Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CO[C:6]1[CH:7]=[CH:8][C:9](OCC2OC2)=[C:10]2[C:15]=1[NH:14][C:13](=O)[CH2:12][CH2:11]2)(=O)C.O[C:23]1C=CC(O)=C2C=1CCC(=O)N2.BrCC(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC(OCC(=O)C)=C2C=1CCC(=O)N2.O.CC(C)=O>[NH2:14][CH:13]1[CH2:12][CH2:11][C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:15]=2)[CH2:23]1
Reactant: O=C1CCc2c(O)ccc(O)c2N1
Reactant: CC(=O)COc1ccc(OCC2CO2)c2c1NC(=O)CC2
Agent: CC(=O)CBr
Agent: CC(=O)COc1ccc(OCC(O)CNC2CCc3ccccc3C2)c2c1NC(=O)CC2
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: NC1CCc2ccccc2C1

Procedure:
Operating as described in Example 27, but starting from 8-acetylmethoxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril, prepared by reacting 5,8-dihydroxy-3,4-dihydrocarbostyril with bromoacetone in the presence of potassium carbonate and in a mixture water/acetone 4/1, at the reflux temperature for 5 hours, and 2-aminotetralin (1.48 g) in absolute ethanol (30 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(8-acetylmethoxy-3,4-dihydrocarbostyril-5-yloxy)propanamine hydrochloride is obtained ((iF): R=H, L"=acetonyloxy, E" and G", taken together, represent a group --CH2 --CH2 --CO--NH--, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCc1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
tert-butyl 2-chloroacetate (0.83 g, 5.55 mmol) and 2-(Aminomethyl)pyridine (1.5 g, 8.32 mmol) were dissolved in 400 mL CH3CN. To this solution was added potassium carbonate (0.76 g, 5.55 mmol) and the mixture was stirred at room temperature for two days. The crude product was obtained as an oil after removal of the solvent and was purified on a silica gel preparative plate that was developed in with a 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2. The product was isolated as pale yellow oil (57%). 1H NMR (CDCl3) δ 8.414 (dd, 1H, Ar), 7.499 (dd, 1H, Ar), 7.200 (d, 1H, Ar), 7.013 (m, 1H, Ar), 3.806 (s, 2H, —CH2—), 3.242 (s, 2H, —CH2—), 2.458 (s, 1H, —CH—), 1.333 (s, 9H, —C(CH3)3).
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].Br[CH2:7]/[CH:8]=[C:9](\[CH3:19])/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>Cl[Cu].C(OCC)C>[CH3:19]/[C:9](/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8]\[CH2:7][CH2:3][C:2]#[CH:1]
Reactant: C#CC[Mg]Br
Reactant: CCCCCCCCC/C(C)=C/CBr
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOCC
Product: C#CCC/C=C(\C)CCCCCCCCC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A diethyl ether solution (100 ml) of propargyl bromide (22.4 g, 190 mmols) was added dropwise to magnesium (5.20 g, 210 mmols) and HgCl2 (360 mg, 1.33 mmols) to obtain propargyl magnesium bromide (Grignard reagent). CuCl (200 mg, 2.02 mmols) was added to this Grignard reagent, and the resulting solution was ice-cooled. After a diethyl ether (100 ml) solution of (E)-1-bromo-3-methyl-2-dodecene (4′) (18.8 g, 72.0 mmols) was added dropwise, the mixture was stirred for 3 hours at 0° C. The reaction mixture was poured into ice water, acidified with diluted hydrochloric acid, and extracted several times with diethyl ether. The organic layers were combined, and washed with water and a saturated aqueous solution of sodium chloride. A small amount of allene type impurities was removed by silica gel column chromatography (elution with hexane) to obtain pure (E)-6-methyl-5-pentadecen-1-yne (5′) (12.7 g, 80%).
Reaction SMILES: [OH:1]O.C(N1[C@H](C)C[N:9]([C@H:13](C2C=C(C=CC=2)C#N)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16](O)[CH:15]=2)[C@@H](C)C1)C=C.[OH-].[Na+].Cl>C(O)C>[C:13]([NH2:9])(=[O:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C#N)c2)C[C@H]1C
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccccc1
Temperature: 60 °C

