Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].C(N(CC)CC)C.C(O)=O>C(OCC)(=O)C.[Pd]>[NH2:12][C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Nc1cc(CO)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A three neck flask fitted with a reflux condenser and an addition funnel was charged with 3,5-dinitrobenzyl alcohol (10 g, 50 mmol), 10% Pd/C (630 mg) and triethylamine (35 mL, 251 mmol). This was placed in a 70° C. oil bath and through the addition funnel was added 90% formic acid (10 mL, 234 mmol) dropwise. The reaction was heated for 30 minutes and cooled to room temperature. The clear yellow supernatant was filtered through celite and the lower layer containing the catalyst was treated with acetone, filtered through celite and rinsed with acetone. The filtered organic layers were combined and concentrated to give an orange oil. The oil was diluted in ethyl acetate which was washed with H2O, dried (MgSO4), filtered and concentrated to give crude 3-amino-5-nitrobenzyl alcohol as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:23])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]2)[O:4][N:3]=1.C(O)(C(F)(F)F)=O.[NH2:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=C(Cl)[C:35]([Cl:42])=[CH:34][N:33]=1.C(N(C(C)C)CC)(C)C>ClCCl.C(O)(C)C>[NH2:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:8]([NH:7][C:5]3[O:4][N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:23])[CH2:15][CH2:14]2)[C:35]([Cl:42])=[CH:34][N:33]=1
Reactant: Cc1cc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)on1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)on1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 4-(2-(3-methylisoxazol-5-ylamino)-2-oxoethyl)piperazine-1-carboxylate (0.087 g, 0.27 mmol) in anhydrous dichloromethane (3 ml) was added TFA (3.7 ml). The reaction mixture was stirred at room temperature for 1 h and 45 min, then the solvent was removed in vacuo and the residue was dried in vacuo over P2O5. To a solution of this material (supposedly 0.27 mmol) in isopropanol (5 ml) was added 2-amino-4,5-dichloro-3-nitro-pyridine (0.050 g, 0.24 mmol) followed by diisopropylethylamine (0.22 ml, 1.25 mmol). The reaction mixture was stirred at 45° C. for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (6 ml). The precipitate was collected by filtration, washed with isopropanol (2×6 ml), and diethyl ether (2×6 ml), and dried. The title compound was obtained as an orange solid (0.042 g). The filtrate was concentrated in vacuo, and purification of the residue by chromatography (10 g isolute column) on elution with dichloromethane/ethyl acetate (v/v; 1:1), and 2% methanol in dichloromethane/ethyl acetate (v/v; 1:1) afforded an additional 0.025 g of the product (overall yield: 63%). 1H-NMR (500 MHz, DMSO-d6) 2.18 (s, 3H, CH3), 2.63 (s, 4H, piperazine N(CH2)2), 3.28 (s, 2H, NCH2CO), 3.10 (s, 4H, piperazine N(CH2)2), 6.15 (s, 1H, isoxazole C—H), 7.00 (s, 2H, NH2), 8.07 (s, 1H, 6-H), 11.37 (s, 1H, CONH);
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[NH:8][CH2:9][CH3:10])([O-:5])=[O:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[N:8]([CH2:9][CH3:10])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([O-:5])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (4.0 ml), 2,4-dinitro-N-ethylaniline (0.42 g (1.99 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, p-toluenesulfonyl chloride (0.57 g (2.99 mmol)) was added. After two hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.47 g (65%) of the title compound as pale yellow crystals.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:11]([C:29](O)=[O:30])=[C:10]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(=O)C(Cl)=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1)[C:11]([CH2:29][OH:30])=[C:10]2[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Cn2c(CO)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
DMF (0.1 ml) was added to a suspension of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (5.5 g) in THF (55 ml), and oxalyl chloride (1.9 ml) was added dropwise under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred for 30 min., and concentrated under reduced pressure. The residue was suspended in a mixture of THF (90 ml) and 1,2-dimethoxyethane (90 ml), and under ice-cooling sodium borohydride (1.62 g) and methanol (3 ml) were added. The mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was poured into water under ice-cooling. 10% Hydrochloric acid was added to acidify the aqueous layer, and THF and methanol were evaporated under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (5.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[I-].CS[C:16]1[S:17][CH2:18][C@H:19]2[CH2:27][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]=12>>[CH3:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:16]1[N:20]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:27][C@@H:19]3[CH2:18][S:17]1)[CH:11]=[CH:10][CH:9]=2
