Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.COC([O:24][CH3:25])OC.[CH3:26]C1C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CCOC(C)=O.CO.C(O)CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[O:24][CH2:25][CH2:26][O:17]1
Reactant: COC(=O)CCC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCC1(c2cccc(C(F)(F)F)c2)OCCO1
Yield: 94 %

Procedure:
A solution of 4-oxo-4-(3-trifluoromethylphenyl)butyric acid methyl ester (2.47 g, 9.50 mmol), trimethylorthoformate (4.8 mL), p-TsOH (181 mg, 0.95 mmol) and ethylene glycol (7.3 mL) was heated at 50° C. for 3 h. The mixture was diluted with EtOAc (500 mL), washed with saturated NaHCO3 (3×200 mL), water (2×200 mL), and brine (150 mL), dried over Na2SO4, filtered and evaporated to give a mixture of esters. The mixture was stirred in MeOH (25 mL) with NaOMe (400 mg) at room temperature for 6 h. The reaction was quenched with saturated NH4Cl and the methanol was removed by evaporation. The residue was dissolved in EtOAc, washed with saturated NH4Cl (2×200 mL), water (2×200 mL) and brine (200 mL), dried over Na2SO4, and evaporated to give 3-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-yl]propionic acid methyl ester (2.71 g, 94%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 4.10–3.99 (m, 2H), 3.80–3.70 (m, 2H), 3.65 (s, 3H), 2.44 (t, J=7.8 Hz, 2H), 2.24 (t, J=7.8 Hz, 2H); 19F NMR (282 MHz, CDCl3) δ −62.9; ESI MS m/z 305 [C14H15F3O4+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](O)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+].[CH3:31][C:32]([CH3:34])=O>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:28][CH2:25][CH2:9][N:8]3[CH2:1][CH2:2][CH2:34][CH2:32][CH2:31]3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2)c1
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc(-c2nc3ccc(OCCN4CCCCC4)cc3n2Cc2ccccc2)c1

Procedure:
The title compound was synthesized by reacting the compound of Example 84, supra, (0.25 g, 0.79 mmol) with 2-(piperdinyl-1-yl)ethyl chloride (17.46 g, 7.9 mmol) in the presence of potassium carbonate (2.20 g, 15.9 mmol) and acetone (150 ml). These contents were added to a flask and refluxed overnight.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:15]>C1COCC1.CCOC(C)=O>[CH3:15][N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][N:10]=[CH:9]1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cncc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.2 %

Procedure:
To a solution of 4-phenylimidazole (500 mg, 3.47 mmol) in 10 mL THF at rt, was added 60% NaH (146 mg, 3.64 mmol). The mixture was stirred at rt for 5 min, then iodomethane (238 μL, 3.82 mmol) was added. The mixture was stirred at rt for 30 min, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (column #1: 0 to 10% MeOH/CH2Cl2 gradient, column #2: 1 to 2 to 5% MeOH/EtOAc, stepwise gradient) to afford 352 mg of Intermediate 13.1 and 166 mg of Intermediate 13.2.
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[C:10]2[CH:15]=[C:14]([CH3:16])C=[CH:12][C:11]=2[OH:17])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].O.[CH3:37][N:38]([CH3:41])[CH:39]=O>>[CH3:37][N:38]([CH3:41])[C:39]1[C:14]([CH3:16])=[CH:15][C:10]([C:9]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=2)=[O:18])=[C:11]([O:17][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:12]=1
Reactant: OCCCCCCCCCl
Reactant: Cc1ccc(O)c(C(=O)c2ccc(N(C)C)cc2)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C(=O)c2ccccc2)c(OCCCCCCCCO)cc1N(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a 50 ml three-necked round-bottomed flask, 1.51 g (5.9 mmol) of 4′-dimethylamino-2-hydroxy-5-methylbenzophenone are dissolved in 10.5 ml of dimethylformamide. 3.24 g (23.17 mmol) of potassium carbonate are then added at room temperature. A temperature rise to approx. 30° C. is observed and the yellow solution immediately becomes orange. The suspension is heated to 100° C. Then, 1.46 g (8.614 mmol) of 8-chloro-1-octanol are added dropwise within 10 minutes. The dark-orange suspension is stirred at 100° C. for 2 hours and then cooled to room temperature. To dissolve the salts, 25 ml of water are added and the brown solution is then extracted using dichloromethane. The organic phase is washed with sodium hydrogencarbonate (w=0.095 g/g) and then concentrated on a rotary evaporator. The resulting brown oil is fractionally filtered through 200 g of silica gel (Merck 0.04-063 mesh) with 1 l of hexane/ethyl acetate (1:1), followed by 1 l of ethyl acetate. The ethyl acetate fraction is then concentrated by evaporation on a rotary evaporator. 1.97 g of a yellow oil are obtained, which crystallizes after 2 days (81.4% of theory); m.p.: 56.9° C.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]2)=[C:8]([CH:12]=1)[C:9](N)=[O:10].Cl.S(Cl)([Cl:23])=O.C(N(CC)CC)C>O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH:14]([CH2:18][CH2:17][Cl:23])[CH2:15][N:16]([CH3:19])[C:9](=[O:10])[C:8]=2[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(Oc2ccc(Br)cc2C(N)=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CC(CCCl)Oc2ccc(Br)cc2C1=O
