Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:43]#[C:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(C#Cc2ccccc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(C#Cc2ccccc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 90 °C

Procedure:
In a 30 mL glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (75 mg, 0.329 mmol) and PdCl2(PPh3)2 (105 mg, 0.150 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The vessel was sealed with a cap and the reaction mixture was heated to 90° C. in an oil bath for 2 hours. The reaction mixture was subsequently diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the mixture was stirred for 1 hour. The volatiles were subsequently evaporated and the residual material was dissolved in DMSO (5 mL) and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give the TFA salt of the title compound as a pale yellow solid (14.5 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 1H), 2.05-2.12 (m, 1H), 3.49-3.66 (m, 2H), 3.76 (d, J=11.62 Hz, 1H), 3.84-4.04 (m, 2H), 4.31-4.51 (m, 3H), 7.16-7.29 (m, 1H), 7.42-7.53 (m, 3H), 7.53-7.67 (m, 2H), 7.92 (br s, 3H), 8.50 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H19FN4O2, 367. found, 367.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([Cl:22])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of piperidine-4-carboxylic acid (1.3 g, 10 mmol) of water (20 ml) was added sodium hydroxide (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.2 g of crude 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid was obtained. To a stirred solution of crude 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (1.05 g, 4 mmol) in anhydrous dichloromethane (10 mL) was added dropwise thionyl chloride (0.573 g, 4.81 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give crude benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate. To a stirred solution of ethyl 3-amino-2-hydroxybenzoate (0.501 g, 3.0 mmol) and triethylamine (0.455 g, 4.5 mmol) in anhydrous dichloromethane (20 mL) was added dropwise a solution of crude benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate (1.014 g, 3.6 mmol) in anhydrous dichloromethane (5 mL) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=30:1 to 5:1) to give benzyl-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (0.25 g, yield 20%; LC-MS (ESI) m/z: 413 (M+1)+) and 1-benzyl 4-(2-(1-(benzyloxycarbonyl)piperidine-4-carboxamido)-6-(methoxycarbonyl)phenyl)piperidine-1,4-dicarboxylate (1.0 g, yield 51%; LC-MS (ESI) m/z: 658 (M+1)+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:18][CH:17]([S:14]([NH:13][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)(=[O:16])=[O:15])[CH3:19]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
(+,−) Cis propane-2-sulfonic acid [2-(4-amino-phenyl)-cyclopentyl]-amide (265 mg, 0.94 mmol, prepared in example 23) was dissolved in 10 mL of methylene chloride and cooled to 0° C. under nitrogen. Benzoyl chloride was added (120 uL, 1.03 mmol) and after stirring 15 min the ice bath was removed and stirring continued for 2 hours. The reaction was diluted with methylene chloride and washed with water, then 0.1 N HCl and dried over sodium sulfate. The organic phase was concentrated in vacuo to 360 mg crude oil. The product was purified by radial chromatography eluting first with 70:30 methylene chloride:hexanes then ethyl acetate was added (→20%) until all bands were removed to give 120 mg (33%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:16]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:11][CH2:12][N:13]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]4[C:26](=[O:27])[C:25]5[C:24](=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]4=[O:32])[CH2:14][CH2:15]3)=[CH:8][S:7][C:6]=2[CH:16]=1
Reactant: Fc1ccc2c(N3CCNCC3)csc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2csc3cc(F)ccc23)CC1
Yield: 69.7 %

Procedure:
A mixture of 1-(6-fluorobenzo[b]thien-3-yl)-piperazine (20.0 g, 84.6 mmol), N-(4-bromobutyl)phthalimide (26.3 g, 93.2 mmol), anhydrous potassium carbonate (17.5 g, 127 mmol), KI (1.40 g, 8.43 mmol), and anhydrous acetonitrile (500 mL) was stirred at reflux for 17 hours. The thick slurry was filtered, the insolubles washed with chloroform (2×100 mL), and the filtrate concentrated in vacuo. The residue was taken up in chloroform (400 mL), washed with water (200 mL), and dried (MgSO4). The solvent was removed in vacuo and the product chromatographed on silica gel, with 20% heptane/ethyl acetate as eluent, to afford 25.8 g of a yellow solid. Recrystallization from ether afforded 10.9 g (29%) of the title compound as a yellow powder: m.p.=94°-95° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:27]1[CH:32]=[N:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>CN(C)C=O>[CH2:33]([C:30]1[N:31]=[CH:32][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:28][CH:29]=1)[CH3:34]
Reactant: CCc1cnc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)cn1

