,5-c]furan-3-one (40 mg, 0.15 mmol) and 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (55 mg, 0.29 mmol), were added to a 5 mL microwave tube containing a stir bar; to the mixture was added EtOH (2.5 mL). The tube was capped, degassed and purged with N2. It was then placed in a microwave reactor and heated at 150° C. for 30 min; LC indicated formation of the desired product. The solution was concentrated to dryness, dissolved in MeOH (3.5 mL), filtered and was then subjected to purification by mass-directed HPLC to give 6-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-1,6,7,8-tetrahydro-3H-indeno[4,5-c]furan-3-one. LC-MS (IE, m/z): 463 [M+1]+.