Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Cu]I.O1CCCC1>[C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCCC
Reactant: Fc1ccccc1Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1ccccc1F
Temperature: 55 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
To a solution of 2-bromofluorobenzene (49 g), 1-dodecyne (210 ml) triethylamine (210 ml), and tetrahydrofuran (50 ml) was added (bis)triphenylphosphine palladium(II)chloride (532 mg) and copper(I)iodide (532 mg). The reaction mixture was warmed to 55° C. and stirred for 24 hr. The mixture was allowed to cool to room temperature and filtered. The precipitate was washed with ethyl acetate, and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled to afford 11 g (15%) of product, bp 175°-180° C. at 1 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=O)[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]([CH3:16])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution (200 mL) of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (15.3 g) synthesized in Example A82(1) in N,N-dimethylformamide were added potassium carbonate (13.1 g) and ethyl bromoacetate (7.7 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, the obtained residue was dissolved in N,N-dimethylformamide (100 mL) again, and 1,8-diazabicyclo[5.4.0]undec-7-ene (12.2 mL) was added to the solution. The reaction mixture was stirred at 80° C. overnight. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the obtained solid was washed with ethanol-isopropyl ether to give the title object compound (3.3 g, 17%) as a colorless solid.
Reaction SMILES: [Sb:1].[H-].[Li+].[CH3:4][Si:5]([CH3:8])([CH3:7])Cl>O1CCCC1>[CH3:4][Si:5]([Sb:1]([Si:5]([CH3:8])([CH3:7])[CH3:4])[Si:5]([CH3:8])([CH3:7])[CH3:4])([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: [Sb]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)[Sb]([Si](C)(C)C)[Si](C)(C)C
Temperature: -20 °C

Procedure:
1.22 g (0.01 mol) of 200 mesh antimony powder, 0.72 g (0.03 mol) of lithium hydride, and 40 ml of tetrahydrofuran (THF) were placed in a 100 ml flask. With stirring, the mixture was refluxed for 4 hours. All of the black powder constituting antimony disappeared, and a muddy colored precipitate was formed. Then, the mixture was cooled down to −20° C.; 3.3 g (0.03 mol) of trimethylchlorosilane was added. The mixture was allowed to warm up to room temperature. After stirring for 4 hours, the mixture was filtered under inert atmosphere. The solvent was removed by distillation. Tris(trimethylsilyl)antimony was purified by vacuum distillation.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH3:19])=[N:5][CH:4]=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[H][H]>[Pd].C(O)C>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH3:19])=[N:5][CH:4]=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1cnc(-c2cc([N+](=O)[O-])ccc2OCC)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cc(N)ccc2OCC)[nH]c1=O
Yield: 31.4 %

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-ethoxy-5-nitrophenyl)pyrimidine-5-carboxylate (0.42 g., 1.26 mmoles) and 10% palladium on carbon (0.07 g.) in ethanol (200 ml.) was treated with hydrogen at a pressure of about 3.5 kg./cm2 until uptake of hydrogen ceased. The mixture was filtered and the filtrate reduced to dryness. The residue was recrystallized from water followed by aqueous ethanol to give the title compound (0.12 g., 31.6%), m.p. 107°-110°.
Reaction SMILES: [Mg].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[N:11]([CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[C:24]([O-:26])=[O:25])=[CH:18][CH:17]=1)[CH3:12].II.[CH3:37]O>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[N:11]([CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([O:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[C:24]([O:26][CH3:37])=[O:25])=[CH:20][CH:21]=1)[CH3:12]
Reactant: CN(CCOc1ccc(CC(Oc2ccc(Cl)cc2)C(=O)[O-])cc1)c1nc2ccccc2o1
Reactant: CO
Agent: II
Agent: [Mg]
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Oc1ccc(Cl)cc1

