Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18])(=[O:11])[CH3:10].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](Cl)=[O:30]>C1COCC1>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](=[O:30])[CH2:10][C:9]([O:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH3:18])=[O:11]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC/C=C\CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC/C=C\CCOC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (133.0 mL of a 2.0 M solution, 0.266 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. cis 3-Hexenyl acetate (17.80 g, 0.125 mol) is dissolved in THF (10 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 2-naphthoyl chloride (22.51 g, 0.118 mol) dissolved in THF (30 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (70 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[C:12]([C:27]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][CH:18]=2)=[CH:15][N:16]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:26][CH2:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[N:16][C:11]([NH2:10])=[C:12]([C:27](=[O:28])[NH:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[N:13]=2)=[CH:18][CH:19]=1)(=[O:39])=[O:38]
Reactant: Nc1ncc(-c2ccc(CCCO)cc2)nc1C(=O)Nc1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Dichloromethane (200 mL) and diisopropylethylamine (2 g, 17.16 mmol) were added to the product of step (vii) (4 g, 11.46 mmol). The resulting solution was cooled to 0° C. and MsCl (2 g, 17.16 mmol) added dropwise. When the addition was completed, the resulting solution was stirred at 0° C. for 10 minutes and at room temperature for 2 hours. The reaction mixture was extracted with dichloromethane and washed with water (×3). The combined organic extract was dried over MgSO4, filtered and concentrated in vacuo, which afforded the subtitle compound (viii) as a yellow brown solid (4.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[N:8][CH:7]=[CH:6]2.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[N:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(O)nccc2c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(OCCN3CCCCC3)nccc2c1
Yield: 92 %

Procedure:
To a solution of 6-methoxyisoquinoline-1-ol (1.00 g, 5.71 mmol) in acetone, K2CO3 (4.73 g, 34.26 mmol) and N-chloroethyl-piperidine hydrochloride salt (1.37 g, 7.42 mmol) were added. The solution was heated to reflux for 6 hours. The solution was evaporated to dryness. The residue was hydrolyzed by adding water, then extracted with ethyl acetate. The organic layers were separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica-gel; methylene chloride/methanol=9/1 v/v) to give a yellow oil product, 1.50 g, 92.0% yield. MS: 287.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz) δ 8.11 (d, 1H, J=9.0 Hz), 7.39 (d, 1H, J=7.5 Hz), 7.10-7.13 (m, 2H), 6.51 (d, 1H, J=7.5 Hz), 4.02 (t, 2H, J=6.6 Hz), 3.86 (s, 3H), 2.55 (t, 2H, J=6.5 Hz), 2.41 (br, 4H), 1.52-1.44 (m, 4H), 1.37-114 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S@:27]([CH3:29])=[O:28])[CH2:17][CH2:16]2)[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:30]([C:33]1[C:42]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=2[C:36]([C:43](Cl)=[O:44])=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S@:27]([CH3:29])=[O:28])[CH2:19][CH2:20]2)[CH2:10][N:11]([CH3:12])[C:43]([C:36]2[C:37]3[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=3[C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)=[O:44])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c2c1CCCC2
Reactant: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: CN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccc([N+](=O)[O-])c2c1CCCC2