Procedure:
The title compound is prepared from 5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and 2-bromo-5-ethylpyrazine in N,N-dimethylformamide following a procedure analogous to that described in Example 10. LC (method 5): tR=1.25 min; Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9]([OH:11])=O)[CH3:2].[CH3:12][C:13]1[N:14]([C:18]2[CH:26]=[CH:25][C:21](C(O)=O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][N:17]=1>>[CH2:1]([C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:11])[C:21]1[CH:25]=[CH:26][C:18]([N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH3:12])=[CH:19][CH:20]=1)[CH3:2]
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1
Reactant: CCc1[nH]c(=O)[nH]c1C(=O)O
Product: CCc1[nH]c(=O)[nH]c1C(=O)c1ccc(-n2ccnc2C)cc1

Procedure:
In a manner similar to Example I react 2,3-dihydro-5-ethyl-2-oxo-1H-imidazole-4-carboxylic acid with 4-(2-methyl-1H-imidazol-1-yl)benzoic acid to produce the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30]>O>[CH2:18]([O:17][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=1)[CH:12]=[N:25][CH2:26][CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CCOC(CN)OCC
Solvent: O
Product: CCOC(CN=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1)OCC
Temperature: 100 °C
Yield: 100.6 %

Procedure:
4.6 g of 3,5-dibenzyloxybenzaldehyde are added to 3.0 g of 1-amino-2,2-diethoxyethane, and the mixture is heated at 100° C for 10 minutes. Then, the mixture is stirred at 60° C for 2.5 hours under reduced pressure until water is removed from the mixture. 6.3 g of 1-[N-(3,5-dibenzyloxybenzylidene)amino]-2,2-diethoxyethane is thereby obtained as an oil. 5.9 g of this product are dissolved in 100 ml of ethanol. 600 mg of sodium borohydride are added to the ethanol solution, and the mixture is refluxed for 2 hours. After the reaction, water is added to the mixture and the aqueous mixture is extracted with ethyl acetate. The extract is dried and then evaporated to remove solvent, whereby 5.9 g of 1-[N-(3,5-dibenzyloxybenzyl)amino]-2,2-diethoxyethane are obtained.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.CCCCCC>CN(C=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:2][C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=1
Reactant: CC(=O)CCl
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
1-Chloro-propan-2-one (1.0 g, 11.63 mmol) and potassium carbonate (2.9 g, 21.15 mmol) were added to a solution of 4-bromo-benzenethiol (2.0 g, 10.58 mmol) in DMF (5.0 mL) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (100% hexane). The reaction mixture quenched with ice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to yield the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 2.0 g of the product (80% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].S(OC)(O[CH3:13])(=O)=O>[OH-].[Na+]>[CH3:13][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a 500 mL round bottom flask containing 4-nitro-1-H-pyrazole (5 g, 44.2 mmol) was added sodium hydroxide (1M, 200 mL) and dimethyl sulfate (31 mL, 330 mmol). The mixture was stirred at room temperature for 72 h and the mixture was extracted with CH2Cl2 (2×150 mL). The organic layer was separated and the solvent was distilled off to yield 1-methyl-4-nitro-1H-pyrazole as a white solid (4.30 g, 76%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([O:37]CC5C=CC=CC=5)=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:45])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:45])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:15])=[O:16])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [H][H]
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)[C@@H](c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Reaction time: 3 h
Yield: 90.6 %

Procedure:
(+)-Benzyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylate (from (f), 374 mg) was dissolved in aqueous ethanol (20 ml of 9:1 ethanol/water) and 50 mg of 5% palladium on carbon was added. After 3 h at 414 kPa (60 psi) of hydrogen at room temperature a further 50 mg of catalyst was added and the hydrogenation continued for a further 3 h. The catalyst was removed by filtration and the filtrate evaporated. The residue was azeotroped several times with dichloromethane to give the title compound (290 mg) in >98%ee (determined by chiral HPLC).
Reaction SMILES: B1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C2CCCC1CCC2.Br[C:18]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][N:28]([CH:36]3[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:25]=2)[N:20]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.CN(C)C=O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH2:10]([C:18]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][N:28]([CH:36]3[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:25]=2)[N:20]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: COCCCn1nc(Br)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCCn1nc(Cc2ccccc2)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A 0.5M solution of B-benzyl-9-BBN in tetrahydrofuran (1.8 ml) was added to a solution of tert-butyl {[3-bromo-1-(3-methoxypropyl)-1H-indazol-6-yl]methy}cyclopropylcarbamate (200 mg), potassium phosphate (290 mg), palladium acetate(II) (4 mg) and S-Phos (15 mg) in N,N-dimethylformamide (5 ml) under argon atmosphere and the mixture was stirred at 60° C. for 18 hours. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=2/1) to give tert-butyl {[3-benzyl-1-(3-methoxypropyl)-1H-indazol-6-yl]methy}cyclopropylcarbamate (198 mg) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH:5]=1
Reactant: BrCCc1ccc2c(c1)CCO2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2occc2c1
Temperature: 25 °C