Procedure:
Magnesium turnings (0.5 g) were added to a mixture of methyl (E/Z) 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(4-chlorophenoxy)propanoate (0.98 g) and a crystal of iodine dissolved in methanol (50 mL) at room temperature. The mixture was warmed gently with a heat gum until reaction ensued, at which pint the heating was stopped and the mixture stirred at room temperature during the addition, over ca 5 minutes, of a further portion of magnesium (2.00 g). The reaction mixture was immersed in a cold water bath and stirring continued until all the metal had dissolved (~4 hrs), then the mixture was evaporated in vacuo. The residue was suspended in water (100 mL) and stirred vigorously during the addition of concentrated hydrochloric acid, to give (once all the suspension had dissolved) a final pH of 1.5. The mixture was extracted with ethyl acetate (2×100 mL) and the combined ethyl acetate layers then washed with water (500 mL), brine (300 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with 3% ethyl acetate in dichloromethane as eluent to afford the title compound, mp 88°-90° C.
Reaction SMILES: CCCCCC.[CH3:7][CH:8]([CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[CH2:9]O.[CH2:18]([O:25]COC[C@@H](C)COS(C1C=CC(C)=CC=1)(=O)=O)[C:19]1C=CC=C[CH:20]=1>O>[CH3:7][C@@H:8]([CH2:11][CH2:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])/[CH:9]=[CH:20]\[CH2:19][CH2:18][OH:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)COCOCc2ccccc2)cc1
Reactant: CC(CO)CCCC(C)(C)O
Solvent: CCCCCC
Solvent: O
Product: C[C@H](/C=C\CCO)CCCC(C)(C)O

Procedure:
UV (hexane) λmax 234.0 (ε27 800), 241.0 (ε30 200), 248.5 (sh, ε19 900) nm; 1H NMR (400 Hz, CDCl3) δ0.86 (3H, d, J=6.5 Hz, CH—CH3), 1.21 [6H, s, C(CH3)2], 2.08 (2H, q, J=6.9 Hz, 4′-H2), 2.26 (1H, dd, J=13.1, 7.1 Hz), 2.39(1H, dd, J=13.4, 7.2 Hz), 2.56 (1H, dd, J=13.5, 4.2 Hz), 2.70 (1H, dd, J=13.3, 4.3 Hz), 4.48 (2H, m, 1- and 3-H), 5.10 (2H, s, C═CH2); 5.70 (1H, dt, J=15.0, 6.9 Hz, 3′-H 6.03 (1H, d, J=10.8 Hz, 1′-H), 6.29 (1H, dd, J=15.0, 10.8 Hz, 2′-H); MS (El) m/z (relative intensity) no M+, 318 (M+−H2O, 19), 300 (8), 285 (4), 59 (100); HRMS (ESI) exact mass calculated for C21H34O2 (M+−H2O) 318.2559, measured 318.2570.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(Cl)cc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,4-Dichloro-benzoic acid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([S:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>>[N:1]1([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([S:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2ncnc(Cl)c2cc1SC
Reactant: c1ccc2c(c1)CCCN2
Product: COc1cc2ncnc(N3CCCc4ccccc43)c2cc1SC
Yield: 35 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 35% yield from 1,2,3,4-tetrahydroquinoline and 4-chloro-7-methoxy-6-methylsulfanyl-quinazoline. (M.P. 193°-196° C.; LC-MS: 338 (MH+)).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18]C(NCCN)=S)=[C:16]([CH3:17])[C:11]=2[N:10]=[C:9]1[CH3:25])=O)(C)(C)C>CO>[CH3:25][C:9]1[NH:10][C:11]2[C:16]([CH3:17])=[C:15]([NH:18][N:10]3[CH2:11][CH2:12][N:8]=[CH:9]3)[CH:14]=[CH:13][C:12]=2[N:8]=1
Reactant: Cc1c(NC(=S)NCCN)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Solvent: CO
Product: Cc1nc2ccc(NN3C=NCC3)c(C)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-(1-t-butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N′-2-aminoethylthiourea (1.33 g, 3.66 mmol) and mercuric acetate (1.45 g, 4.54 mmol) in methanol (150 mL) is stirred at room temperature for 1 hour. The resulting black mixture is filtered on Celite with a methanol wash of the solids. The filtrate is rotary evaporated and the residue is purified by flash chromatography on a short pad of silica gel, eluting with 10% methanol/chloroform containing 1% of ammonium hydroxide. The product-containing fractions are collected and rotary evaporated to afford 2,4-dimethyl-5-(2-imidazolinylamino)benzimidazole as a white solid.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][Cl:6].[BH4-].[Na+]>CO>[OH:1][CH:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][Cl:6]
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(O)CCCCl)ccc2N1
Temperature: 25 °C

