Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH2:25].Cl.C(O)(C)C>CC(O)CCC.CN(C=O)C>[ClH:1].[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1nccn1C
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)cnnc2cc1OCc1nccn1C
Temperature: 0 °C
Yield: 79.5 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline (109 mg, 0.35 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (70 mg, 0.5mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (3 ml), DMF (0.5 ml) and a 5M solution of hydrogen chloride in isopropanol (74 μl, 0.35 mmol) was heated at reflux for 3 hours. The solution was then cooled to 0° C. and the resulting solid filtered off and washed with ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline hydrochloride as a yellow solid (124 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:22]([NH:29][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)NCc1ccccc1
Yield: 90.9 %

Procedure:
To a solution of crude N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid (22.2 mg, 0.074 mmol) in anhydrous methylene chloride (0.50 mL) were added benzyl amine (9.7 mg, 0.091 mmmol) and 1-hydroxybenzotriazol monohydrate (11.1 mg, 0.082 mmol). To the reaction mixture stirred under ice-cold condition was added 1,3-dicyclohexylcarbodiimide (18.0 mg, 0.087 mmol), and the mixture was stirred for 0.5 hour. After removal of the ice bath, the mixture was stirred for 16 hours at room temperature, and then chloroform (20 mL) was added. The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (2×3 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude oily material (47 . 7 mg). The crude oil was purified by column chromatography (silica gel 2g, about 15% ammonia/methanol-chloroform (1:100)) to obtain N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl amide (26.2 mg) as a colorless oily material [yield 90% from N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl ether].
Reaction SMILES: C(Cl)(=O)C.C(O)C.Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:17]N)[CH:14]=[CH:15][CH:16]=1.O=[C:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH2:22][CH2:21]1>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:14]([C:21]3[CH2:22][CH:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])[CH2:24][CH2:25][C:20]=3[NH:17]2)=[CH:15][CH:16]=1
Reactant: COc1cccc(NN)c1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: CCO
Product: COc1ccc2c3c([nH]c2c1)CCC(NC(=O)C(C)C)C3
Yield: 31.1 %

Procedure:
Follow the procedures essentially as described in Preparation 6, above, using acetyl chloride (26 mL, 360 mmol) and absolute ethanol (90 mL) with 3-methoxyphenylhydrazine hydrochloride (5.24 g, 30 mmol) and N-(4-oxo-cyclohexyl)-isobutyramide (5.50 g, 30 mmol). When complete, dilute the reaction with ethyl acetate (200 mL) and wash with 0.5N NaOH and sodium bicarbonate solution. Filter the solids in the organic phase, triturate in dichloromethane and filter to give 2.67 g (31%) gray solid. MS (ES): m/z 287 (M+1), 285 (M−1); 1H NMR(DMSO-d6): δ 10.52 (s, 1H), 7.83 (d, 1H, J=7.5 Hz), 7.21 (d, 1H, J=8.4 Hz), 6.78 (s, 1H), 6.60 (d, 1H, J=8.4 Hz), 4.00 (m, 1H), 3.75 (s, 3H), 2.87 (dd, 1H, J=14.8, 5.1 Hz), 2.76 (m, 2H), 2.48-2.36 (m, 2H), 2.48-2.36 (m, 2H), 1.76 (m, 1H), 1.03 (d, 6H, J=6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:15]1[CH:16]=[C:17]([CH3:22])[C:18]([CH3:21])=[CH:19][CH:20]=1.[OH-].[K+]>C1(C)C=CC=CC=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[CH3:22][C:17]1[CH:16]=[C:15]([N:1]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:20]=[CH:19][C:18]=1[CH3:21]
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(I)cc1C
Agent: [K+]
Agent: [OH-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 130 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
In a 250 milliliter round-bottomed flask equipped with mechanical stirrer and fitted with a Dean-Stark trap under a reflux condenser were placed 8.46 grams (0.05 mole) of 4-aminobiphenyl, 25.53 grams (0.11 mole) of 4-iodo-ortho-xylene, 0.25 gram (0.0025 mole) of cuprous chloride, 0.45 gram (0.0025 mole) of 1,10-phenanthroline, 22.4 grams (0.4 mole) of flake potassium hydroxide and 30 milliliters of toluene solvent. The reaction was heated quickly to a reflux temperature of 130° C. and maintained at this temperature for 4 hours, after which time chromatographic analysis revealed the reaction to be complete. The reaction mixture was allowed to attain room temperature, about 25° C., and was partitioned between 200 milliliters of toluene and 150 milliliters of deionized water. The resulting organic layer was separated and water was removed by