Temperature: 15 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of 9.6 g (0.24 mole) of sodium hydroxide in 200 ml of water was added 37 g (0.12 mole) of 5-bromo-2-[(1-methyl-3-pyrrolidinyl)oxy]-benzamide and the mixture was heated at reflux for 18 hr. The pH of the mixture was adjusted to 6.7 with concentrated hydrochloric acid solution. The solution was concentrated under reduced pressure and the residue was boiled in 250 ml of isopropyl alcohol for 1 hr. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in chloroform and to the solution was added 28.3 g (0.24 mole) of thionyl chloride. The mixture was heated at reflux for 0.5 hr and cooled to 15° C. with an ice bath. To the mixture was added dropwise 26.6 g (0.26 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The reaction mixture was stirred at room temperature for 1 hr, then washed consecutively with 3N hydrochloric acid, 15% aqueous sodium hydroxide and water. The chloroform layer was dried over magnesium sulfate and concentrated under reduced pressure to give 23 g (60%) of brown solid. A portion of the solid was recrystallized from ethyl acetate-isopropyl ether, m.p. 92°-94° C.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:17][N:18]1[CH2:24][CH2:23][CH2:22][O:21]C(CN)[CH2:19]1.NCC1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=1.CO>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:17][N:18]1[CH2:24][CH2:23][CH2:22][O:21][CH:11]([CH2:12][NH:8][C:1]([NH:3][CH2:7][C:6]2[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=2)=[O:2])[CH2:19]1
Reactant: NCc1ccc(C(N)=O)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCCO1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ccc(CNC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCCO2)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (0.041 g) in dichloromethane (2 ml) at 0° C. was added dropwise a solution of Intermediate 41 (0.079 g) in dichloromethane (2 ml). The mixture was stirred at 0° C. for 1 h and at 22° C. for 1 h, re-cooled to approximately 0° C. and a solution of 4-aminomethylbenzamide (0.041 g) in a 1:1 mixture of dichloromethane and N,N-dimethylformiamide (4 ml) was added dropwise. The mixture was stirred at 0° C. for 1 h and at 22° C. for 1 h, and applied in two equal portions to ion exchange cartridges (2 g Isolute SCX pre-conditioned with methanol). Elution with methanol (3 column volumes) followed 10% 0.880 ammonia in methanol (2 column volumes) and evaporation of the basic fractions in vacuo gave the crude product. Purification by Biotage flash chromatography on a silica gel cartridge (89), eluting with 150:8:1 dichloromethane/ethanol/0.880 ammonia, gave the title compound as a white solid (0.0186 g).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.I[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27].C(OCC)C.[BrH:38]>C(O)(=O)C.O>[Br-:38].[O:17]([C:15]([C:13]1[C:12]2[C:7]([N+:6]([CH2:25][C:26]([OH:28])=[O:27])=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Br
Reactant: O=C(Oc1ccccc1)c1c2ccccc2nc2ccccc12
Reactant: CC(C)(C)OC(=O)CI
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)C[n+]1c2ccccc2c(C(=O)Oc2ccccc2)c2ccccc21
Product: [Br-]
Temperature: 110 °C

Procedure:
A mixture of phenyl acridine-9-carboxylate (100 mg) and t-butyl iodoacetate is stirred and heated at 110° C. for five hours. The resulting solution is poured into diethyl ether (25 ml) and the resulting precipitate isolated by filtration. Part of this precipitate (10 mg) is stirred with 33% hydrobromic acid in acetic acid (1 ml), and heated at 50° C. for two hours. The reaction mixture is poured into water, and the resulting precipitate (ca. 6 mg) isolated. MS: 358, 314, 300, 237, 220, 206.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C>CCCCCCC.CCOCC.C1(C)C=CC=CC=1>[CH3:6][N:7]([CH2:3][C:2]#[CH:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: CNc1ccccc1
Agent: C#CCBr
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#CCN(C)c1ccccc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
34 ml of a 2.7M solution of n-butyllithium in n-heptane are added dropwise at room temperature under nitrogen in the course of 1 hour to a solution of 10 g (93 mmol) of N-methylaniline in 100 ml of absolute ether. The temperature increases to reflux of the reaction mass. After 1 hour's reflux, the yellow solution is cooled to −10° C. and then in the course of 30 minutes a solution of 11.3 g (102 mmol) of propargyl bromide in toluene is added dropwise. The mixture is then stirred at room temperature for 8 hours. After customary aqueous working-up, the product of formula (101a) is purified by distillation. A yellow oil is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6]([O:32][CH3:33])=[CH:7][C:8]2[C:9]([CH:31]=1)=[N:10][C:11]1[N:12]=[CH:13][C:14]([C:29]#[N:30])=[C:15]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=3[Cl:28])[C:16]=1[CH:17]=2.[I].[Na].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:28][C:20]1[CH:21]=[C:22]([Cl:27])[C:23]([O:25][CH3:26])=[CH:24][C:19]=1[NH:18][C:15]1[C:16]2[CH:17]=[C:8]3[CH:7]=[C:6]([O:32][CH3:33])[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][C:9]3=[N:10][C:11]=2[N:12]=[CH:13][C:14]=1[C:29]#[N:30]