Procedure:
Using a procedure analogous to that described in Example 3, N-[(S)-2-(3,4-dichlorophenyl)4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride [prepared from 4-nitro-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (T. Nakayama, T. Okutome, R. Matsui, M. Kurumi, Y. Sakurai, T. Aoyama, S. Fujii, Chem. Pharm. Bull. 32(10) 3968 (1984))] and the product was converted to the citrate salt MS: m/z 656 (M+H). Analysis for C34H39Cl2N3O4S.C6H8O7.1.0H2O: calculated: C, 54.42; H, 5.70; N, 4.85. found: C, 55.03; H, 5.55; N, 4.94.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:12]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl>C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1([NH2:12])[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N=C(c2ccccc2)c2ccccc2)CCOCC1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C1(N)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
To a solution of 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid ethyl ester (16.0 grams, 0.047 mole) in diethyl ether (120 mL) was added 1M aqueous hydrochloric acid solution (100 mL). The mixture was stirred vigorously at room temperature for 16 hours. The layers were separated and the aqueous layer washed with diethyl ether. The aqueous layer was brought to pH 10 with dilute aqueous ammonium hydroxide solution and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated to give 4-aminotetrahydropyran-4-carboxylic acid ethyl ester (7.128 g, 71.7%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH:17]=1)[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11].[O-][Cl:30].[Na+]>>[Cl:30][N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[C:10](=[O:11])[C:9]1[CH:17]=[C:5]([O:4][C:3]2[CH:21]=[CH:22][C:23]([C:25]([F:27])([F:26])[F:28])=[CH:24][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:18]([O-:20])=[O:19]
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: [O-]Cl
Agent: [Na+]
Product: CS(=O)(=O)N(Cl)C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitro-N-methanesulfonyl benzamide, m.p. 215°-218° C. was chlorinated with "Clorox" (aqueous NaClO), following procedure I, to yield a product, m.p. 160°-161° (crystallizes from chloroform/ether).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23]C(=O)C)[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([S:7]([N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Oc1cccc2c1c1ccccc1n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1c2ccccc2c2c(O)cccc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
A solution of 0.96 g of acetic acid 9-benzenesulfonyl-9H-carbazol-4-yl ester (2.62 mmol) in 15 ml of methanol was treated with 3.5 ml of 4 M sodium hydroxide (14 mmol) and stirred at 50° C. for 1.5 h. After cooling to room temperature, methanol was removed from the reaction mixture by rotary evaporation and the residue was partitioned between t-butyl methyl ether and 2N aq. HCl. After drying (Na2SO4) the organic phase was evaporated to dryness to afford 0.84 g (99%) of 9-benzenesulfonyl-9H-carbazol-4-ol as an orange brown oil.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: COc1ccc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)cc1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (4-methoxybenzyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10-1.13 (m, 1H), 1.24-1.35 (m, 3H), 1.62 (d, J=13.16 Hz, 1H), 1.72 (d, J=9.94 Hz, 4H), 1.87 (s, 3H), 2.22 (s, 3H), 3.72 (s, 3H), 3.94 (s, 1H), 4.46 (d, J=5.37 Hz, 2H), 6.88 (s, 2H), 7.26 (s, 2H), 7.57 (s, 1H), 8.01 (s, 1H), 12.66 (bs, 1H); MS (ESI) m/z 341.7 (M+1)+.
Reaction SMILES: Cl.[CH:2]([NH:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:10][C:9]=1[NH:19]C(=O)OC(C)(C)C)([CH3:4])[CH3:3]>O1CCOCC1.CO>[NH2:19][C:9]1[CH:10]=[CH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:13][C:8]=1[NH:7][C:6]([NH:5][CH:2]([CH3:4])[CH3:3])=[O:27]
Reactant: CC(C)NC(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)NC(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A 4M solution of HCl in dioxane (2 mL) was added to a stirred solution of tert-butyl (2-(3-isopropylureido)-4-(thiophen-2-yl)phenyl)carbamate (0.15 g, 0.40 mmol, 1 equiv.) in methanol (4 mL) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was then concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added. The obtained solid was filtered, washed with water and dried to yield 1-(2-amino-5-(thiophen-2-yl)phenyl)-3-isopropylurea (0.10 g, 91% yield). ESI+ MS: m/z 276 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 7.67 (d, J=2.0 Hz, 1H), 7.47 (s, 7.33 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.09 (dd, J=1.5, 8.0 Hz, 1H), 7.05-7.01 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.08 (d, J=8.0 Hz, 1H), 4.87 (s, 2H), 3.76 (sept, J=7.0 Hz, 1H), 1.10 (d, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:25]([O:32][C:33](=[O:41])[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33](=[O:41])[CH2:34][N:35]1[CH2:36][CH2:37][N:38]([C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[CH:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:39][CH2:40]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C(=O)O)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Reactant: O=C(CN1CCNCC1)OCc1ccccc1
Product: CC(C)(C(=O)N1CCN(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Yield: 71.9 %