Reactant: CSC1=[N+]2c3ccccc3C[C@@H]2CS1
Reactant: Cc1cc2c(N)cccc2cn1
Agent: [I-]
Product: Cc1cc2c(N=C3SC[C@H]4Cc5ccccc5N34)cccc2cn1
Yield: 67.5 %

Procedure:
Following the procedure of Example 1 but starting with 5-amino-3-methylisoquinoline (5.7 g) and (R)-3-methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (11.4 g), (R)-3-[(3-methylisoquinol-5-yl)imino]-9,9a-dihydrothiazolo[3,4-a]indole (7.3 g) is obtained, after recrystallisation from ethanol, in the form of white crystals melting at 181° C. [α]D20 =+92.0±1.5° (c=1, chloroform)
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C@@H:7]1[C@@:31]2([CH3:32])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10][C@@H:9]([O:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:8]1)=[O:5])[CH3:2].BrN1C(C)(C)C(=O)N(Br)C1=O.CC1C=C(C)N=C(C)C=1>CCCCCC.C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([O:6][C@@H:7]1[C@@:31]2([CH3:32])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10][C@@H:9]([O:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OCC)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OCC)C1
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 111.8 %

Procedure:
To a solution of 1α,3β-diethoxycarbonyloxycholest-5-ene (2.73 g, 5 m moles) in dry hexane (50 m), 1,3-dibromo-5,5-dimethylhydantoin (858 mg, 3 m moles) was added dropwise under stirring and heating at oil bath temperature of 95° C., and the mixture was continued to react under the irradiation of infrared rays for 15 minutes. The reaction mixture was cooled, and the resulting precipitate was removed by filtration, the filtrate was concentrated at reduced pressure at 40° C. to afford a residual product. Xylene was added to this substance to form a solution. The resulting solution was added dropwise to a solution held at 170° C. of s-collidine (12.5 ml) in dry xylene (16.5 ml), and the reaction was carried out for additional 20 minutes. After the reaction, the resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure at 40° C. to give a residual product. The product was dissolved in ethyl acetate (100 ml). The ethylacetate solution was washed with 1 N hydrochloric acid (3×50 ml), saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 3.04 g of residual product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:21]=[CH:20][C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:22]([NH2:25])(=[O:24])[CH3:23].N[C@@H]1CCCC[C@H]1N.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][NH:14][CH2:13][C:12]1[CH:20]=[CH:21][C:9]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH:25][C:22](=[O:24])[CH3:23])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC(N)=O
Reactant: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Oc2ccc(CNCCC(C)C)cc2)nc1
Temperature: 100 °C
Yield: 5.4 %

Procedure:
To a solution of [4-(5-Bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (0.493 g, 1.411 mmol), acetamide (0.0938 g, 1.588 mmol), and CuI (0.0309 g, 1.622 mmol) in 1,4-dioxane (3.0 ml) is added (+/−)-trans-1,2-diaminocyclohexane (0.020 mL, 1.67 mmol) and K2CO3 (0.400 g, 0.891 mmol). The reaction mixture is then warmed to 100° C. overnight. Additional amounts of CuI (0.0270 mg, 0.142 mmol) and (+/−)-trans-1,2-diaminocyclohexane (0.020 mL, 1.67 mmol) are added. The reaction mixture is placed in a microwave reactor (CEM Discover, 50W) for 60 min. The mixture is filtered through celite, loaded onto silica gel, and eluted with chloroform with a gradient from 10% of methanol to 30% of methanol to give N-(6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-pyridin-3-yl)-acetamide (0.025 g, 5%) as a brown oil. 1NMR (400 MHz, CD3OD) δ ppm: 8.30 (d, J=2.7 Hz, 1H), 8.04 (dd, J=2.5, 8.7 Hz, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.07-7.03 (m, 2H), 6.91 (d, J=8.9 Hz, 1H), 3.82 (s, 2H), 2.68 (dd, J=7.7, 8.0 Hz, 2H), 2.18 (s, 3H), 1.70-1.61 (m, 1H), 1.52-1.44 (m, 2H), 0.96 (d, J=6.6 Hz, 6H); MS (ES): [M+H]+ calcd for C19H26N3O2=328.2025, found 328.2000
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)CC(OCC)=O.[O-:31][CH2:32][CH3:33].[Na+]>C(O)C>[O:31]=[C:32]1[O:1][C@H:2]([C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:33]1
Reactant: CC[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