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3nc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Agent: [I]
Agent: [Na]
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl
Yield: 47 %

Procedure:
A mixture of 8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile (202 mg, 0.40 mmol) and sodium iodine (70 mg, 0.47 mmol) in 4 mL of morpholine is heated at reflux for 2 hours. The reaction mixture is concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Ethyl acetate is added to the residue and the orange solid is collected by filtration to provide 105 mg (47%) of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile, mp 242-244° C. dec.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Cl-].[N+:22]([C:25]1[CH:50]=[CH:49][CH:48]=[CH:47][C:26]=1[CH2:27][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:24])=[O:23].[Li+].[CH3:52]C([N-]C(C)C)C>>[CH3:52][O:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](/[CH:9]=[CH:27]/[C:26]1[CH:47]=[CH:48][CH:49]=[CH:50][C:25]=1[N+:22]([O-:24])=[O:23])=[CH:5]2
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: CC(C)[N-]C(C)C
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3ccccc3[N+](=O)[O-])cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2-nitrobenzyl)(triphenyl)phosphonium chloride using the procedure described in example 37, except that the ratio of LDA:aldehyde was 1.37:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (536) as red-orange crystals (the pure E isomer) (47%), mp 136–138° C. 1H NMR (CDCl3) δ 8.25 (br s, 1H), 7.98 (dd, J=8.2, 1.2 Hz, 1H), 7.78 (dd, J=7.9, 1.0 Hz, 1H), 7.61 (td, J=7.6, 0.9 Hz, 1H), 7.41 (d, J=16.3 Hz, 1H), 7.39 (td, J=7.8, 1.3 Hz, 1H), 7.27 (m, 1H), 7.13 (d, J=16.3 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.90 (dd, J=8.8, 2.5 Hz, 1H), 6.62 (d, J=1.8 Hz, 1H), 3.86 (s, 3H). Found: C, 69.44; H, 4.49; N, 9.70. C17H14N2O3 requires C, 69.38; H, 4.79; N, 9.52.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20][C:21](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:20]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH3:21]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (110 ml) was added potassium tert-butoxide (2.65 g). The mixture was stirred for 20 mins, bromoethane (5.88 ml) was added, and the reaction mixture was refluxed for 6.5 hrs. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extractions were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was adhered to silica and flash chromatographed (20% ethyl acetate/hexane) to yield 4.53 g (82%) of 1-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][NH:19][CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][N:19]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:25][CH2:26]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc2c(c1)CN(C1CCOCC1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Temperature: 40 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
Tetrahydro-pyran-4-one (68 mg, 0.68 mmol) was added to a solution of the amine of example 4 (130 mg, 0.34 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (217 mg, 1.0 mmol) was added, and the reaction mixture was stirred for a further 18 hours. Further tetrahydro-pyran-4-one (68 mg, 0.68 mmol) and sodium triacetoxyborohydride (217 mg, 1.0 mmol) were added and the reaction mixture was heated to 40° C. for 24 hours. The reaction mixture was partitioned between 2N aqueous sodium carbonate solution (10 ml) and ethyl acetate (50 ml). The organic layer was washed three times with 2N aqueous sodium carbonate solution (10 ml), once with saturated aqueous brine, and then dried over magnesium sulphate before filtering and evaporating the filtrate under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate in pentane (0% to 30%) as eluant, followed by chromatography on silica gel using a gradient of methanol in dichloromethane (0% to 5%) as eluant, to afford the title compound as a brown foam (80 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH:12]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[N:11]=1.[I-].[Na+].ClC[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1.[CH3:43]N(C)C=O>O.C(O)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[C:13](=[O:21])[C:12]([CH3:43])([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[N:11]=1
Reactant: ClCc1cccnc1