Procedure:
Hydrogen peroxide (0.5 mL of a 30% by weight solution) was added to a mixture of the benzonitrile (0.50 g, 1.4 mmol), 0.7 mL of 10 N aqueous sodium hydroxide and 3 mL of ethanol. The reaction was exothermic with gas evolution and formation of a white precipitate. After a few minutes, the mixture was carefully heated under a reflux condenser in an oil bath at 60° C. for three hours. After cooling to room temperature, 6 N aqueous hydrochloric acid was added to adjust the pH to 8. The mixture was evaporated to dryness under vacuum, and the residue was extracted between ethyl acetate and pH 8 buffer solution. The organic layer was washed with pH 8 buffer and brine, dried over sodium sulfate, and the solvent was evaporated to give 0.42 g (79%) of (±)-3-((αR*)-α-((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide as a bright yellow solid.
Reaction SMILES: C(O[BH-](O[C:11](=O)[CH3:12])OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]([CH2:24][NH:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]3[CH:49]=[CH:48][C:47]4[CH2:46][CH2:45][CH2:44][NH:43][C:42]=4[N:41]=3)[CH2:36][CH2:35]2)[N:29]=[CH:28][N:27]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>O1CCCC1>[CH2:31]([CH:32]([CH2:11][CH3:12])[CH2:33][NH:15][CH:16]([CH2:24][NH:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([N:34]2[CH2:35][CH2:36][CH:37]([C:40]3[CH:49]=[CH:48][C:47]4[CH2:46][CH2:45][CH2:44][NH:43][C:42]=4[N:41]=3)[CH2:38][CH2:39]2)[N:29]=[CH:28][N:27]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH3:30]
Reactant: CCc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1c(NCC(NCC(CC)CC)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reaction time: 0.17 h

Procedure:
75 mg (0.35 mmoles) of sodium triacetoxyborohydride in 6 ml of tetrahydrofuran is left under stirring for 10 minutes at TA. Then a mixture of 100 mg (0.208 mmoles) of tert-butyl 2-amino-3-{5-ethyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate and 0.228 mmoles of 2-ethyl-butylaldehyde in solution in 3 ml of tetrahydrofuran is added. The reaction mixture is stirred at ambient temperature for 4 hours 30 minutes. Then it is extracted with ethyl acetate after washing with a saturated solution of sodium bicarbonate. The organic phase obtained is dried over magnesium sulphate before being concentrated to dryness under reduced pressure (2 kPa). The residue is then chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane/methanol (80/20) 50-50. A mass my of expected product is obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=O)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C(O)(C)(C)C>[C:16]1([C:14]2[CH2:2][C:1](=[O:3])[C:4]3[C:5](=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)[N:13]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1cccc3ccccc13)OCO2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1CC(c2cccc3ccccc23)=Nc2cc3c(cc21)OCO3
Yield: 52 %

Procedure:
Into a suspension of 150 (2.95 mmol) in t-butyl alcohol (100 mL) was added potassium t-butoxide (1.66 g, 14.7 mmol). The mixture was refluxed under argon for 12 h, cooled, and poured into a 10% ammonium chloride solution (100 mL). The solid precipitate was collected and washed with EtOH. The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOH 16:1-10:1). Yield 52% from 150 as a grayish-white solid; mp>350° C.; ESI-MS (Positive mode): m/z 316 [M+H]+; 1H-NMR (DMSO-d6, 8): 6.08 (1H, s), 6.15 (2H, s), 7.03 (1H, s), 7.46 (1H, s), 7.56-7.63 (2H, m), 7.63-7.70 (2H, m), 7.83 (1H, d, J=7.6 Hz), 8.06 (1H, d, J=7.6 Hz), 8.11 (1H, d, J=7.6 Hz), 11.90 (1H, s). IR (KBr): 1653 (C═O) cm−1; Anal. Calcd for C20H13NO3: C, 76.18; H, 4.16; N, 4.44. Found: C, 75.60; H, 3.94; N, 4.29.
Reaction SMILES: [CH3:1][C:2]1[C:3](C=C)=[C:4]([CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[C:5]([O:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11].[OH-].[Li+].S([O-])(O)(=O)=[O:38].[Na+]>CO.O>[OH:38][C:3]1[C:2]([CH3:1])=[C:10]2[C:6]([C:7](=[O:11])[O:8][CH2:9]2)=[C:5]([O:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[C:4]=1[CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: O=S(=O)([O-])O
Reactant: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=CCc1c(O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2)CCC(=O)O

Procedure:
A solution of methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinyl isobenzofuran-5-yl)-4-methyl-4-hexenoate (0.37 g) and lithium hydroxide (0.4 g) in methanol (6 ml) and water (6 ml) was heated at 62° C. for 15 hours. The reaction was acidified with aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate/hexane/acetic acid to give (E) 6-(1,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, m.p. 148° 149° C. (tert-butylmethyl ether/hexane).
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:3](C=O)[CH:2]=1.S([O-])([O-])(=O)=O.Cl.C(NO)(C)(C)C.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1cc(C=O)c2cccccc1-2
Agent: CC(C)(C)NO
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: c1ccc2cccc-2cc1
Temperature: 95 °C
Yield: 225.1 %