Procedure:
A mixture containing 5-(2-bromoethyl)-2,3-dihydrobenzo[2,3-b ]furan (3 g--see Preparation 13), freshly recrystallised N-bromosuccinimide (2.37 g), benzoyl peroxide (0.03 g) and carbon tetrachloride was heated under reflux for 2 hours. On cooling to room temperature, water (100 ml) and sodium metabisulphite (1 g) were added, the layers were separated and the aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing toluene (5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 1.25 g.
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[N:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.N1CCCCC1.CCOCC>CO>[Br-:1].[CH2:2]([N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[CH:31][C:30]1[CH:29]=[CH:28][C:27]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:34][CH:33]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC[n+]1ccccc1C
Reactant: O=Cc1ccc(N2CCCCC2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC[n+]1ccccc1C=Cc1ccc(N2CCCCC2)cc1
Yield: 24.7 %

Procedure:
1-Dodecyl-2-methylpyridinium bromide (2.3 g, 0.0067 mole) and 4-piperidinobenzaldehyde (1.27 g, 0.0067 mole) were refluxed in methanol (20 ml) in the presence of piperdine (0.1 ml) under nitrogen for three hours. The solution was cooled and addition of ether gave a crystalline solid which was collected giving 1-dodecyl-2-[(4-piperidino)styryl]pyridinium bromide (0.85 g), melting point 203°-205° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20].N1CCCCC1>C(O)C>[NH2:22][C:21]1[O:1][C:2]2=[C:3]3[C:8](=[CH:9][CH:10]=[C:11]2[CH:17]([C:16]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:18]=1[C:19]#[N:20])[CH:7]=[N:6][CH:5]=[CH:4]3
Reactant: COc1ccc(C=C(C#N)C#N)cc1OC
Reactant: Oc1cccc2cnccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C2C(C#N)=C(N)Oc3c2ccc2cnccc32)cc1OC
Temperature: 25 °C

Procedure:
To a stirred suspension of 5-hydroxyisoquinoline (2.90 g) and 3,4-dimethoxy benzylidenemalononitrile (4.28 g) in ethanol (11 ml) was added dropwise piperidine (1.70 g). The suspension was then heated at reflux temperature for one hour forming a red solution. This was then allowed to cool to room temperature, depositing a brown solid. This was filtered off and washed with ethanol and ether and dried in vacuo at 60° C., yielding 2-amino-4-(3,4-dimethoxyphenyl)- 4H-pyrano[2,3-f] isoquinoline-3-carbonitrile as a yellow-brown solid, m.p. 225°-228° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:37])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=2)=[N:8][C:7]=1[CH2:18][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2cncc(Br)c2)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2cncc(Br)c2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.3 %

Procedure:
A mixture of 4-bromomethyl-2-(5-bromo-pyridin-3-yl)-thiazole-5-carboxylic acid ethyl ester (880 mg, 2.18 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (552 mg, 2.18 mmol) and potassium carbonate (452 mg, 3.27 mmol) in anhydrous dimethylformamide (8 mL) was stirred at room temperature for 24 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (495 mg): MS: (+) m/z 600.40, 602.20 (M+Na+, 79Br/81Br).
Reaction SMILES: [C:1]([C:3]1([C:9](OC)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].CO.[BH4-].[Li+]>O1CCCC1>[OH:10][CH2:9][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C#N)CCCCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(CO)CCCCC1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a solution of methyl 1-cyanocyclohexanecarboxylate (prepared according to Fleming et. al, J. Org. Chem. 2005, 70, 2200) (8.54 g, 51.10 mmol) in anhydrous tetrahydrofuran (300 mL) was added anhydrous methanol (3.1 mL, 78.00 mmol) and lithium borohydride (4.0 M solution in tetrahydrofuran 19 mL, 76 mmol). The reaction solution was heated to reflux under a nitrogen atmosphere for 4 hours, cooled to ambient temperature. The mixture was quenched by the slow addition of saturated aqueous ammonium chloride (5 mL). The mixture was diluted with ethyl acetate (400 mL), washed with a 2:1 mixture of saturated aqueous ammonium chloride and water (2×300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless oil (6.30 g, 89%): 1H NMR (300 MHz, CDCl3) δ 3.55 (s, 2H), 2.78 (br s, 1H), 1.98-1.93 (m, 2H), 1.74-1.69 (m, 4H), 1.63-1.48 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Br)c1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Product: COCC1COc2cc3ncnc(Nc4cccc(Br)c4)c3cc2O1
Yield: 55 %

Procedure:
The titled compound (25 mg, 63%, m.p. 268-274° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (30 mg, 0.113 mmol) and 3-bromoaniline (39 mg, 0.226 mmol).