Procedure:
2.0 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril was mixed with 100 ml of methanol, and the mixture was stirred at a room temperature. Then 1.0 g of sodium borohydride was added to the mixture gradually. After the reaction mixture was stirred at a room temperature for 2 hours, methanol was removed by distillation under a reduced pressure. The residue was extracted with chloroform and the chloroform layer was washed with water, and dried. Chloroform was removed by distillation under a reduced pressure, then the residue thus obtained was recrystallized from ethanol-water to obtain 1.2 g of 6-(1-hydroxy-4-chlorobutyl)-3,4-dihydrocarbostyril in colorless needle-like crystals. Melting point: 120°-121° C.
Reaction SMILES: C1([S:7]P(C2C=CC=CC=2)(=S)O)C=CC=CC=1.[CH2:17]([O:19][C:20](=[O:26])[C:21]([C:24]#[N:25])([CH3:23])[CH3:22])[CH3:18]>C(O)(C)C>[NH2:25][C:24](=[S:7])[C:21]([CH3:23])([CH3:22])[C:20]([O:19][CH2:17][CH3:18])=[O:26]
Reactant: CCOC(=O)C(C)(C)C#N
Reactant: OP(=S)(Sc1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: CCOC(=O)C(C)(C)C(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
A mixture of diphenyldithiophosphonic acid (ALFAAESAR, 1.42 g, 5.67 mmol) and 2-cyano-2-methylpropionic acid ethyl ester (ABCR, 0.412 mL, 2.83 mmol) in isopropanol (30 mL) was heated under reflux for 4 h. Reaction mixture was cooled to room temperature and a precipitate was formed. Reaction flask was placed in the freezer for 1 h. Reaction mixture was filtered and filtrate was concentrated. Residue was taken up in DCM (100 mL) and washed with water (20 mL), 1N NaOH (20 mL), saturated NaHCO3 (20 mL) and dried over sodium sulfate and concentrated. The resulting oil was loaded on a 25 g silica cartridge and eluted with linear gradient 0-50% hexane-ethyl acetate to yield the title compound (110 mg, 0.628 mmol, 22.2% yield). Another impure batch was loaded on a 10 g silica cartridge and eluted with linear gradient 0-50% hexane-ethyl acetate to recover the title compound (120 mg, 0.685 mmol, 24.17% yield). Total yield: (230 mg, 1.313 mmol, 46.32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.70 (br s, 1H), 8.86 (br s, 1H), 4.05 (q, 2H), 1.39 (s, 6H), 1.15 (t, 3H). [ES+MS] m/z 176 (MH+).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: Cc1ccccc1CN
Product: Cc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-methylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): m/e 316.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.43 (br s, 1H); 8.05 (br s, 1H); 7.85 (d, J=8.7 Hz, 1H); 6.84 (d, J=5.4 Hz, 1H); 4.73 (d, J=5.7 Hz, 1H); 2.43 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:8][C:9]1[N:10]=[C:11]([Cl:16])[N:12]=[C:13]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nc(Cl)nc(OCc2ccccc2)n1
Reactant: Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1nc(OCc2ccccc2)nc(Oc2ccccc2)n1
Yield: 94.1 %