azeotropic distillation of water under a Dean-Stark trap. The product was decolorized by slurry treating the toluene solution with 36 grams of Filtrol-24™, an acid-washed clay, and 24 grams of Alcoa CG-20 alumina. After 3 hours stirring at reflux, the solution was cooled to room temperature and filtered. The product of N,N-bis(3,4-dimethylphenyl)-4-biphenylamine was recovered from the filtrate by evaporation of the solvent. Recrystallization from 40 milliliters of a one to one mixture of ethylacetate-isopropanol provided 13.2 grams (70 percent) of the above product. Chromatographic analysis by high performance liquid chromatography illustrated an excellent product purity of 99.8 percent and a melting temperature, which was determined by differential scanning calorimetry to be 113.21° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.[CH3:18][NH2:19]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:19][CH3:18])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
To a mixture of 5-bromo-2-fluorobenzoic acid (200 mg, 0.91 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.16 mL, 1.8 mmol), followed by 1 drop of N,N-dimethylformamide. The reaction was stirred at room temperature for 1.5 hours. The reaction was concentrated and the resulting residue was dissolved in dichloromethane (3 mL) and cooled to 0° C. Methylamine (2.3 mL, 5 mmol, 2 M in tetrahydrofuran) was added and the reaction was allowed to stir at 0° C. for 30 minutes. The reaction was quenched with water and the mixture was concentrated. The residue was diluted with water and the resulting solids were filtered, rinsed with water, and dried under vacuum to give the title compound (196.6 mg, 93%) as a white solid. +ESI (M+H+1) 234.1; 1H NMR (400 MHz, CDCl3, δ); 8.22 (dd, J=6.83, 2.73 Hz, 1H), 7.55 (ddd, J=8.68, 4.49, 2.63 Hz, 1H), 7.00 (dd, J=11.32, 8.58 Hz, 1H), 6.67 (br. s., 1H), 3.02 (dd, J=4.88, 1.17 Hz, 3H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.C(O)CCCCCCCCC[OH:28].C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:28])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: OCCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 4.85 g quantity of 9-fluorenone-4-carbonyl chloride (0.02 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, and then 1.74 g of 1,10-decanediol (0.01 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 2 g of triethylamine (0.02 mole, obtained from Aldrich). The solution was refluxed for 6 hours and filtered hot to remove triethylamine hydrochloride salt by-product, and the filtrate was evaporated to dryness. A liquid product was obtained, which solidified upon standing at room temperature for a couple of hours. The crude product was recrystallized from ethyl acetate with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a second dimeric fluorenone derivative, which was a yellow solid (2.5 g, 43% yield). The product had a melting point of 101–102° C. A 1H-NMR spectrum (300 MHz) in CDCl3 yielded chemical shifts (ppm) as follows: 1.15–1.61 (m, 12H); 1.71–1.92 (q, 4H); 4.34–4.47 (t, 4H); 7.32–7.37 (m, 4H); 7.50 (td, 2H); 7.70 (d, 2H); 7.82 (dd, 2H); 7.93 (dd, 2H); 8.28 (d, 2H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:8])[CH3:7].CN([CH:22]=[O:23])C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[S:15][C:16]([CH:22]=[O:23])=[CH:17][CH:18]=1)(=[O:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(=O)OCCCSc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)OCCCSc1ccc(C=O)s1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
POCl3 (3.4 mL, 0.036 mol) was added dropwise to a solution of 61 (4.9 g, 0.023 mol) and dry DMF (3.5 mL, 0.045 mol) in 1,2-dichloroethane (100 mL) at 0° C. The resultant mixture was refluxed for 2 hours, poured into ice water and neutralized by addition of 6 M sodium carbonate. The reaction mixture was extracted with methylene chloride (3×100 mL). The combined extracts were washed with saturated brine, dried (MgSO4). After filtration, methylene chloride was removed using a rotary evaporator. The residue was purified by column chromatography over silica gel, eluting with 10% ethyl acetate in methylene chloride. The product was obtained as orange liquid (4.5 g, 82%). 1H NMR δ: 2 (m, 2 H, CH2—CH2—OCOCH3), 2.03 (s, 3 H, CH3), 3.04 (t, 2 H, J=7.2 Hz, S—CH2), 4.15 (t, 2 H, J=6.2 Hz, CH2—OCOCH3), 7.04 (d, 1 H, J=3.9 Hz, aromatic H), 7.59 (d, 1 H, J=3.9 Hz, aromatic H), 9.75 (s, 1 H, CHO); λmax/nm (εmax/dm3 mol−1cm−1) 339 (14,200); HRMS (EI+) calc. for C10H12O3S2: 244.0231. found 244.0228. The product was used without further purification in preparation of 63.
