Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 4-bromo-3-methylbenzoate (2.0 g, 8.7 mmol) in dry THF (10 mL) was added to an ice-cooled suspension of lithium aluminiumhydride (400 mg, 10.4 mmol) in dry THF (30 mL). After addition, the mixture was warmed to room temperature and then stirred for 3 h. The excess lithium aluminiumhydride was quenched by successive addition of water (0.4 mL), 15% NaOHaq (0.4 mL), and water (1.2 mL) under ice cooling. The insoluble material appeared was removed by filtration (celite), and the precipitate was washed by AcOEt (20 mL×5). The combined filtrates were washed with brine (50 mL) and then dried over Na2SO4. The solvent was evaporated, and the obtained product (1.6 g, 100%) was used for next step without further purification. 1H-NMR (CDCl3, 400 MHz): δ7.53 (1H, d, J=8.1 Hz), 7.26 (1H, d, J=1.5 Hz), 6.40 (1H, dd, J=8.1, 1.5 Hz), 4.68 (2H, s), 2.44 (3H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1.C(Cl)Cl>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: CCOc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1ccc(-c2nccnc2N2CCNCC2)cc1

Procedure:
Deprotect 3′-(4-ethoxyphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (1.80 g, 4.7 mmol) using 4 M HCl in 1,4-dioxane (38 mL) in DCM (100 mL). Concentrate and dissolve the residue in DCM and 10% aqueous sodium carbonate. Separate the layers and extract the aqueous layer with DCM (2×150 mL). Combine the organic layers, wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title preparation (1.12 g, 84%). MS (ES): m/z=285 [M+H]+.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].Cl[CH2:16][CH2:17][O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN1C(=O)CCC1>[C:4]([O:6][CH2:16][CH2:17][O:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CCOC(=O)OCCCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)OCCOC(=O)/C=C/C(=O)OC
Yield: 85.3 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.39 g, 3.0 mmol) in NMP (8 mL) was reacted with CsHCO3 (0.69 g, 3.6 mmol) and ethyl (chloroethoxy)formate (0.64 g, 4.2 mmol) to afford 0.63 g (85% yield) of the title compound (39) after isolation and purification. 1H NMR (CDCl3, 400 MHz): δ 6.89 (d, J=15.6 Hz, 1H), 6.82 (d, J=15.6 Hz, 1H), 6.84 (q, J=5.6 Hz, 1H), 4.23 (q, J=7.2 Hz, 3H), 3.81 (s, 3H), 1.58 (d, J=5.6 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H). MS (ESI): m/z 247.01 (M+H)+.
Reaction SMILES: O=[C:2]1O[C:6]2[C:8]3[C:13]([CH2:14][C:5]=2[C:4]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]1[C:21]#[N:22])=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:27][O:28][C:29]1[CH:25]=[CH:26][C:4]2[CH2:5][C:6]3[C:2](=[C:3]([C:21]#[N:22])[C:4]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[C:5]4[CH2:14][C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[C:6]4=3)[C:3]=2[CH:2]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)c2c(oc1=O)-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)-c1c(C#N)c(N3CCCCC3)c3c(c1C2)-c1ccccc1C3

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-2,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (292 mg), 6-methoxyindanone-1 (162 mg) and NaH (48 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 216-218° C.; IR (KBr) 2213 cm−1 (CN); MS (ESI) 392 (M+); 13C NMR (150 MHz, CDCl3) δ 24.39, 26.94, 35.47, 36.96, 53.14, 55.54, 99.39, 110.62, 113.05, 118.84, 122.72, 123.26, 124.94, 127.11, 127.93, 131.65, 132.25, 134.54, 140.38, 142.59, 144.41, 144.74, 146.32, 152.27, 160.02.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.Br[CH2:14][CH2:15]Br>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:15][CH2:14]2)[CH:2]=1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: BrCCBr
Product: CCOC(=O)C1(c2cccnc2)CC1

