Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4]1/[CH:5]([O:12][CH3:13])[N:6]2[C@H:9]([O:10]/1)[CH2:8][C:7]2=[O:11].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(OCC)C.C(OCC)(=O)C>[CH3:13][O:12][CH:5]1[N:6]2[C@H:9]([O:10]/[C:4]/1=[CH:3]\[CH2:2][O:1][C:21](=[O:22])[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][C:7]2=[O:11]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC1/C(=C/CO)O[C@@H]2CC(=O)N12
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1/C(=C/COC(=O)Cc2ccccc2)O[C@@H]2CC(=O)N12
Reaction time: 15 h
Yield: 69.2 %

Procedure:
(Z)-(5R)-3-(2-Hydroxyethylidene)-2-methoxy-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (15 mg.) was dissolved in dry diethyl ether (2 ml.) and the solution was stirred and ice-cooled with exclusion of moisture while phenylacetyl chloride (30 mg.) followed by dry pyridine (15 mg.) were added. The mixture was kept at 4° with exclusion of moisture for 15 hours. The mixture was diluted with ethyl acetate (30 ml.) and was washed with 5% sodium chloride solution (10 ml.) and saturated sodium chloride solution (10 ml.). The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to yield a yellow gum. Chromatography of the gum on silica gel (10 g.) using ethyl acetate/petroleum ether (b.p. 60°-80°) gave the title compound as a colourless gum (17 mg.). [α]D22 =+45.6° (c=1.0, CHCl3). νmax (CHCl3): 1798 (β-lactam C=O), 1730 (ester C=O), 1710 (sh.) (olefinic C=C)cm-1. δ (CDCl3): 2.96 (d, J 16 Hz, 1H, C(6)H), 3.34 (dd, J 16, J' 2 Hz, 1H, C(6)H), 3.36 (s, 3H, OCH3), 3.56 (s, 2H, CH2Ar), 4.60-4.90 (complex, 3H, CH2O and olefinic H), 5.25 (s, 1H, C(2)H), 5.52 (d, J 2 Hz, 1H, C(5)H), 7.22 (s, 5H, Ar-H). m/e: 234 (2%), 229 (C13H11NO3, 13%), 168 (19), 118 (12), 99 (22), 91 (100).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH:10]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])=O>C(O)C>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=1[N:1]=[CH:10][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccccc1C=O
Reactant: Cc1ccc(O)c(N)c1
Solvent: CCO
Product: COC(=O)c1ccccc1C=Nc1cc(C)ccc1O
Yield: 76.5 %

Procedure:
A solution of 2-amino-p-cresol (7.4 g) and methyl 2-formylbenzoate (obtained as described in J. Chem. Soc. (C), 1969, 1818) (9.8 g) in ethanol (120 ml) was heated under reflux for 2 hours. The solvent was removed by evaporation and the residue recrystallised from hexane to give 2-hydroxy-5-methyl-N-(2-methoxycarbonylbenzylidene)aniline (B) (12.3 g), m.p. 82°-83° C; NMR: 2.35 (s, 3H), 4.0(s, 3H), 6.9(d, 1H), 7.0(d, 1H), 7.05(br s, 1H), 7.15(d, 1H), 7.5-7.7(m, 2H), 7.95(dd, 1H), 8.2(dd, 1H), 9.45(s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(OCC)C>[N:17]1[C:16]2[NH:20][CH:21]=[CH:22][C:15]=2[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: CCOCC
Product: NC1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (57 mg, 0.18 mmol) was added HCl (1 ml, 4M solution in dioxane, 4 mmol). The solution was stirred at room temperature for 1 hour, and then diethyl ether was added (4 ml). The ethereal layer was discarded and the solid triturated with a further portion of ether (4 ml) and dried [product mass 27 mg]. A portion of the product was dissolved in methanol, absorbed onto an acidic resin SCX-2 cartridge, and the free base was eluted with 1M ammonia in methanol. LC/MS (LCT) Rt 0.81 [M+H]+ 218
Reaction SMILES: [C:1]1([C@H:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26]Br)[CH3:23].[OH-].[Na+]>CN(C)C=O.C(Cl)Cl>[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[CH2:26][NH:15][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:23]
Reactant: N[C@H](Cc1ccccc1)c1ccccc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(CN[C@H](Cc1ccccc1)c1ccccc1)OCC
Temperature: 100 °C
Yield: 84.9 %

