Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)[CH:8]=2)[CH2:3]1.FC(F)(F)C(O)=O.C[O:36][C:37](=O)[CH2:38][C:39](=O)[CH3:40]>C(O)(=O)C>[CH3:1][C:2]1([CH3:27])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:11]3[C:37](=[O:36])[CH2:38][C:39]([CH3:40])=[N:12]3)[CH:8]=2)[CH2:3]1
Reactant: CC1(C)Cc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2C1
Reactant: COC(=O)CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC1=NN(c2ccc3c(c2)CC(C)(C)C3)C(=O)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
Di-tert-butyl 1-(2,2-dimethyl-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 45c (3.3 g, 8.78 mmol) was dissolved in 12 mL of acetic acid followed by addition of 6 mL of trifluoroacetic acid and 3-oxo-butanoic acid methyl ester (1.5 mL, 13.8 mmol). Upon completion of the addition, the reaction mixture was stirred at 90° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the residue was diluted with 30 mL of water and 30 mL of ethyl acetate. After mixing well, the separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(2,2-dimethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 45d (464 mg, yield 22.1%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(NC(C)C)(C)C.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
To a solution of 4-fluoro-2-nitroaniline (1.56 g) and diisopropylamine (1.68 ml) in dichloromethane (20 ml) was added dropwise under ice-cooling phenyl chloroformate (1.51 g). After stirring the mixture at room temperature overnight, the reaction solution was washed with water, saturated saline, dried over anhydrous MgSO4 and the solvent was distilled off. Crystallization of the residue from diisopropyl ether afforded phenyl 4-fluoro-2-nitrophenylcarbamate (0.79 g, 29%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][CH2:7][CH:8]=[CH2:9])([O-])=O.[H][H]>CO>[CH2:7]([NH:6][C:5]1[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=1[NH2:1])[CH:8]=[CH2:9]
Reactant: [H][H]
Reactant: C=CCNc1ccccc1[N+](=O)[O-]
Solvent: CO
Product: C=CCNc1ccccc1N

Procedure:
35 g of 2-nitro-N-allylaniline in 400 ml of methanol are hydrogenated in the presence of 1.5 g of the catalyst described in Example 6, at 75° C and 100-120 bars of hydrogen, for 1.5 hours, to give N-allyl-o-phenylenediamine. The solution which has been freed from the catalyst by filtration is distilled.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CNCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Yield: 81.8 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 4-methoxybenzaldehyde (0.78 g) were reacted and treated in the same manner as in Example 121 to give 2.15 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(4-methoxybenzylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC1C=C[C:35]2[NH:34][CH:33]=[C:32]3C(=O)N(C4C=CC=CC=4)N=C3[C:30]=2[N:29]=1>>[C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[C:18]([N:29]5[CH2:30][CH2:35][NH:34][CH2:33][CH2:32]5)=[N:17][CH:16]=[CH:15][C:14]=4[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3c(N4CCNCC4)nccc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 4 for synthesis for 6a using 16 instead of 5a. 1H-NMR (DMSO-d6) δ (ppm): 3.2 (4H, brm), 3.48 (4H, brm), 7.13 (1H, m), 7.46 (2H, m), 7.78 (1H, d, J=5.2 Hz), 8.18 (2H, d, J=7.7 Hz), 8.30 (1H, d, J=5.2 Hz), 8.50 (1H, s). m/z 347.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O.CN(C=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To 4-bromo-1-methyl-2-nitro-benzene (500 mg), tris (dibenzylideneacetone) dipalladium (120 mg) and potassium phosphate (928 mg), morpholine (242 mg), S-Phos (95 mg) and deaerated DMF (5 ml) were added, followed by irradiation of ultrasonic wave for 5 minutes. This was stirred at 110° C. for 5 hours. After cooling to room temperature, water was added, followed by extraction with ethyl acetate, and the organic layer was washed with brine, and dried over magnesium sulfate. After the magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (hexane/ethyl acetate=4/1), to obtain the desired compound as an orange solid (478 mg, 93%).
Reaction SMILES: Br[CH2:2][C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[C:19]([OH:22])(=[O:21])[CH3:20]>C([O-])(=O)C.[Ag+].[Ag]Br>[C:19]([O:22][CH2:2][C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CBr)cc1
Agent: Br[Ag]
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2COC(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(Bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one (3.1 g) is dissolved in 80 ml of acetic acid by warming on a steam bath. The solution obtained is allowed to cool to about 25°-45° C. and 1.7 g of silver acetate is added. The mixture is stirred at 25° C. for 16 hours and the precipitate which forms (silver bromide) is removed by filtration. The filtrate is concentrated to about 10 ml and a solid crystallizes. This is separated by filtration and recrystallized from acetic acid to give 4-[(acetyloxy)methyl]-1,3-dihydro-5-(4-methoxybenzoyl)-2H-imidazol-2-one melting at about 155°-162° C. This compound has the following structural formula: ##STR7##
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:26](#[N:29])[CH:27]=[CH2:28]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:27](=[CH2:28])[C:26]#[N:29])=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(-c2cnc(Cl)c(C=O)c2)cc1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1cc(-c2ccc(OC)cc2)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.99 g.).