Procedure:
Next, 5.70 mL of dichloromethane solution containing 896.2 mg (3.50 m mol) of 6-benzyloxy-2,4-dichloro-1,3,5-triazine, 2.00 mL of dichloromethane, 365.0 mg (3.88 m mol) of phenol and 0.738 mL (4.23 m mol) of N,N-diisopropylethylamine was added to a 30 mL eggplant flask, and reacted at 0 degree under a nitrogen atmosphere for 6 hours. After the reaction, 20 mL of dichloromethane was added, which was washed with 20 mL of 1 N hydrochloric acid, 20 mL of 1 N hydrochloric acid, 20 mL of water and 20 mL of saturated salt water. A resulting organic phase was dried by magnesium sulfate, from which dichloromethane was distilled away, and the residue was recrystallized to obtain 1033.2 mg of 6-benzyloxy-2-chloro-4-phenoxy-1,3,5-triazine (yield: 94%).
Reaction SMILES: O.[CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]([O:13]O)=[O:12])=[CH:4][CH:3]=1>CO>[C:11]1(=[O:12])[O:13][C:8](=[O:10])[C:6]2=[CH:7][CH:2]=[CH:3][CH:4]=[C:5]12
Reactant: O=C(O)c1ccccc1C(=O)OO
Solvent: O
Solvent: CO
Product: O=C1OC(=O)c2ccccc21

Procedure:
0.81 g of 20-formamido-Δ4,17(20) -pregnadien-11β, 21-diol-3-one, 6.4 ml of water and 6.4 ml of methanol were mixed together under an inert gas atmosphere and 0.8 ml of 50% perphthalic acid (obtained from 2 g of phthalic anhydride solubilized at 40° C. over 15 minutes in a mixture of 1 ml of 50% hydrogen peroxide and 2 ml of methanol) were added with stirring at 22°-23° C. Then after 90 minutes of stirring, another 0.8 ml of perphthalic acid was added. After 4 hours, another 0.5 ml of perphthalic acid was added and after 3 hours of stirring, the mixture was cooled to 5° C. The crystals were separated and washed with water and with an aqueous solution of sodium bicarbonate and dried to obtain 0.586 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][NH:5][C:6]([CH3:12])=[N:7]2>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([CH3:12])=[N:7]2
Reactant: CC1=Nc2cccc(F)c2CN1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ncc2c(F)cccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
To a solution of 5-fluoro-2-methyl-3,4-dihydroquinazoline (0.74 g, 4.51 mmol) in chloroform (100 mL) at room temperature was added manganese (IV) oxide (4.0 g, 46.0 mmol) and the reaction mixture stirred at room temperature for 20 h. The reaction mixture was filtered through a plug of celite, washing with dichloromethane. The filtrate was evaporated in vacuo to give the title compound as a yellow solid (0.715 g, 98%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([SH:12])[NH:10][N:11]=2)[CH:2]=1.C(N(CC)CC)C.Cl[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:23]>CN(C=O)C>[Cl:31][C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH2:21][S:12][C:9]2[NH:10][N:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:8]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Sc1nc(-c2cccnc2)n[nH]1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CSc1nc(-c2cccnc2)n[nH]1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
The thiol intermediate prepared in Step B (101 mg, 0.567 mmol) was dissolved in DMF (2 ml) and triethylamine (0.24 ml, 1.7 mmol). 2,3′-dichloroacetanilide (116 mg, 0.567 mmol) was added and allowed to stir at room temperature overnight. The mixture was loaded directly onto an HPLC reverse phase column and purified by water to acetonitrile gradient in the presence of 0.1% trifluoroacetic acid. The aqueous phase was evaporated by lyophilization to yield the title compound as a fluffy white solid (166 mg, 85% yield). MS (ES) 346.5 (M+H)+
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.[O-]CC.[ClH:26]>O.C(O)C>[ClH:26].[C:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)=[C:2]([C:3]1[CH:4]=[CH:5][N:6]=[CH:7][CH:8]=1)[OH:10])#[N:22]
Reactant: CCOC(=O)c1ccncc1
Reactant: N#CCc1ccc(F)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: N#CC(=C(O)c1ccncc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
17.3 g (0.75 mol) of metallic sodium were treated dropwise with 250 ml of absolute ethanol. 75.8 g (0.5 mol) of ethyl isonicotinate and 67.6 g (0.5 mol) of 4-fluorophenylacetonitrile were added to the ethoxide. The reaction mixture was stirred at 100° C. for 15 min. The mixture was then cooled in an ice bath and treated with 600 ml of dist. water. On acidifying to pH 1 using 90 ml of conc. HCl, the title compound deposited as a yellow precipitate. The precipitate was filtered off, washed with dist. water and dried over P2O5 in vacuo. Yield: 85.0 g (62%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:10]=1)[CH2:2][CH3:3].Cl[C:30]1[C:39]2[C:34](=[CH:35][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:30]4[C:39]5[C:34](=[CH:35][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=5)[N:33]=[CH:32][CH:31]=4)=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:10]=1)[CH2:2][CH3:3]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: CCCOc1cc(OCCC)cc(N2CCN(Cc3ccc(N)cc3)CC2)c1
Product: CCCOc1cc(OCCC)cc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 1-(3,5-dipropoxyphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(3,5-dipropoxyphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>C(OCC)(=O)C>[Si:18]([O:8][CH2:7][C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](C)CO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C