Procedure:
Prepared in a similar manner to that described above by reacting ethyl 2-pyridin-3-ylacetate with 1,2-dibromoethane to give ethyl 1-pyridin-3-ylcyclopropane-1-carboxylate which was then hydrogenated to give the desired compound as a brown oil (quantitative reaction).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[C:35](O)=[O:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:36]
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cnc4ccccc4n3)cc2)c2ccc3ccccc3c2N1
Yield: 20.9 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.101 mmol) obtained in Example 1, (3), quinoxaline-2-carboxylic acid (35 mg, 0.202 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.111 mmol) were dissolved in DMF (2.0 mL), then the solution was added with triethylamine (20 mg, 0.202 mmol), and the mixture was stirred over night. The reaction mixture was treated in a conventional manner to obtain the title compound (10 mg, yield 21%) as yellow crystals.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]=[O:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(tert-butyl-diphenylsilyloxy)-1-propanol (1 mmole) in methylene chloride (7 mL) was treated with powder molecular sieves (4 A, 0.5 equiv. wt/wt) and pyridinium chlorochromate (1.5 mmole) at 0° C. The resulting mixture was stirred at room temperature for 2 h, and diluted with diethyl ether (7 mL) and stirred at room temperature for another 30 min. Filtration, evaporation and chromatography gave 3-(tert-butyldiphenylsilyloxy)-1-propanal as a clear oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:34][C:35](=[O:37])[CH3:36])[CH2:6]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[Br:43]N1C(C)(C)C(=O)N(Br)C1=O>CCCCCC>[C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11]([Br:43])[C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@@H:20]([F:25])[C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:34][C:35](=[O:37])[CH3:36])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 80 °C

Procedure:
A mixture of 0.520 g. (0.0010 mole) of [1α,3β,24R]-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.45 g. of sodium bicarbonate, 0.192 g. (0.00066 mole) of 1,3-dibromo-5,5-dimethylhydantoin and 25 ml. of hexane was heated at reflux (80° C.) for 1 hr and cooled. The mixture was filtered and the solids were triturated with hexane and filtered. The filtrates were evaporated to dryness to yield [1α,3β,7ξ,24R]-7-bromo-24-fluorcholest-5-en-1,3,25-triol 1,3-diacetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]#[N:30].[I-].[K+]>CC(C)=O.O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:28][C:29]#[N:30])[CH:3]=1
Reactant: N#CCCl
Reactant: O=c1c(-c2ccccc2Cl)coc2cc(O)cc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCOc1cc(Cl)c2c(=O)c(-c3ccccc3Cl)coc2c1
Yield: 88.7 %