Reaction SMILES: C[O:2][P:3]([CH2:19][CH:20]([C:25](=[O:36])[NH:26][C@H:27]([C:32](=[O:35])[NH:33][CH3:34])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:5][N:6]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18])=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:23][CH:22]([CH3:24])[CH2:21][CH:20]([C:25](=[O:36])[NH:26][C@H:27]([C:32](=[O:35])[NH:33][CH3:34])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:19][P:3]([CH2:5][N:6]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]1=[O:18])(=[O:2])[OH:4]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)C=C(c2ccccc2)C1=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)C=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
0.1 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(2-phenylmaleimido)methyl]phosphinic acid methyl ester was dissolved in 1 ml of dichloromethane and 2 ml of trifluoroacetic acid were added. The mixture was stirred at room temperature for 2 hours and the solvent was then removed by evaporation. The residue was taken up in 30 ml of acetone/dichloromethane (1:1) and the solution was evaporated to give 95 mg of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl][(2-phenylmaleimido)methyl]phosphinic acid in the form of a tan colored foam.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:8]([N:15]1[C:24](=[O:25])[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:26])[CH:21]=2)[C:16]1=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[CH2:8]([N:15]1[C:24](=[O:25])[CH:23]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:26])[CH:21]=2)[C:16]1=[O:27])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C1Cc2cc(Cl)ccc2C(=O)N1Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)C1C(=O)N(Cc2ccccc2)C(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
Isopropylsulfonyl chloride (140 mg, 0.962mmol) was added to a solution of 250 mg (0.875 mmol) 2-benzyl-6-chloro-4H-isoquinoline-1,3-dione and 270 mg (1.75 mmol) DBU in 2.5 mL methylene chloride under Argon, which was cooled in ice-EtOH to -10° C. After 30 min, the reaction was allowed to warm to room temperature and was stirred overnight. The reaction was diluted with EtOAc, washed three times with 2N HCl dried (Na2 SO4) and concentrated. The residue was triturated with EtOH, petroleum ether was added and the resulting crystals were filtered. Recrystallization from MeOH-petroleum ether gave 186 mg of the title compound, mp 150°-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl-].[Li+].C([O-])([O-])=O.[Na+].[Na+].[CH2:20]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH:29]=[C:30](OS(C(F)(F)F)(=O)=O)[CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[CH2:20]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH:29]=[C:30]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=S(=O)(OC1=CC2CCC(C1)N2Cc1ccccc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C2=CC3CCC(C2)N3Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenyl boronic acid (0.50 g), lithium chloride (0.26 g), Pd(PPh3)4 (0.17 g), and finally 2 M aqueous Na2CO3 solution (3.2 mL) are added in turn to a flask charged with a stir bar, trifluoromethanesulfonic acid 8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester (1.0 g), water (5 mL), and 1,2-dimethoxyethane (25 mL) under argon atmosphere. The resulting mixture is stirred at reflux temperature for 5 h. After cooling to ambient temperature, brine is added and the mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0→1:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Fc1ccccc1Oc1cncc(Cl)n1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccccc3F)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method EE with 2-chloro-6-(2-fluorophenyloxy)-pyrazine (200 mg, 0.89 mmol) and 3,4,5-trimethoxyaniline (196 mg, 1.07 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (234 mg). Yield: 71%. 1H NMR (250 MHz, DMSO-d6) δ 3.42 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.69 (s, 2H, Harom2′+6′), 7.24-7.41 (m, 4H, Harom), 7.83 (s, 1H, HPz 5), 7.96 (s, 1H, HPz 3), 9.57 (s, 1H, NH).