Procedure:
Methyl (S)-(+)-2-methyl-3-hydroxypropionate (1.0 g; 8.47 mmole) and imidazole (1.15 g; 16.9 mmole) were dissolved in dry dimethylfofmamide (10 ml), t-butyl dimethylchlorosilane (1.30 g; 8.62 mmole) was added thereto, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (60 ml), washed with an aqueous sodium chloride solution (50 ml) three times and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give methyl (S)-3-t-butyldimethylsilyloxy-2-methylpropionate
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:5]=2[N:4]=1.S(=O)(=O)(O)O.[CH3:20]O>>[Cl:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:20])=[O:13])=[CH:11][C:5]=2[N:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc2[nH]c(CCl)nc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2[nH]c(CCl)nc2c1
Yield: 71 %

Procedure:
To 2-(Chloromethyl)-1H-benzimidazole-5-carboxylic acid (4) (0.5 g; 2.4 mmole) suspended in anhydrous methanol (20 ml) was added dropwise Sulfuric acid (0.2 ml). The reaction mixture was maintained at reflux for 16 hours. The solvent was evaporated to give the crude oily product, which was purified by column chromatography (silica, 10% methanol: dichloromethane) to obtain 0.4 g (71% yield) of product 5.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[C:5](=[C:9]([CH3:11])[CH3:10])[CH2:4]1.CO>CCOC(C)=O.[Pt](=O)=O>[OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1
Reactant: CC(C)=C1C[C@H](CO)NC1=O
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C1C[C@H](CO)NC1=O
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of (R)-5-(hydroxymethyl)-3-(propan-2-ylidene)pyrrolidin-2-one (2.223 g, 14.32 mmol) and platinum (iv) oxide (0.325 g, 1.432 mmol) in EtOAc (40 mL)/MeOH (4 mL) at room temperature was stirred in the pressure bottle reactor under H2 (28 psi to 2 psi) overnight. The resulting mixture was filtered through a pad of Celite, washed with EtOAc, and concentrated to give (5R)-5-(hydroxymethyl)-3-isopropylpyrrolidin-2-one (2.251 g, 14.32 mmol, 90% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.56-6.71 (m, 1H), 3.64-3.80 (m, 2H), 3.37-3.53 (m, 1H), 2.48 (td, J=9.9, 4.5 Hz, 2H), 2.14-2.27 (m, 1H), 1.97-2.13 (m, 1H), 1.50 (ddd, J=12.7, 10.7, 8.3 Hz, 1H), 0.98 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H). m/z (ESI, +ve) 158 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:24](=[O:25])[C:23]2[N:26]3[C:16](=[CH:17][N:18]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH2:15]1)=O)(C)(C)C.[ClH:27]>C(O)C>[ClH:27].[ClH:27].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:24](=[O:25])[C:23]2[N:26]3[C:16](=[CH:17][N:18]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCCCCN1Cc2cnc3cccc(n23)C1=O
Agent: Cl
Solvent: CCO
Product: NCCCCCN1Cc2cnc3cccc(n23)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.24 g (6.25 mmol) of 4,5-dihydro-4[5-(tert-butoxycarbonylamino)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylen-5-one in 20 ml of ethanol was added 20 ml of conc. HCl. The mixture was stirred for 1.5 hour at room temperature. The solvent was distilled off to leave 2.05 g of the desired compound (quant. a pale brown solid). This product was used in the subsequent reaction without further purification.