Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:16][CH2:1][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])(=[O:27])=[O:26]
Reactant: C=CCCCCCCCCC=CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCCCCCC=CCCCOS(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,14-pentadecadien-1-ol (15.0 g) and triethylamine (14 ml.) in dry methylene chloride (320 ml.) at -8° C. is added methanesulfonylchloride (5.73 ml.), dropwise. The reaction mixture is stirred at -10° C. for 30 minutes and then diluted with methylene chloride, extracted with ice-water (250 ml.), followed by cold 10% HCl (200 ml.); cold saturated sodium bicarbonate (200 ml.) and cold brine (200 ml.). The organic phase is dried (MgSO4) and the solvent removed in vacuo to provide 4,14-pentadecadien-1-yl methanesulfonate as a clear oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[CH:31][CH:32]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCCCOC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Product: CCCCOC(=O)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1

Procedure:
2850 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 2190 mg of the product obtained in stage 1 above are added. 60 mg of the expected product are thus obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[CH2:30]([N:11]([C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:18][CH2:19]1)=[O:13])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccccc1N1CCN(C(=O)Nc2cc(C)c(C)nc2OC)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)N(Cc2ccccc2)c2cc(C)c(C)nc2OC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine(100 mg, 0.27 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.5 mg, 0.27 mmol) was added, followed by stirring at room temperature for 1 hr, and successively benzyl bromide(46.2 mg, 0.27 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>[I-].[Na+].CC(C)=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCCCCCCBr)cc1
Yield: 70.9 %

Procedure:
A mixture of 23.8 g (0.2 mole) of 4-cyanophenol, 55.3 g (0.4 mole) of milled potassium carbonate, 97.6 g of 1,6-dibromohexane, 0.5 g of sodium iodide and 750 ml of acetone was stirred at reflux for two days. The solid was filtered off and the filtrate concentrated in vacuo. The residue was partitioned between water and methylene dichloride, and the organic phase was dried and concentrated. The residue was distilled to give 40 g of 4-(6-bromohexyloxy)benzonitrile, b.p. 150°-160° C.(0.05 mm).
Reaction SMILES: C1(C[O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:16][O:17][C:11]=3[CH:10]=2)C=CC=CC=1>C1COCC1.CCO.[Pd]>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(OCc3ccccc3)ccc2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2cc(O)ccc2C1
Yield: 100.1 %

Procedure:
1,1-Dimethylethyl 8-[(phenylmethyl)oxy]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 29) (7.35 g, 20.68 mmol) in a mixture of THF (40 ml) and EtOH (40 ml) was hydrogenated with 10% palladium on carbon (0.735 g, 6.91 mmol) for 18 hours then filtered and evaporated to give the title compound (5.49 g) as a white solid. MS (ES) C14H19NO4 requires 265; found 166 [M+H−100]+.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH:17]=[O:18])[CH:12]=[CH:13][C:14]=1[CH3:15].C(Cl)(Cl)Cl.CCCCCC>C(O)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccc(C(=O)C=O)cc1C
Reactant: CNN=CC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(=O)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 12.8 %

Procedure:
2-Oxopropanal methylhydrazone (8.18 mmol, 819 mg) synthesized in Reference Synthetic Example 1 and (3,4-dimethylphenyl)(oxo)acetaldehyde (7.57 mmol, 1.227 g) synthesized in Reference Synthetic Example 5 were dissolved in acetic acid (30 mL) and stirred at 100° C. for about 5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and subjected to silica gel column chromatography (n-hexane/AcOEt=2/1, and 4/1) to give the crude product. The crude product was stirred with CHCl3/n-hexane for a while, and then recovered by filtration. The filtered solid was combined with a solid obtained by silica gel thin layer chromatography purification (n-hexane/AcOEt=4/1) of the filtrate to give the desired product as an orange solid (237.5 mg, yield 13%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CC(C)=O>[Cl:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1CC(=O)N(c2ccc(OCCCCl)cc2)C1
Yield: 50 %