Reaction SMILES: [Cl-:1].[Cl-].C([Al+2])CCCCCCC.[CH2:12]([Al:20](CCCCCCCC)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CCCCCC>CCCCCC.CCCCCCC>[Cl-:1].[CH2:21]([Al+:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCC[Al](CCCCCCCC)CCCCCCCC
Agent: CCCCCCCC[Al+2]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCCCCCC
Product: CCCCCCCC[Al+]CCCCCCCC

Procedure:
A 1 weight percent solution of dioctyl aluminum chloride in hexane/heptane was prepared by mixing octyl aluminum dichloride (2.11 g, 0.01 mol), a 25.3 weight percent solution of trioctyl aluminum (14.5 g, 0.01 mol) and hexane (561 g) together under an atmosphere of argon.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[C:9]([S:10](O)(=[O:12])=[O:11])=[C:8]([CH3:14])[N:7]=[C:4]2[S:5][CH:6]=1.C([N:18](CCC)CCC)CC>O(Cl)Cl>[CH3:1][C:2]1[N:3]2[C:9]([S:10]([NH2:18])(=[O:12])=[O:11])=[C:8]([CH3:14])[N:7]=[C:4]2[S:5][CH:6]=1
Reactant: CCCN(CCC)CCC
Reactant: Cc1nc2scc(C)n2c1S(=O)(=O)O
Agent: ClOCl
Product: Cc1nc2scc(C)n2c1S(N)(=O)=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of 2.8 g of 3,6-dimethylimidazo [2,1-b]thiazole-5-sulfonic acid in 3.4 ml of phophorus oxychloride, 1.8 g of tri-n-propylamine is added under cooling and stirred for 30 minutes at 60° C. The reaction solution after cooling is poured into ice water and extracted with dichloromethane. The dichloromethane layer is collected, dried and then distilled to remove dichloromethane. The residue is dissolved in 35 ml of acetonitrile, to which 3.8 ml of aqueous ammonia is added under cooling and stirred for 30 minutes at room temperature. The acetonitrile is distilled off under reduced pressure, and to the residue is added water. The precipitated crystalline solid is collected by filtration and washed with tetrachloromethane to give 1.5 g of the title compound as colorless crystals. mp. 177°-178° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:24])[C@@H:15]([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:24])[C@@H:15]([NH:23][C:40](=[O:42])[CH3:41])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H]1CO[C@@H](CCC2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Dissolve 5-(R)-(2-(S)-amino-1-(S)-hydroxy-3-phenylpropyl)-2-(S)-(2-cyclohexylethyl)-morpholine-4-carboxylic acid tert-butyl ester (140 mg, 0.31 mmol) in dry tetrahydrofuran (3 mL). Add triethylamine (0.05 mL, 0.35 mmol) followed by acetic anhydride (0.03 mL, 0.35 mmol) and stir at room temperature for 1 hour. Dilute with dichloromethane, wash with 0.1 N hydrochloric acid/saturated aqueous sodium chloride (30 mL), dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 40:60 to 60:40 ethyl acetate:dichloromethane) acetate/dichloromethane to give the title compound (83 mg, 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:25](B(O)O)[CH:26]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[C:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:26]=1
Reactant: OB(O)c1cc(F)ccc1OCC1CCOCC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cc(F)ccc3OCC3CCOCC3)n2)c1

Procedure:
Example 21 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [5-fluoro-2-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]boronic acid (FCH Group Company). The batch was purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:21][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c2ccccc12
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) in CCl4 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min. AIBN (0.3 g, 2.1 mmol) was added, and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, diluted with H2O and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7]3=[CH:11][S:12][C:13]([N:14]4C(=O)C5C(=CC=CC=5)C4=O)=[C:6]3[C:5](=[O:25])[C:4]=2[CH:3]=1.O.NN>C(O)C>[NH2:14][C:13]1[S:12][CH:11]=[C:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5](=[O:25])[C:6]=12