Procedure:
The same procedure as in Example 2-(6-2) was performed with N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanine (0.4 g, 1.24 mmol) and piperazineacetic acid benzyl ester (0.87 g, 3.72 mmol) to yield an oil of N-4-cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperazineacetic acid benzyl ester (0.48 g, 70.0%).
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[CH:21]([NH:22]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20](=[O:42])[N:11]3[C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:22][CH:21]1[C:20](=[O:42])[N:11]2[C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:44][CH:43]=3)[CH2:8][S:9][C@H:10]12
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(N)C(=O)N12
Temperature: 25 °C
Yield: 64.7 %

Procedure:
t-Butyl 3-p-fluorobenzyl-7-triphenylmethylamino-3-cephem-4-carboxylate (IX) (72 mg) was dissolved in acetone and the solution cooled to 0°. p-Toluene sulphonic acid (25 mg) in acetone (0.5 ml) was added dropwise over a few minutes and the solution left to warm to room temperature with stirring. After 2.5 hours a solid had formed but t.l.c. still showed some unchanged (IX) to be present. The mixture was again cooled to 0° and a further quantity of p-toluene sulphonic acid (5 mg) in acetone added. After leaving at room temperature for a further 1.5 hours, the white solid was filtered off. This solid was suspended in ethyl acetate and treated with saturated sodium bicarbonate solution. The organic layer was washed with brine, dried and evaporated to give t-butyl 7-amino-3-p-fluorobenzyl-3-cephem-4-carboxylate (XI) (28 mg) shown to be pure by t.l.c. ##SPC18##
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5](=[O:18])[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]=[CH:8][C:9]=1Cl.C([OH:21])C>O>[Cl:3][C:4]1[C:5](=[O:18])[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:7]=[CH:8][C:9]=1[OH:21]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1c(Cl)c(O)cnn1-c1ccc(Cl)cc1

Procedure:
In 140 ml of water was dissolved 18.3 g (0.28 mol) of potassium hydroxide, and thereto were added 25.6 g (0.093 mol) of 4,5-dichloro-2-(4-chlorophenyl)-3(2H)-pyridazinone and 140 ml of ethanol. The reaction mixture was refluxed for 6 hours. After allowing to cool, ethanol was distilled off from the mixture under reduced pressure and then 300 of water was added to the mixture. Insoluble matter was removed by filtration and filtrate was acidified with hydrochloric acid. The solid thus precipitated was taken out by filtration, washed with water, and recrystallized from ethanol to give 11.1 g of the intended compound having melting point (hereinafter referred to as "m.p.") of 270°-271° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:19][OH:20])[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:26]([Si:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Cl)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:19][O:20][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(CO)(CCOCc2ccccc2)CO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCOCc2ccccc2)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95.1 %

Procedure:
459 mg (1.64 mmol equivalents) of 5-benzyloxyethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane was dissolved in 8 mL of dimethylformamide, 197 mg (3.20 mmol equivalents) of imidazole and 0.51 mL (1.92 mmol equivalents) of t-butyldiphenylchlorosilane were added thereto, and the mixture was stirred at room temperature (25° C.) for 22 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added thereto, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=20/1) to give 570 mg (1.56 mmol equivalents) of 5-benzyloxyethyl-2,2-dimethyl-5-(t-butyldiphenylsiloxymethyl)-1,3-dioxane.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[ClH:8].Cl.[NH2:10][C:11]1[CH:12]=[C:13]([C:19](=[O:40])[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH2:38][CH3:39])[CH2:24][CH2:23]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].C(N(CC)CC)C>O1CCCC1>[ClH:8].[CH2:38]([O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][C:19]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([NH:10][C:1](=[O:3])[CH3:2])[CH:12]=2)=[O:40])[CH2:23][CH2:24]1)[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(N)c2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OCCN1CCC(CCC(=O)c2ccc(OC)c(NC(C)=O)c2)CC1
Reaction time: 12 h