Procedure:
The general procedure of Suzuki, T., et al., Chem. Pharm. Bull 34:1988 (1986), was adapted for the following alkylation. To a stirred mixture at 90° C. of 249.5 mg (1.3 mmoles) of (-)-1(R),2-diphenylethylamine and 193.6 mg (1.4 mmoles) of anhydrous potassium carbonate (Baker, used as received) in 2.5 ml of N,N-dimethylformamide (Baker, used as received) was added dropwise, over two hours, a solution of 284.1 mg (1.4 mmoles) of bromoacetaldehyde diethylacetal (Aldrich, distilled, bp 83° C./40 mm). The resulting mixture was heated (95-105° C.) with stirring. After 16 hours the reaction mixture was cooled to 10° C., 50 mL of 1N NaOH was added followed by 25 mL of CH2Cl2. The layers were separated and the aqueous layer was extracted with 2×15 mL of CH2Cl2. The combined organic layers were washed with 10 mL of 1N NaOH, dried (K2CO3) and the solvent evaporated at reduced pressure to give 346.1 mg of brown oil. The oil was distilled (180-190° C., 0.05 mm/Hg) using a Kugelrohr apparatus to give 315.5 mg of light yellow oil. The yellow oil (304.2 mg) was chromatographed (10 g silica gel) using 25 mL Et2O followed by 40 mL 3:1 Et2O/THF then 40 mL 2:1 Et2O/THF as eluent. The fractions containing the less polar material Rf 0.56) were combined and the solvent removed at reduced pressure yielding 283.3 mg of N-(1(R),2-dipbenylethyl)aminoacctaldehyde diethyl acetal as a clear, light yellow liquid (71% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH3:13].[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[H-].[Na+]>CN(C)C=O.O>[CH3:13][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][O:14][CH2:15][C:16]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(Bromomethyl)-1-methoxy-4-nitrobenzene (100.0 mg, 0.34 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (93.0 mg, 0.38 mmol) were combined in dimethylformamide (4 mL) and cooled to 0° C. The reaction was treated with sodium hydride (9.0 mg, 0.38 mmol), stirred at 0° C. for 1 hr and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 110 mg (71%). 1H-NMR (CDCl3, 500 MHz) δ 8.11 (dd, J=6.1, 3.1 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.34 (m, 4H), 7.21-7.24 (m, 1H), 6.80 (d, J=8.9 Hz, 1H), 4.37 (s, 2H), 3.85 (s, 3H), 3.74-3.75 (m, 2H), 3.48 (s, 2H), 3.02-3.07 (m, 2H), 2.21-2.24 (m, 2H), 1.87-1.93 (m, 2H), 1.43 (s, 9H). Mass spec.: 479.16 (MNa)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-nitrophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.30 (d, J=7.4, 1H), 8.27-8.21 (m, 2H), 8.04 (d, J=7.8, 1H), 8.02-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.67 (d, J=8.6, 2H), 3.84-3.81 (m, 4H), 3.70 (s, 2H), 3.11-3.07 (m, 4H); MS (ESI−) M/Z 408 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[C:25]([NH2:39])=[CH:26][C:27]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29][C:28]=2[CH:38]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:39][C:25]2[C:24]([O:23][CH3:22])=[CH:38][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][O:36][CH3:37])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CNC(=O)c1cc(OC)ccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(OC)ccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-methoxy-N-methyl-benzamide of Example 607 was reacted with 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-methoxy-N-methyl-benzamide as a lyophylate (8%); 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H, exchangeable), 9.75 (bs, 1H, exchangeable), 8.74 (bs, 1H, exchangeable), 8.42 (d, J=9.35 Hz, 1H), 8.15 (s, 2H, 1 exchangeable), 7.68 (s, 1H), 7.31 (s, 1H), 7.00 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.70 (m, 2H), 3.6 (bs, water+H), 3.40 (m, 2H), 3.34 (s, 3H), 3.3-2.95 (m, 4H), 2.80 (d, J=4.04 Hz, 3H); MS (m/e) 541.37 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([I:9])[C:4]=1[CH2:10]Br.[C:12]1([C:18]([NH2:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[I:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]2[C:4]=1[CH2:10][N:31]([C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:2]2
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1cccc(I)c1CBr
Product: Ic1cccc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2 (b) from 1,2-Bis-bromomethyl-3-iodo-benzene and triphenylmethylamine. White solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH3:13])=[C:10]([CH3:14])[NH:9][C:8]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br>C(O)=O>[C:1]1([C:7]2[C:11]([C:12]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:13]=3)=[C:10]([CH3:14])[NH:9][C:8]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]c(C)c(CC)c1-c1ccccc1
Agent: Br
Solvent: O=CO
Product: CCOC(=O)c1[nH]c(C)c(-c2ccccc2)c1-c1ccccc1
Temperature: 100 °C