Procedure:
A mixture of methyl 1-(4-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylate a51 (3.48 g, 14.8 mmol, 1 eq), potassium carbonate (4 g, 29.6 mmol, 2 eq) and 1-bromo-3-chloropropane a2 (1.6 ml, 16.2 mmol, 1.1 eq) in acetone (80 ml) is stirred at reflux overnight. The mixture is concentrated under vacuum then the residue is dissolved in ethyl acetate, and washed with a saturated solution of aqueous sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate and concentrated under vacuum to give 2.3 g of methyl 1-[4-(3-chloropropoxy)phenyl]-5-oxopyrrolidine-3-carboxylate a53 as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.[CH:14](OC)(OC)[O:15][CH3:16].C(OC(=O)C)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:15][CH3:16]
Reactant: O=C1Cc2cc(Br)ccc2C(=O)N1
Reactant: COC(OC)OC
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 125 °C
Yield: 76 %

Procedure:
6-Bromo-4H-isoquinoline-1,3-dione (120 mg, 0.500 mmol) and trimethyl orthoformate (106 mg, 1.00 mmol) are suspended in 1.25 ml of a 1:4 ratio mixture of acetic anhydride and dimethylformamide. Mixture is heated at 125° C. for 2 hours causing a yellow solid to form. Mixture is cooled to room temperature and filtered. Residue is washed with 20 ml of ethyl ether to afford the product as a yellow solid (109 mg, 0.380 mmol, 77%); 1H NMR (DMSO-d6) δ 4.25 (s, 3H), 7.60 (dd, J=1.9, 8.4 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 8.07 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 11.38 (s, 1H); mass spectrum [(+) ESI], m/z 282/284 (M+H)+.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][C:39]=1[N+:40]([O-])=O)[CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH3:36]>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:30][N:31]2[CH:35]=[CH:34][N:33]=[C:32]2[CH3:36])[CH:37]=[CH:38][C:39]=1[NH2:40]
Reactant: COc1cc(Cn2ccnc2C)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(Cn2ccnc2C)ccc1N

Procedure:
2-Methoxy-4-(2-methyl-imidazol-1-ylmethyl)-phenylamine was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with 1-(3-Methoxy-4-nitro-benzyl)-2-methyl-1H-imidazole.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].OC[C:11]1[C:16]([OH:17])=[C:15]([CH2:18][OH:19])[CH:14]=[C:13](C)[CH:12]=1.SCCC(O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)C1C(=CC=CC=1)O>C(O)(=O)C>[C:1]1([C:14]2[CH:13]=[CH:12][CH:11]=[C:16]([OH:17])[C:15]=2[CH:18]=[O:19])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Reactant: Cc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CCS
Solvent: O
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1O
Product: Cc1cccc(O)c1-c1cccc(O)c1C=O
Reaction time: 8 h

Procedure:
A mixture of 146.0 g m-cresol, 25.2 g 2,6-bis(hydroxymethyl)-p-cresol, 5.0 g 3-mercaptopropionic acid and 1.5 g p-toluene-sulfonic acid monohydrate in 200 ml glacial acetic acid were charged into a 1-L reaction vessel equipped with a paddle stirrer, reflux condenser and a nitrogen inlet tube. The mixture was heated to reflux and maintained at reflux to allow formation of the alternating copolymer. After 8 hours, 146.5 g salicylaldehyde were added over time to the reaction mixture to form substantially m-cresol-salicylaldehyde block segments. Reflux was continued for 8 hours. The reaction mixture was slowly poured into 7 L deionized water to precipitate the resin. Once the solvent had exchanged with water, the product was collected on a filter, slurried once in warm deionized water for about 30 minutes, again collected, rinsed with water and dried in a vacuum oven under about 125 mm Hg and at about 100 to 105° C. About 281 g of a block copolymer resin having a number average molecular weight, Mn, of 1472 Daltons and a Tg of 233° C. were obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7].Cl[C:10]([N:12]1[CH:21]2[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14][CH2:13]1)=[O:11].CCOC(C)=O>C1COCC1.CCN(CC)CC>[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH:7][C:10]([N:12]1[CH:21]2[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)CCN
Reactant: O=C(Cl)N1CCCC2CCCCC21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)N1CCCC2CCCCC21
Yield: 67.1 %