Procedure:
1,3-Azulenedicarboxaldehyde (600 mg) is dissolved in 6.5 ml of pyridine. Magesium sulfate (1200 mg) and N-tert-butylhydroxylamine hydrochloride (1638 mg) is added to the solution. The mixture is heated with stirring to 95° C. under nitrogen and is stirred for 13 hours. Upon cooling to rt, the reaction mixture is poured into a separator funnel containing 60 ml of CHCl3 and 60 ml of sat aq. NaHCO3. The aqueous layer is separated and washed with three 30 ml portions of CHCl3. The combined organic layers are dried over anhydrous MgSO2, filtered, and evaporated to give the bis-nitrone 34 (940 mg, 89% yield) as dark green crystals. Oxidation potential equals 0.72 V vs SCE. 1H NMR (CDCl3): 10.35 (s, 1 H), 8.65 (d, 2 H, J=10 Hz) 8.11 (s, 2 H), 7.68 (t, 1 H, J=10 Hz), 7.32 (t, 2 H, J=10 Hz), 1.67 (s, 18 H). 13C NMR (CDCl3): 139.9, 135.0, 134.2, 125.8, 125.6, 123.2, 120.5, 69.8. 28.4. IR (thin film): 3052, 2972, 1644, 1564, 1452, 1404, 1356, 1261, 1196, 1124, 1052, and 892 cm−1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([O:21]CC)=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:24]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(SC)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reaction time: 20 h
Yield: 93.3 %

Procedure:
To a solution of ethyl 7-(4-methylthiophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (132 mg) in ethanol-tetrahydrofuran (5 ml-5 ml) was added 1N sodium hydroxide (1.0 ml) at room temperature, and the mixture was stirred for 20 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (2 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The resulting crystal was collected by filtration to give 7-(4-methylthiophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (113 mg) as colorless crystals.
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].Br[C:27]([CH3:30])([CH3:29])[CH3:28]>CC(N(C)C)=O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:27]([O:4][C:3]([CH:2]1[CH2:6][CH:7]([OH:8])[CH2:9][N:1]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:5])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)Br
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C1CC(O)CN1C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A suspension of Cbz-Hyp-OH (4.854 g, 18 mmol) in DMA (135 ml), benzyltriethylammonium chloride (4.105 g, 18 mmol), K2CO3 (64 g, 46 mmol) and 2-bromo-2-methylpropane (99 ml, 859 mmol) was stirred at SS C for 18 hours. The mixture was diluted with iced water and extracted with EtOAc (3×). The organic phase washed with water, 0.5N NaHSO4 solution and brine dried and the solvent in vacuo to yield the title compound as a yellow oil (5.368 g, 98% yield). 1H-NMR (500 MHz, CDCl3) δ 1.33 (s, 5H), 1.47 (s, 4H), 2.01-2.14 (m, 1H), 2.22-2.38 (m, 1H), 3.50-3.72 (m, 2H), 4.34-4.45 (m, 1H), 4.45-4.53 (m, 1H), 5.04-5.20 (m, 2H), 7.22-7.42 (m, 5H). Analytical HPLC 10.14 min. LC-MS (ES+) m/e=322.2 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([OH:23])[C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)[O:23][CH3:29])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Example 277B (100 mg, 0.287 mmol) in THF (2 mL) was treated with NaH (95%, 8.7 mg, 0.344 mmol). After stirring at room temperature for 20 minutes, the mixture was treated with methyl iodide (1.2 eq, 21.4 μL) and stirred for 1 hour. The mixture was concentrated under reduced pressure and CH2Cl2 (10 mL) was added. The organic layer was washed with water (5 mL×3), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 363 (M+H)+; MS (ESI−) m/z 361 (M−H)−; 1H NMR (DMSO, 300 MHz) rotamers δ 1.25 (s, 9H), 3.32 (s, 3H), 4.27 (d, J 6.1, 2H), 5.37 (s, 1H), 7.18 (d, J 8.5, 2H), 7.32 (d, J 8.5, 2H), 7.70 (t, J 7.1, 1H), 7.83 (d, J 6.1, 1H), 8.07 (m, 2H), 8.43 (d, J 6.1, 1H), 8.80 (t, J 6.1, 1H), 9.35 (s, 1H); Anal. Calcd for C23H26N2O2+0.3H2O: C, 75.09; H, 7.29; N, 7.61. Found: C, 75.02; H, 7.34; N, 7.43.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([O:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:33]=2)[CH:29]=[CH:30]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Yield: 94 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 67), 6-hydroxyindole (96 mg, 0.715 mmol) in DMF (3 ml) containing cesium carbonate (291 mg, 0.894 mmol) was heated at 90° C. for 4 hours. After cooling, the mixture was diluted with water, the precipitate was filtered, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (90/10 increasing to 50/50) to give 4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (240 mg, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]=[C:8]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])[C:9]([CH3:11])=O)([O-:3])=[O:2].[NH2:21]/[C:22](/[CH3:38])=[CH:23]\[C:24]([O:26][CH2:27][CH2:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:30])=[O:25]>C(O)(C)C>[CH3:14][O:13][P:12]([O:15][CH3:16])([C:8]1[CH:7]([C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:23]([C:24]([O:26][CH2:27][CH2:28][N:29]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:30])=[O:25])=[C:22]([CH3:38])[NH:21][C:9]=1[CH3:11])=[O:17]
Reactant: COP(=O)(OC)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Solvent: CC(C)O
Product: COP(=O)(OC)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 21.1 %