Procedure:
Pyrromethene Hydrobromides and BF2Complexes. Crude pyrromethene hydrobromides 6 were obtained from a α-pyrrole carboxylate esters 4 (Kleinspehn, 1955) and converted without purification to P-BF2 dyes 7. A mixture of ethyl 3-phenyl-4-ethyl-5-methylpyrrole-2-carboxylate 40 (2.57 g, 10 mmol), hydrobromic acid (3 ml, 48%) and formic acid (3.5 g) was heated at 100° C. for 4 h. The reaction mixture was cooled to 0° C. to bring about the separation of crude 3,3'-diphenyl-4,4'-diethyl-5,5'-dimethylpyrromethene hydrobromide 6u 1.3 g(55%) mp 235° C. (dec); ethyl 3,4-diphenyl-5-methyl-pyrrole-2-carboxylate 4p gave crude 3,4,3',4'-tetraphenyl-5,5-dimethylpyrromethene hydrobromide 6v (75%) mp 280° C. (dec) (lit. mp 280° C. (dec)); and ethyl 3-phenyl-4-acetyl-5-methylpyrrole-2-carboxylate 4q gave crude 3,3'-diphenyl-4,4'-diacetyl-5,5'-dimethylpyrromethene hydrobromide 14 (50%) mp 230° C. (dec). In similar conversions 3,5-dimethyl-4-tert-butylpyrrole-2-carboxylate 4g gave crude 3,5,3',5'-tetramethyl-2,6-di-tert-butylpyrromethene hydrobromide 6x and ethyl 3,4-diethyl-5-methylpyrrole-2-carboxylate 4k gave crude 3,4,3',4'-tetraethyl-5,5'-dimethylpyrromethene hydrobromide 6y.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.C1(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[O:23]1[C:16]2([CH2:17][CH2:18][C:19]([O:22][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[CH:20][CH2:21]2)[O:15][CH2:14][CH2:13]1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (7.6 mL, 54.3 mmol) in 200 mL THF cooled to −78° C. was added n-butyllithium (21.8 mL 2.5 M in hexane, 54.3 mmol) under argon.The solution was stirred for 10 minutes, then a solution of 1,4-cyclohexanedione monoethylene ketal (8.5 g, 54.3 mmol) in 75 mL THF was added slowly. The solution was stirred for 10 min, then a solution of N-phenyltrifluoromethane sulfonamide (19.5 g, 54.3 mmol) in 150 mL THF was added slowly. The reaction solution was warmed to r.t., poured onto saturated sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was passed through silica (3% methanol, dichloromethane) to give the product as an oil.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1>>[CH3:21][C:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:23]4[C:32]5[C:27](=[CH:28][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc(N2CCN(Cc3ccc(N)cc3)CC2)cc1
Product: Cc1ccc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(p-tolyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(p-methylphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:8]=1)C.C1COCC1.[OH-].[Na+]>CCO>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[C:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[C:5]([CH3:33])[C:4]([OH:34])=[O:3])=[CH:12][CH:11]=1)=[C:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([CH3:26])=[CH:17]2
Reactant: CCOC(=O)C(C)=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(C=C(C)C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Yield: 87.9 %

Procedure:
As described above, 3-[4-(6-Methoxy-3-methyl-2-phenyl-naphthalen-1-yloxy)-phenyl]-2-methylacrylic acid ethyl ester (219) (0.189 g, 0.418 mmol), THF (3 mL), EtOH (3 mL) and 1 N NaOH (4 mL) afforded 0.156 g (88%) of title compound (220) as a solid. 1H NMR (400 MHz, d-CDCl3): δ 2.07 (s, 3H), 2.24 (s, 3H), 3.93 (s, 3H), 6.61 (d, J=8.8 Hz, 2H), 7.04 (dd, J1=2.5 Hz, J2=9.2 Hz, 1H), 7.12-7.14 (m, 3H), 7.17-7.21 (m, 2H), 7.23-7.27 (m, 3H), 7.56 (s, 1H), 7.64 (s, 1H), 7.74 (d, J=9.1 Hz, 1H).
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27]C)=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.C(O)(=O)C>O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH:17]3[C:26]4[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)CCCC2C1CCN(CCc2ccc(F)cc2)CC1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CCCC2C1CCN(CCc2ccc(F)cc2)CC1
Yield: 76.4 %