Procedure:
0.5 g (3.5 mmol) of the 3-aminopropionic acid methyl ester hydrochloride are dissolved in 5 mL of anhydrous THF and 0.9 mL of Et3N. Once dissolved, 650 mg of 1-chlorocarbonyloctahydroquinoline are slowly added and it is refluxed for 18 h. AcOEt is then added and the resulting solution is sequentially washed with water, 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 580 mg of intermediate IIIb.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:28]=[N:29][C:24]([N:23]([CH3:22])[CH3:41])=[CH:25][CH:26]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:39])[CH3:40])=[CH:34][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)nc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)nc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 78.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(6-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.54 g) as starting materials, 5-benzyloxy-N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) was obtained.
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C@H:13]3[CH2:14][CH2:15][C@:16]4([CH3:22])[C:20](=O)[CH2:19][CH2:18][C@H:17]4[C@@H:12]3[CH2:11][CH2:10][C@H:9]1[CH2:8][C@@H:7]([OH:23])[CH2:6][CH2:5]2.O.NN.Cl>C(O)CO>[CH3:22][C@:16]12[CH2:15][CH2:14][C@H:13]3[C@@H:12]([CH2:11][CH2:10][C@@H:9]4[C@:4]3([CH3:3])[CH2:5][CH2:6][C@H:7]([OH:23])[CH2:8]4)[C@@H:17]1[CH2:18][CH2:19][CH2:20]2
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: C[C@@]12CCC[C@H]1[C@@H]1CC[C@H]3C[C@@H](O)CC[C@]3(C)[C@H]1CC2
Temperature: 25 °C
Reaction time: 23 h
Yield: 81.9 %

Procedure:
In a flame-dried flask, potassium hydroxide (1.58 g, 28.2 mmol) was dissolved in ethylene glycol (10 mL) by heating. The solution was cooled at room temperature before adding trans-androsterone (2.00 g, 6.89 mmol) and hydrazine hydrate (0.98 mL, 20.2 mmol). The solution was heated to reflux at 208° C. After 23 h, the solution was cooled at room temperature before adding HCl (14.1 mL, 2M). It was extracted with CH2Cl2 (4×30 mL). The organic layer were collected, combined, dried over Na2SO4, and concentrated under reduced pressure. The resulting solid residue was recrystallized in MeOH to afford 5α-androstan-3β-ol (1.56 g, 82%). 1H NMR (300 MHz, CDCl3): d 3.58 (heptet, J=4.9 Hz, 1H), 1.76-1.82 (m, 1H), 1.70-1.75 (m, 2H), 1.65-1.69 (m, 2H), 1.61-1.63 (m, 1H), 1.57-1.60 (m, 1H), 1.52-1.57 (m, 2H), 1.47-1.50 (m, 1H), 1.40-1.45 (m, 1H), 1.33-1.39 (m, 1H), 1.29-1.30 (m, 1H), 1.22-1.28 (m, 4H), 1.04-1.17 (m, 4H), 0.9-1.02 (m, 1H), 0.85-0.93 (m, 2H), 0.80 (s, 3H), 0.68 (s, 3H) 0.60-0.65 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[B].[N+:4]([C:7]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])([O-:6])=[O:5].C(OCC)(=O)C>O1CCCC1.O>[N+:4]([C:7]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:14][CH:13]=[CH:12][C:8]=1[CH2:9][OH:10])([O-:6])=[O:5]
Reactant: O=C(O)c1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [B]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1c(CO)cccc1Oc1ccccc1Cl
Reaction time: 3 h
Yield: 97.6 %

Procedure:
Sodium borohydride (4.4 g) and boron trifluoridediethyl ether (23.7 ml) were added to a solution of 2-nitro-3-(2-chlorophenoxy)benzoic acid (11.3 g) in dried tetrahydrofuran (100 ml), and the mixture was stirred for 3 hrs. at room temperature. To the reaction mixture were added ethyl acetate (200 ml) and water (200 ml), and the mixture was filtered. The ethyl acetate layer was separated from the filtrate, washed with aqueous sodium bicarbonate and saline, dried and then evaporated in vacuo. The oily residue (15.1 g) was subjected to column chromatography on silica gel (150 g) and eluted with methylene chloride to give 2-nitro-3-(2-chlorophenoxy)benzyl alcohol (10.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH2:8]1)(=[O:21])[CH3:20]
Reactant: Cc1ccc2c(n1)CCNC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(C)ccc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
To a solution of 2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine [Shiozawa et al., Chem. Pharm. Bull., 32, 2522, (1984)] (2.73 g, 0.0184 mol) in CH2Cl2 (30 ml) and triethylamine (5.1 ml, 0.0368 mol) was added acetyl chloride (1.57 ml, 0.0221 mol) at 0° C. The reaction mixture was stirred for 24 h at room temperature, after which time the reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate, H2O, saturated brine, dried over MgSO4 and evaporated under reduced pressure to afford the subtitle compound (3.27 g, 93%). Rf 0.5 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 191 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>CN(C=O)C.CC(CC(C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([F:9])[C:7]=1[O:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 92 %