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1N1C(=O)c2ccccc2C1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N(c2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.32 g of a 60% dispersion in mineral oil) in N,N-dimethylformamide (30 ml) was added gradually (3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1 H-1,4-benzodiazepin-2-one (2.87 g) under nitrogen atmosphere at cooling in an ice-bath. The mixture was stirred under the same condition for 0.5 hour and at ambient temperature for 1 hour. The mixture was cooled in an ice-bath and a sodium iodide (1.18 g) was added thereto in one portion. To the mixture was added dropwise a solution of 3-chloromethylpyridine (1.00 g) and stirred for 0.5 hour at the same temperature. The mixture was stirred overnight at ambient temperature. To the resultant was added acetic acid (1.5 g) under cooling in an ice-bath. The resultant mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The aqueous layer was adjusted to pH 7.0-8.0 with sodium carbonate and extracted with ethyl acetate (2×50 ml). The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated in vacuo to give a crude compound. The crude compound was purified by flash chromatography on silica gel [eluent (CHCl3 :ethyl acetate =1:1)] to afford (3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1-(pyridin-3-yl)-methyl-1H -1,4-benzodiazepin-2-one as a colorless crystalline solid (0.67 g).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6](Cl)(Cl)=[S:7].[NH2:10][OH:11]>COCCOC.O>[CH:2]12[CH2:1][CH:5]([CH:4]=[CH:3]1)[C:6](=[N:10][OH:11])[S:7]2
Reactant: C1=CCC=C1
Reactant: S=C(Cl)Cl
Reactant: NO
Solvent: COCCOC
Solvent: O
Product: ON=C1SC2C=CC1C2
Reaction time: 8 h

Procedure:
A stirred solution of 33 g (0.5 m) of cyclopentadiene in 150 ml of petroleum ether was maintained at 0° to -10° C. as 23 g (0.2 m) of thiophosgene was added over 25 minutes. The colorless solution was stripped of volatiles. A solution of the residue in 200 ml of 1,2-dimethoxyethane was added over one hour at 0° C. to 2.0 m of hydroxylamine in 500 ml of water. The reaction mixture was stirred overnight and allowed to come to room temperature. A dried methylene chloride extract was stripped to yield a semi-solid residue which was purified by dry column chromatography (silica gel, ethyl ether:hexane::1:1 ). Two bands were observed. Extraction of each individually yielded 2.4 g of the less polar material, m. 87°-88° C. and 5.9 g of the more polar, m. 137°-137.5° C. The NMR and IR spectra indicate these to be the E and Z isomers of the title compound. The more polar material was identified as the Z isomer by X-ray crystallography.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]2[CH2:13][CH:12]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:10]2=[O:30])[CH2:4][CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[O:30]=[C:10]1[CH:9]([CH2:8][CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)[CH2:13][CH:12]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]1[C:21]1[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1cc(C)c(C2C(=O)C(CC3CCC(O)CC3)CC2OC(=O)C(C)(C)C)c(C)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)C(CC3CCC(=O)CC3)CC2OC(=O)C(C)(C)C)c(C)c1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
The 2,2-dimethyl-propionic acid 4-(4-hydroxy-cyclohexylmethyl)-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester (100 mg) is dissolved in acetone and cooled to 0° C. The Jones reagent (1.3 ml, 167 M) is added dropwise over a period of 30 minutes. The reaction is allowed to warm to room temperature over 1 hour. The reaction is poured into water and extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure to give a white crystalline solid. The solid is purified by flash chromatography to give the 2,2-dimethyl-propionic acid 3-oxo-4-(4-oxo-cyclohexylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester (72 mg).
Reaction SMILES: [NH2:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.COC(OC)OC.[C:32]1([CH3:42])C=CC(S(O)(=O)=O)=CC=1.[CH3:43][NH:44][CH2:45]C>>[CH3:23][C:22]1[CH:21]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]([CH3:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)[C:4]([CH3:24])=[CH:3][C:2]=1[N:1]=[CH:43][N:44]([CH2:32][CH3:42])[CH3:45]
Reactant: Cc1cc(Oc2ccnc(N(C)c3ccccc3)n2)c(C)cc1N
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: CCN(C)C=Nc1cc(C)c(Oc2ccnc(N(C)c3ccccc3)n2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 252 mg (0.7 mmol) of [4-(4-Amino-2,5-dimethyl-phenoxy)-pyrimidin-2-yl]-methyl-phenyl-amine and 4 ml of trimethoxymethane, 20 mg of p-toluene sulfonic acid were added. The reaction mixture was refluxed for 2 hrs and concentrated in vacuo. The mixture was solved in 10 ml of dichloromethane and 62 mg (1.05 mmol) methyl ethyl amine was added. After stirring 18 hrs at ambient temperature the mixture was evaporated and yielded 280 mg (89%) with a purity of 87%; log P (pH 2.3)=1.61.