Procedure:
In 50 ml of acetone was dissolved 1.4 g of 5-chloro-3-(2-chlorophenyl)-7-hydroxy-4-oxo-4H-1-benzopyran, and 0.7 g of anhydrous potassium carbonate, 0.38 g of chloroacetonitrile and 0.15 g of potassium iodide were added to the solution, followed by refluxing for 8 hours. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 1.4 g of the entitled compound having a melting point of 174° to 175° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[ClH:56]>O1CCCC1.CC(C)=O>[ClH:56].[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2C1CCNC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 65 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.610 g, 21.49 mmol) in tetrahydrofuran (200 mL) was added rac-tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate (6.039 g, 32.25 mmol), triphenylphosphine (11.273 g, 42.98 mmol), and diethyl azodicarboxylate (7.485 g, 6.77 mL, 42.98 mmol). The reaction mixture was stirred at room temperature for 6 days and then concentrated to afford an orange-brown oil. Acetone (100 mL) and 5 N hydrochloric acid (50 mL) were added and the solution was heated at 40° C. for 18 h and then cooled to room temperature. The resulting yellow precipitate was filtered, and the filter cake was washed with diethyl ether and dried to afford rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride as an off-white solid (5.153 g, 65%). RP-HPLC Rt 4.079 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 331 (MH+).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([Li])CCC.IC>C1COCC1>[C:1]1([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cccc2ccccc12
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
1-Naphthylacetic acid (10 g, 53.7 mmol) is dissolved in dry THF (150 mL) under nitrogen. The solution is cooled to -10° C., treated with 1.6M butyl lithium in hexanes (72 mL, 115 mmol), and stirred for 15 minutes. A solution of iodomethane (3.7 mL, 59.4 mmol) in dry THF (50 mL) is added, and the mixture is allowed to warm to room temperature and stir for several hours. The solvent is removed in vacuo, and the residue dissolved in 5% sodium hydroxide solution (500 mL), washed with ether (3×200 mL), and then acidified by the addition of 6N hydrochloric acid. The aqueous is then extracted with dichloromethane (3×200 mL), the organic extracts are dried over sodium sulfate, and the solvent removed to leave 2-(1-naphthyl)propionic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH:8](O)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:26]=[C:24]1[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](=[O:31])[N:25]1[CH:8]([CH2:7][O:6][C:5]1[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(O)COc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(COc1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 1.5 g of rac-tert-butyl [3-(4-fluorophenoxy)-2-hydroxypropyl]carbamate (5.26 mmol, 1 equivalent), 0.93 g of phthalimide (6.31 mmol, 1.2 equivalents) and 2.07 g of triphenylphosphine (7.9 mmol, 1.5 equivalents) were initially charged in 22 ml of dry THF. 1.56 ml of diisopropyl azodicarboxylate (7.9 mmol, 1.5 equivalents) were added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (Biotage Isolera; cyclohexane/ethyl acetate gradient as mobile phase). This gave 1.97 g of the title compound (90% of theory).
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.O>CS(C)=O>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:11][C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)[CH2:35][C:36]5[CH:43]=[CH:42][C:39]([CH3:40])=[CH:38][CH:37]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Reactant: Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(CN(Cc2ccc(C)cc2)c2nccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 175.3 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol) and sodium hydroxide (38 mg, 0.96 mmol) were added in dimethylsulfoxide (1 mL), and stirred at 100° C. for 30 minutes. This solution was added with a solution of 4-methylbenzyl bromide (71.6 μL, 0.53 mmol) in dimethylsulfoxide (1 mL) at 100° C. for 30 minutes, and stirred for 5 hours. This solution was cooled and added with water (100 mL) and a saturated saline solution, and allowed to stand for 24 hours. The precipitated crystalline material was purified by column chromatogram (silica gel, hexane:EtOAc=8:1) to obtain the title compound (131 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH2:29]([S:31]SCC)[CH3:30]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([S:31][CH2:29][CH3:30])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCSSCC
Reactant: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCSc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
A solution of 0.50 g (1.31 mmol) (4R,9aR)-7-bromo-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 6, intermediate) in 30 mL diethyl ether was cooled to −100° C. and 1.05 mL tert-butyl-lithium (1.57 mmol; 1.5M solution in n-pentane) was added dropwise. After 15 min. diethyl disulfide was added and the reaction was stirred at −78° C. for 1 h. The reaction mixture was quenched with 10% aqueous citric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:4) as eluant to give the product as a light yellow solid (57.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:8][C:5]1[CH:4]=[N:3][C:2]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[N:7][CH:6]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: OC1CCNCC1
Product: Cc1cnc(N2CCC(O)CC2)nc1