450 g of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate was treated with 1.1 equivalents of diethyl malonate and 1.05 equivalents of sodium ethoxide in 1200 mL of ethanol at 5° C. for 0.5 hr, then at 25° C. for 5 hrs. The reaction mixture was quenched with acetic acid till the pH of the mixture was about 6. The reaction mixture was extracted with ethyl acetate (4 L) and the isolated organic phase was washed sequentially with 25% brine (4 L), 5% NaHCO3 (5L), and 25% brine (4 L), dried over NaSO4, filtered, concentrated and chased with 2 L of methyl tert-butyl ether to dryness. The oil was dissolved in 950 mL of methyl tert-butyl ether and warmed to 45° C., added heptane (4L) and cooled to −5° C. The solid was isolated by filtration to provide tert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate. A mixture of the tert-butyl (1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate (400 g, 1.028 mol), the product of Example 111-7 (321 g, 1.08 mol, 1.05 equivalents) in absolute ethanol (3.35 L) was cooled to 5° C. was treated with a solution of sodium ethoxide (77.5 g sodium ethoxide in 0.65 L of absolute ethanol, 1.05 equivalents) over 1 hour. The reaction mixture was stirred at 3° C. for 3 hours. Lithium hydroxide monohydrate (215.6 g, 5.138 mol, 5 equivalents) was added all at once and the temperature rose to 10° C. The mixture was stirred at 10° C. for 2 hours, treated with acetic acid (308.6 gm, 5.138 mol, 5 eq) and stirred at 60° C. for 17 hours. The reaction mixture was treated with distilled water (4 L) over 20 minutes while maintaining the internal temperature >55° C. The slurry was cooled slowly to 14° C. over 2.5 hours, filtered, washed with 1:1 ethanol:water (total volume=2 L), heptanes (2 L) and dried at 55° C. vacuum oven under N2 for 40 hours to give the title compound (451.9 g, 91% yield). 1H NMR (CDCl3): δ 8.65(m, 1H), 7.90(m, 2H), 7.65-7.75 (m, 2H), 7.17-7.30(m, 8H), 4.63(m, 1H), 4.32(m, 1H), 3.95(m, 1H), 3.32(m, 1H), 2.7-3.0(m, 4H), 2.10 (m, 1H), 1.74(m, 1H), 1.36 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)c2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)c2cc[nH]c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
4-Bromo-6-amino indole (100 mg, 0.47 mmol) and triethylamine (0.1 ml, 0.71 mmol) were stirred together in pyridine at 0° C. Benzene sulphonyl chloride (84 mg, 0.47 mmol) was then added and the mixture stirred for 1 hour, then allowed to warm to room temperature. The mixture was loaded directly onto an aminopropyl cartridge (10 g) and eluted with methanol. Solvent was evaporated to afford the title compound as an orange/brown gum (90 mg).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[NH:10][C:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2].[H-].[Na+].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH2:38]Br)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[CH:1]([C:3]1[C:11]2[N:10]=[C:9]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:8]([CH2:38][CH2:37][CH2:36][CH:33]3[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[CH2:31][CH2:32]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Reactant: C=Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]benzimidazole (670 mg, 2.24 mmol) and anhydrous N,N-dimethylformamide (34 ml). To this solution was added sodium hydride (60% in mineral oil, 98.67 mg, 2.46 mmol). The resulting mixture was stirred at room temperature for 45 minutes, and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (755 mg, 2.47 mmol) was added. The resulting mixture was heated to 100° C. and stirred at this temperature for about four hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between ethyl acetate and brine. The aqueous fraction was extracted twice with brine. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)O)cc2C1
Reactant: CCNCC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2

Procedure:
3 g (0.009 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxycarbonylmethoxy-tetralin, 0.93 ml of N,N-diethylamine (0.009 mole), 4 g (0.009 mole) of BOP and 1.9 ml (0.0135 mole) of triethylamine in 90 ml of anhydrous DMF were stirred at ambient temperature for 6 hours. The solvent was evaporated off and the residue was taken up in ethyl acetate. It was washed with a sodium bicarbonate solution. An emulsion was obtained which was filtered over celite. The filtered solution was washed with acetic acid and then with water. The organic phase was dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The product was purified by flash chromatography, eluting with a 1:1 ethyl acetate/hexane mixture. The product of the heading was obtained in the form of a very dense oil.