Reactant: Cc1ccc2c(c1)C(=O)c1c-2csc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)C(=O)c1c-2csc1N
Temperature: 25 °C

Procedure:
To a suspension of 2-(6-methyl-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione (0.45 mmol, Example 11, Part E) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether:ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]12[CH2:14][CH2:13][C:10]([CH2:15][OH:16])([CH2:11][CH2:12]1)[CH2:9][CH2:8]2)=[O:6]>C1COCC1.CO>[OH:16][CH2:15][C:10]12[CH2:13][CH2:14][C:7]([C:5]([OH:6])=[O:4])([CH2:8][CH2:9]1)[CH2:12][CH2:11]2
Reactant: COC(=O)C12CCC(CO)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C12CCC(CO)(CC1)CC2
Reaction time: 16 h

Procedure:
Lithium hydroxide (2 N, 250 ml) is added to a mixture of 4-hydroxymethyl-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (XVI, Example 91) in a mixture of THF (50 ml) and methanol (75 ml). The resulting reaction mixture is stirred at 20-25° for 16 hr, and then concentrated. The residue is diluted with water (30 ml) and washed with methylene chloride (100 ml) and ethyl acetate (100 ml). The aqueous layer is acidified with concentrated hydrochloric acid pH about 0 and extracted with ethyl acetate (3×250 ml). The ethyl acetate layers are combined and washed with saline (3×50 ml), dried over anhydrous sodium sulfate and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 3.09, 1.72 and 1.29.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([O:20][CH2:21][O:22][CH3:23])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[CH3:23][O:22][CH2:21][O:20][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[O:19][N:18]=1
Reactant: COCOc1cc(-c2ccc(OCc3ccccc3)cc2)on1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCOc1cc(-c2ccc(O)cc2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed solution of 5-(4-(benzyloxy)phenyl)-3-(methoxymethoxy)isoxazole (1.44 g) in methanol (15 ml) and tetrahydrofuran (15 ml), 200 mg of 10% palladium-carbon catalyst was added, and the reaction solution was stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (10:90-50:50)) to afford the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 1.98 g (5 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 1.16 g (6.25 mmol) of tert-butyl 1-piperazinecarboxylate, and 1.29 g (10 mmol) of DIPEA in 100 mL of THF was stirred at room temperature for 1 hr, and the solution was concentrated under vacuum. The residue was diluted with water (100 mL) containing 1 mL of acetic acid. The resulting precipitate was collected, washed with water, and dried to give 2.71 g (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: mp (MeOH) 221-223° C.; 1H NMR (CDCl3) δ 7.88 (dd, J=8.4, 0.6 Hz, 1H), 7.47 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H); Anal. Calcd. for C25H32F2N8O4: C, 54.9; H, 5.9; N, 20.5. Found: C, 54.9; H, 5.9; N, 20.5%.
Reaction SMILES: [C:1]1([C:7]2([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]=[C:22]=[O:23]>C(OC(=O)C)C>[CH3:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[C:15]=1[NH:21][C:22]([NH:12][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:23]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: NC1(c2ccccc2)CCCC1
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1NC(=O)NC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-phenylcyclopentyl amine (1.0 gm, 0.006 mole) in 30 ml of ethylacetate, 2,6-dimethylphenyl isocyanate (0.91 g; 0.006 mole) is added and the reaction mixture is stirred at room temperature for 20 hours. Volatiles are removed under reduced pressure and the residue is crystallized from ethylacetate-hexane yielding 1.65 g of N-(2,6-dimethylphenyl-N'-(1-phenylcyclopentyl) urea having a melting point of 227°-229° C.