Procedure:
47% hydrobromic acid (45 ml) was added to 1-[2-(4-fluorophenyl)ethyl]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)piperidine (2.718 g, 7.57 mmol) and the resultant mixture was heated under reflux for 1 hr. After adding glacial acetic acid (20 ml), the resultant mixture was heated under reflux for additional 1.5 hr. Then the mixture was allowed to cool followed by addition of water thereto. The resulting precipitate was collected by filtration, chloroform and a saturated aqueous solution of sodium bicarbonate were added thereto and the layers were separated. The resulting solution was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (2.043 g) as a brown amorphous substance (yield: 76.4%).
Reaction SMILES: [NH2-].[Na+].[C:3](#[N:5])[CH3:4].[CH:6]1([C:12](OC)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl>O1CCCC1>[CH:6]1([C:12](=[O:13])[CH2:4][C:3]#[N:5])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)C1CCCCC1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of sodium amide (1.87 g) in tetrahydrofuran (10 ml) was added acetonitrile (2.72 ml) dropwise at −50-−40° C. and then thereto was added cyclohexane carboxylic acid, methyl ester (2.86 ml) and the mixture was stirred for 1 hour at −20° C. The reaction mixture was poured into cold hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (0.91 g) having the following physical data.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:10](=[O:12])[C:9]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:6]=2[S:5][C:4]=1[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C.[CH3:45][NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OC(C)C)(C)C.CN(C)C=O>[CH2:47]([N:46]([CH2:2][C:3]1[C:11]2[C:10](=[O:12])[C:9]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:6]=2[S:5][C:4]=1[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)[CH3:45])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CN(C)Cc3ccccc3)c2c1=O
Temperature: 35 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-nitrophenyl)-4-oxothieno[2,3-b]pyridine (32 g), N,N-dimethylformamide (64 ml) and N-ethyldiisopropylamine (8.84 g) were mixed and treated dropwise with N-methylbenzylamine (8.29 g) with cooling on ice, and the reaction mixture was stirred at 30 to 40° C. for 5 hours. The reaction mixture was poured into a mixture of a solution of potassium carbonate (9.5 g) in water (320 ml) and diisopropylether (320 ml) and the reaction mixture was stirred at room temperature for 2 hours and then with cooling on ice for 1 hour, and the crystal precipitated was recovered by a filtration, washed with water (600 ml) and diusopropylether (160 ml), dried in vacuo at 50° C. for 4 hours to obtain the title compound (33.58 g, 97.9%).
Reaction SMILES: [N:1]([CH:4]1[CH:7]([CH:8]=[O:9])[N:6]([CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:21])=[N+:2]=[N-:3].[BH4-].[Na+].Cl.[Cl-].[Na+]>C(O)C.O>[N:1]([CH:4]1[CH:7]([CH2:8][OH:9])[N:6]([CH:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:21])=[N+:2]=[N-:3]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COC(=O)C(c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1CO
Temperature: -5 °C
Yield: 41 %

Procedure:
A mixture of methyl 2-(3-azido-4-formyl-2-oxo-1-azetidinyl)-2- phenylacetate (2.30 g.), sodium borohydride (310 mg), ethanol (40 ml.) and water (5 ml.) was stirred at -10 to 0° C. for an hour. The reaction mixture was adjusted to pH 4 to 5 with 10% hydrochloric acid at the same temperature, whereafter the ethanol was removed by distillation from the solution to give an aqueous residue, to which sodium chloride was added. The resultant solution was extracted twice with chloroform and the extract was washed with an aqueous sodium chloride. After drying the solution over magnesium sulfate, the solution was evaporated to dryness under reduced pressure to give a residue (2.02 g.), which was subjected to column chromatography on alumina (20 g.). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation inder reduced pressure to give methyl 2-(3-azido-4-hydroxymethyl-2-oxo-1-azetidinyl)-2-phenylacetate(0.95 g.).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][CH:9]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)=[O:7]>CO.[C].[Pd]>[F:47][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=1)=[O:7]
Reactant: COCCOCOc1cc(CC2CN(C(=O)OCc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: [Pd]
Solvent: CO
Product: COCCOCOc1cc(CC2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Yield: 69.6 %

Procedure:
A solution of 1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (1.6 g) in methanol (20 ml) was hydrogenated over 10% palladium-carbon (50% wet, 0.2 g) at room temperature under atmospheric pressure for 4 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of dichloromethane and methanol (40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (0.89 g) as an oil.