Procedure:
3-Chloro-4,5-difluorobenzotrifluoride (99 g) was dissolved in dry MBIK (100 cm3) and 25 drops of dry DMF and dry potassium carbonate (48 g) added. The mixture was stirred and brought to reflux when a solution of 4-methyl-3-nitrophenol (35 g) in dry MIBK (70 cm3) was added over 1 hour. When the addition was complete stirring and reflux were continued for 2 hours. The solvent was removed from the reaction mixture under vacuum and the residue triturated with water (500 cm3). The solid obtained was filtered off, washed with water and air dried. The crude solid was recrystallised from ethanol to give 4-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrotoluene (73.5 g) as an off white solid, m.p. 112.8°-115.4° C.
Reaction SMILES: O[Li].O.C([C@@H]1COC(=O)N1[C:17](=[O:35])[C@@H:18]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])C1C=CC=CC=1.C[O:37]C1C=C(OC)C=CC=1C=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:23]([O:22][C:21]([NH:20][CH2:19][C@H:18]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:17]([OH:35])=[O:37])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Agent: O=S([O-])[O-]
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
35% 11202 (0.240 mL, 2.91 mmol) was added to a solution of LiOH—H2O (0.0978 g, 2.33 mmol) in 2:1 THF:H2O (33 mL). The reaction mixture was stirred at room temperature for 35 minutes, and then cooled to 0° C. A solution containing a mixture of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol) in THF (7 mL) was added dropwise by addition funnel. The ice bath was allowed to slowly warm, and the reaction mixture was stirred overnight. The reaction mixture was then cooled to 0° C., and 1M Na2SO3 (7 mL) was added. The mixture was stirred for 5 minutes, and then warmed to room temperature and stirred an additional 20 minutes. The reaction mixture was then transferred to a separatory funnel and washed with ether (3×). The aqueous layer was acidified with KHSO4(s), and the mixture was extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M-BOC+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:30])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.Cl>O>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:30])[CH2:10][CH2:9]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2cc(C)ccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2[nH]c(=O)n(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)c2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 9.6 parts of 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one in 80 parts of ethanol are added 24 parts of a concentrated hydrochloric acid solution and 50 parts of water (exothermic reaction: temperature rises to 50° C.). Stirring is continued for 30 minutes at room temperature. The reaction mixture is evaporated and the residue is triturated in 2-propanone. The hydrochloride salt is filtered off and the free base is liberated in the conventional manner with ammonium hydroxide. Methylbenzene is added and the precipitated free base is filtered off. It is crystallized from a mixture of 2-propanol and a small amount of N,N-dimethylformamide, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-6-methyl-2H-benzimidazol-2-one; mp. 195.7° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[CH3:20])=[O:11])[CH2:3]1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:7]1[C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[CH3:20])=[O:11])[CH2:5][C@H:6]1[CH3:8])(=[O:33])=[O:32])(=[O:24])=[O:23]
Reactant: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N[C@@H](C)C1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2ccccc2S(C)(=O)=O)[C@@H](C)C1

Procedure:
The title compound was prepared from the product of Example 60 step (i) (0.503 mmol) and 2-methanesulphonylbenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 17 mg
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][CH2:27][CH2:28][NH2:29]>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([NH:29][CH2:28][CH2:27][OH:26])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Clc1nc(N2CCOCC2)c2ncnc(NCc3ccccc3)c2n1
Product: OCCNc1nc(N2CCOCC2)c2ncnc(NCc3ccccc3)c2n1

Procedure:
This compound was prepared analogous to Example 2 from 8-benzylamino-2-chloro-4-morpholino-pyrimido[5,4-d]pyrimidine (melting point: 139°-141° C.) and 2-hydroxyethylamine.