Procedure:
The title compound is prepared from 2-chloro-5-methyl-pyrimidine and 4-hydroxy-piperidine following a procedure analogous to that described in Intermediate 37. LC (method 1): tR=0.48 min; Mass spectrum (ESI+): m/z=194 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[F:29][C:28]([F:30])([F:31])[C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=2)[CH:14]=1)=[O:32]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc(CCl)c1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 37, 3-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide to give the title compound in 94% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 4.85 (s, 2H), 7.25 (d, 1H), 7.6 (m, 3H), 7.8 (m, 2H), 7.95 (d, 2H), 8.05 (s, 1H), 8.16 (m, 2H), 9.96 (s, 1), 10.44 (s, 1H); Mass Spectrum: M−H− 445.
Reaction SMILES: [C@@H:1]12[O:11][CH2:10][C@@H:8]([O:9]1)[C:6](O)=[C:4](O)[C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][CH3:43])[CH:41]=1)[C:36](O)=[O:37].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:43][O:42][C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([O:32][CH3:31])[CH:41]=1)[C:36]([O:3][C@@H:2]1[CH:4]=[CH:6][C@H:8]2[CH2:10][O:11][C@@H:1]1[O:9]2)=[O:37]
Reactant: COc1cc(OC)cc(C(=O)O)c1
Reactant: OC1=C(O)[C@H](O)[C@@H]2OC[C@H]1O2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)O[C@@H]2C=C[C@H]3CO[C@@H]2O3)c1
Yield: 83.8 %

Procedure:
1.28 g (10.0 mmol) of 1,6-anhydro-β-D-threo-hex-3-enopyranose, 5.25 g (20.0 mmol) of triphenyl phosphine, and 3.64 g (20.0 mmol) of 3,5-dimethoxybenzoic acid were added to 16 ml of dry THF, and a solution obtained by dissolving 3.48 g (20.0 mmol) of diethylazodicarboxylate in 16 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 45 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=5:1) to obtain 2.45 g (yield: 83.7%) of 1,6-anhydro-3,4-dideoxy-2-O-(3,5-dimethoxybenzoyl)-β-D-erythro-hex-3-enopyranose. This product was recrystallized from a solvent mixture of hexane and diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=O)[C:31]([OH:33])=[O:32])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:30]([C:31]([OH:33])=[O:32])[CH2:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C(O)C(=O)CCCN1CCOCC1
Product: O=C(O)C(CCCN1CCOCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 13, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be stirred with 5-morpholino-2-oxopentanoic acid to give 7-chloro-2-[(1-carboxy-4-morpholinobutylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)c2ccc(Br)cc2n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To an ice cold solution of 7-bromo-2,4-dichloro-quinazoline (7 g, 0.0255 mol) in DCM (150 mL), morpholine (4.43 mL, 0.0509 mol) was slowly added and the reaction was continued at 0° C. for 30 min. The solvent was evaporated to dryness to get the crude compound. The crude product was purified, using column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to get the title compound (7 g, 84%). 1H NMR (300 MHz, CDCl3): δ 8.17 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 3.72-3.74 (m, 8H): LC-MS (ESI): Calculated mass: 327.0; Observed mass: 329.8 [M+H]+ (RT: 0.45 min).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.Br[CH:21]([CH3:31])[C:22]([O:24][CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][O:27]1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:6][C:5]1[CH:18]=[CH:19][C:2]([O:1][CH:21]([CH3:31])[C:22]([O:24][CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][O:27]3)=[O:23])=[CH:3][CH:4]=1)[CH:16]=[N:15]2
Reactant: CC(Br)C(=O)OCC1CCCO1
Reactant: Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)OCC1CCCO1
Yield: 85 %

Procedure:
To a 500 milliliter roundbottom flask were added 0.055 mole of 2-(4-hydroxyphenoxy)-6-chloroquinoxaline, 0.055 mole of 2-tetrahydrofuranylmethyl 2-bromopropanoate, 0.110 mole of anhydrous potassium carbonate, and 250 milliliters of acetonitrile. The mixture was refluxed for 5.5 hours and the solvent removed. The residue was filtered through a column of alumina with dichloromethane. Solvent removal and recrystallization from boiling hexane resulted in an 85% yield of 2-tetrahydrofuranylmethyl 2-[4-(6-chloro-2-quinoxalinyloxy)phenoxy]propanoate. The material melted over a range of 52°-55° C.