Procedure:
Acetic acid anhydride (0.132 ml) was added to a solution of 1-(3-amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy) ethyl]-4-piperidinyl}-1-propanone dihydrochloride (300 mg) obtained in Example 327 and triethylamine (0.195 ml) in tetrahydrofuran (10 ml) at room temperature, the mixture was stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure. Water (30 ml) and ethyl acetate (40 ml) were added to the residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give a free base compound of the title compound as a colorless oil (276 mg), The free base compound (270 mg) was treated with a hydrogen chloride-ethanol solution to give the title compound (277 mg) as colorless crystals having a melting point of 127 to 129° C.
Reaction SMILES: [CH3:1][NH2:2].[I:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7]>O1CCCC1>[CH3:1][NH:2][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[I:3]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1I

Procedure:
A total of 40 ml of a 40% by weight aqueous solution of methylamine was reacted with a solution of 16 g of o-iodobenzoyl chloride in 25 ml of tetrahydrofuran for 10 minutes. The excess solvent was evaporated in a hot water bath at 65°. The mixture was allowed to cool and 40 ml of water was added to precipitate the crude product which was recovered and washed with 1 N NaOH, 1 N HCl, and then water until the washings were neutral. The crude product was dried under vacuum and purified by recrystallization from toluene to yield 12.6 g of N-methyl-o-iodobenzamide as white crystals, m.p. 153°-154°, Rf 0.75 on thin layer chromatography using silica gel 60 and methanolchloroform-acetic acid (15:85:1) mixture.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH:17]1[CH:18]=[CH:19][C:20]([OH:25])=[C:21]([CH:23]=O)[CH:22]=1>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:23][C:21]3[CH:22]=[CH:17][CH:18]=[CH:19][C:20]=3[OH:25])[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: O=Cc1ccccc1O
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccccc1O
Temperature: 25 °C

Procedure:
218 g (1 mole) of 1-p-carboxyphenyl-3-methyl-2-pyrazolin-5-one were suspended in 1000 ml of acetic acid. The suspension was heated to boiling temperature and 112 g (1 mole) of salicyladehyde were added. In the resulting solution the dye started crystallizing very quickly. After 2 h of refluxing the reaction mixture was cooled to room temperature. The dye was filtered with suction and rinsed with acetone.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:21]([N:23]([C:30]1[CH:31]=[N:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=1)[CH2:24][C:25]1[CH:26]=[N:27][NH:28][CH:29]=1)=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:21]([N:23]([C:30]1[CH:31]=[N:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=1)[CH2:24][C:25]1[CH:29]=[N:28][N:27]([CH2:40][C:41]2[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=2)[CH:26]=1)=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)ccc(F)c32)cn1
Reactant: Cc1ccnc(CCl)c1
Agent: Cl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)ccc(F)c43)c3ccc(C(C)C)nc3)cn2)c1
Yield: 84.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.81 g) and 2-chloromethyl-4-methylpyridine (0.54 g) as starting materials, 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:15]2[N:14]=[N:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)(C)(C)C.[F-].[NH4+].[NH4+].[NH4+].[NH4+].[F-].[F-].[F-]>O1CCCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([OH:6])[C:15]=3[N:14]=[N:13]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2nnc3c(O[Si](C)(C)C(C)(C)C)cccc32)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc3c(O)cccc32)cc1

Procedure:
To a solution of EXAMPLE 342B (2.59 g) in tetrahydrofuran (40 mL) was added tetraammonium fluoride (1M in tetrahydrofuran, 21.03 mL). The solution was mixed at room temperature for two hours. The solvent was removed under vacuum, the residue was taken up in ethyl acetate, and the solution was vacuum filtered over a pad of silica gel. The filtrate was concentrated and purified by flash column chromatography on silica gel using 35% ethyl acetate in hexanes.