Procedure:
To a mixture of 3.42 grams of dimethyl 1-(3-nitrobenzylidene)-acetonylphosphonate and 3.13 grams of 2-(N-benzyl-N-methylamino)-ethyl 3-aminocrotonate was added 50 ml of isopropanol and the mixture was heated to reflux for four hours with stirring. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate, to this was added 5% hydrochloric acid solution followed by separation, chloroform was added the lower layer followed by separation, the chloroform layer was washed with 5% calcium carbonate solution and then with water, and dried. Chloroform was evaporated in vacuo, the residue was purified by subjecting to silica gel column chromatography (100 grams of silica gel being used; eluting solution is ethyl acetate), and the resulting crystals were recrystallized from a mixture of ethyl acetate and ether to give 1.28 grams (yield 20%) of 2-(N-benzyl-N-methylamino)-ethyl 5-dimethoxyphosphinyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate, pale yellow crystals, melting point 101°-3° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]([S:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)(=[O:21])=[O:20])[CH:17]=[C:16]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)[CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]([S:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)(=[O:21])=[O:20])[CH:17]=[C:16]([CH2:28][NH:29][CH3:30])[CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(Cc1cc(-c2ccc(-c3ccc(Cl)nc3)nc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccc(-c3ccc(Cl)nc3)nc2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl {[5-(6′-chloro-2,3′-bipyridin-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in ethanol (8 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 70° C. for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=99:1→19:1) to give a free salt of the title compound. The obtained free salt was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (116 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 61 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[C:34]([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH2:43][S:44][CH3:45])[NH2:41])([CH3:37])([CH3:36])[CH3:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=3)=[CH:13][C:9]=2[C:10]([NH:41][C@@H:40]([CH2:42][CH2:43][S:44][CH3:45])[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:46])=[O:11])=[CH:4][CH:3]=1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Reactant: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1nccs1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)c1cc(OC(Cc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoic acid (0.74 g, 1.63 mmol), DMAP (1.0 g, 8.2 mmol), L-methionine tert-butyl ester HCl (1.0 g, 4.92 mmol), EDC (0.63 g, 3.27 mmol) and HOBT (0.22 g, 1.63 mmol) in DMF (50 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness and washed with aqueous citric acid (1M, 20 ml) and extracted with dichloromethane (20 ml). The extracts were washed with saturated brine and dried and applied directly onto a silica flash column which was eluted with ethyl acetate/methanol (9:1 and 4:1) to give tert-butyl (2S)-2- {2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfanylbutyrate. The product was dissolved in ethyl acetate and treated with 1M ethereal HCl (10 ml). The resulting solid was isolated by centrifuging, flirther washing with diethyl ether and finally drying under high vacuum to give tert-butyl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.57 g, 54% Yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:16][CH:17]=3)[C:12](=[CH2:25])[C:11]([CH3:27])([CH3:26])[CH2:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:16][CH:17]=3)[CH:12]([CH3:25])[C:11]([CH3:26])([CH3:27])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: C=C1c2cc(OCCN(C)C)ccc2C(c2ccc(Cl)cc2)CC1(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1c2cc(OCCN(C)C)ccc2C(c2ccc(Cl)cc2)CC1(C)C

Procedure:
A solution of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-methylidene tetralin hydrochloride (4 g) in ethanol (150 ml) was hydrogenated in the presence of 10% palladium on charcoal (0.4 g) until hydrogen uptake was complete. After filtration the solvent was removed in vacuo to give 4-(4-chlorophenyl)-1,2,2-trimethyl-7-(2-dimethylaminoethoxy)tetralin hydrochloride. Recrystallisation from ethanol-ether gave white prisms, m.p. 173°-6° (3.6 g, 90%).