Reaction SMILES: [C:1]1([CH:7]([NH:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3([CH3:44])[CH2:28][C:27]4[C:29]([CH3:43])=[C:30]([NH:35]C(=O)OC(C)(C)C)[C:31]([CH3:34])=[C:32]([CH3:33])[C:26]=4[O:25]3)[CH2:19][CH2:18]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(O)C.C(=O)([O-])O.[Na+]>C(O)C>[NH2:35][C:30]1[C:31]([CH3:34])=[C:32]([CH3:33])[C:26]2[O:25][C:24]([CH2:23][N:20]3[CH2:21][CH2:22][CH:17]([CH2:16][CH2:15][NH:14][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:18][CH2:19]3)([CH3:44])[CH2:28][C:27]=2[C:29]=1[CH3:43]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CN1CCC(CCNC(c3ccccc3)c3ccccc3)CC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CCNC(c3ccccc3)c3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl [2-[[4-[2-[(diphenylmethyl)amino]ethyl]-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate (1.6 g) in ethanol (3 mL) was added 10 mL of 4N-HCl/ethanol and the mixture was stirred at room temperature for 15 hours. This reaction mixture was made basic with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 1.3 g of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphenylmethyl)-4-piperidineethylamine. Yield 97%. This product was treated with 4N-HCl solution in ethanol and the resulting trihydrochloride was recrystallized from ethanol/diethyl ether to provide 1.3 g of the title compound. Yield 76%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:14][CH2:15]I.C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C>[CH3:23][O:24][C:25](=[O:31])[CH:26]([CH2:15][CH2:14][C:3]1[CH:4]=[C:5]([O:10][CH:11]([CH3:13])[CH3:12])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Br:1])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1cc(Br)c(CCI)cc1OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1cc(OC(C)C)c(OC)cc1Br)C(=O)OC

Procedure:
1-Bromo-2-(2-iodoethyl)-4-(1-methylethoxy)-5-methoxybenzene (18.0 g, 45.1 mmol), potassium carbonate (32.0 g, 321 mmol, anhydrous, freshly ground) and malonic acid dimethyl ester (50.0 g, 378 mmol) are stirred in absolute DMF (200 ml) for 12 hours at 80° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:11]=[N:10][CH:9]=[C:8]([C:12]([O:14]C)=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:16].[OH-]>CO>[OH:1][C:2]1[C:3]2[CH:11]=[N:10][CH:9]=[C:8]([C:12]([NH2:16])=[O:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cncc2c(O)ncnc12
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cncc2c(O)ncnc12
Yield: 41.1 %

Procedure:
The mixture of methyl 4-hydroxypyrido[4,3-d]pyrimidine-8-carboxylate (47 mg, 0.1 mmol), NH4OH (3 mL) and MeOH (10 mL) was heated to reflux for 20 hours in a sealed tube. The mixture was then concentrated and purified by prep-HPLC to afford the title compound as a white solid (yield 41.1%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2
Reactant: Oc1ccc2[nH]ccc2c1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCC1CCN(C)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (300 mg, 0.9 mmol) and 4-fluoro-5-hydroxyindole (162 mg, 1 mmol), (prepared as described for the starting material in Example 242), in DMF (4.5 ml) containing potassium carbonate (185 mg, 1.3 mmol) was stirred at 90° C. for 1 hour. After cooling, the mixture was filtered and the solid was washed with DMF. The filtrate was evaporated and the residue was purified by column chromatography, eluting with methylene chloride followed by methanol/methylene chloride (1/99) followed by methanol saturated with ammonia/methylene chloride (2/98). The fractions containing the expected product were combined and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (282 mg, 69%).