Reaction SMILES: Br.C(O)(=O)C.Cl.COC[N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH:12]([NH2:27])[C:11]1=[O:28].CCOCC.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>O1CCCC1.[OH-].[Na+]>[O:28]=[C:11]1[NH:10][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH:12]1[NH:27][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]
Reactant: COCN1C(=O)C(N)CN(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NC1CN(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
25% Hydrobromic acid-acetic acid (150 ml) was added to 1-methoxymethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine hydrochloride (12.2 g). The resultant mixture was stirred for 30 minutes at room temperature. Ether was added thereto, and solid matter so precipitated was collected by filtration, to thereby obtain 2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine hydrobromide. Water (100 ml) was added thereto so as to obtain a suspension. Benzyl chloroformate (6.23 g) in tetrahydrofuran (100 ml) and 1N aqueous sodium hydroxide (75 ml) were added to the suspension under cooling on ice, followed by stirring for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added thereto, followed by extraction with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 9.6 g of the title compound (yield: 67.9 %).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[CH:13]=[C:12]1[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[CH:13]=[C:12]1[C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C(c2cccc(O)c2)=CC2CCC1C2
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add H2O (392 mg, 21.8 mmol) and TMSCl (1.4 g, 12.9 mmol) to a solution of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (2.8 g, 10.9 mmol) in 2-butanone (200 mL). Stir the reaction mixture at ambient temperature for 12 hours. Collect the precipitate by filter, and wash with EtOAc (30 mL×2), dry under vacuum to give 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol hydrochloride as white solid (2.41 g, Yield: 75.5%). 1H NMR (400 MHz, D2O) δ 7.20-7.24 (t, J=15.6, 1H), 6.76-6.81 (m, 2H), 6.72 (s, 1H), 6.15 (d, J=6.4, 1H), 3.58-3.61 (d, J=12.8, 1H), 3.08-3.14 (t, J=26.0, 1H), 2.89-2.92 (m, 1H), 2.88 (s, 3H), 2.76 (s, 3H), 2.56 (m, 1H), 2.45 (m, 1H), 1.72-1.83 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: COCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCCCCCOC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (9.5 g) in N,N-dimethylformamide (200 ml) was added portionwise sodium hydride (abt. 60% oil suspension) (2.6 g) under ice-cooling and nitrogen atmosphere. After stirring for 2 hours at room temperature, the reaction mixture was stirred for 1 hour at 60° C. To the reaction mixture was added a solution of 7-methoxyheptyl 4-methylbenzenesulfonate (15.0 g) in N,N-dimethylformamide (50 ml) at 60° C. and then the reaction mixture was stirred for 2 hours at 60° C. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1→5:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 8-(7-methoxyheptyloxy)-1,4-dioxaspiro[4.5]decane (9.77 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][C:17](O)=[O:18])[CH:11]=[C:12]([Cl:14])[CH:13]=1.[OH-].[Na+].[NH4+].[Cl-]>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][OH:18])[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: O=C(O)CCc1cc(Cl)cc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: OCCCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
LiAlH4 (1M in Et2O, 10 mL, 10 mmol) wasslowly added to a solution of 3-(3,5-dichlorophenyl)-propionic Acid (2.19 g, 10 mmol) in Et2O (50 mL). The reaction was heated at reflux for 2 h. The reaction was cooled to room temperature and 2N NaOH (1 mL) and aqueous NH4Cl (satd., 3 mL) as carefully added. The solution was filtered through Celite and the filtrate was dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (25% EtOAc/hexanes) to afford 3-(3,5-dichlorophenyl)-propanol (640 mg). 1H NMR (400 MHz, CDCl3) δ 7.17 (m, 1H), 7.07 (m, 2H), 3.64 (m, 2H), 2.65 (t, 2H), 1.84 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:21][CH3:22])[C:8]2[C:9]([CH2:16][O:17]COC)=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>O1CCOCC1.O>[CH:1]1([CH2:6][N:7]([CH2:21][CH3:22])[C:8]2[C:9]([CH2:16][OH:17])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1COCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CO
Temperature: 50 °C
Reaction time: 19 h
Yield: 93.5 %

Procedure:
A solution of N-(cyclopentylmethyl)-N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (8.39 g, 27.2 mmol) in a mixture of dioxane (400 mL) and water (100 mL) was added dropwise with concentrated hydrochloric acid (20 mL), and the mixture was stirred at 50° C. for 19 hours. The reaction mixture was made basic by adding aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain {3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methanol (6.72 g, 94%) as pale yellow oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]2=[O:26].I[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(O)C.[OH-].[Na+].C(OCC)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:28][CH3:29])[CH:16]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]2=[O:26]
Reactant: CCOC(=O)c1c[nH]c2ccc(NC3Cc4ccccc4C3)nc2c1=O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2ccc(NC3Cc4ccccc4C3)nc2c1=O
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of ethyl 6-(2,3-dihydro-1H-inden-2-ylamino)-1,4-dihydro-4-oxo-1,5-naphthyridine-3-carboxylate (600 mg), iodoethane (1 g) and potassium carbonate (600 mg) were heated at 90° C. in DMF (20 ml) overnight. After a standard ethyl acetate/aqueous work-up, the residue from the evaporated organic layer (crude cyclized ethyl ester), was heated at 80° C. in a mixture of ethanol (25 ml) and 2M NaOH (10 ml) for 2 h. This was then cooled to room temperature, aq. HCl was added to adjust the pH to 5, at which point the product precipitated and was filtered off, washed with water, and dried to give the crude product (˜350 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])=[O:8])=[O:4].[OH-].[Na+:22]>>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH:10]([C:16]([O-:18])=[O:17])[C:11]([O-:13])=[O:12])=[O:8])=[O:4].[Na+:22].[Na+:22]
Reactant: CCOC(=O)C(NC(=O)CNC(=O)CCl)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(CCl)NCC(=O)NC(C(=O)[O-])C(=O)[O-]

Procedure:
Diethyl 2-[[N-(chloroacetyl)glycyl]amino]malonate (0.68 g) is added to 1N aqueous sodium hydroxide (4.7 ml), and the mixture is reacted at room temperature for 10 hours, and the reaction mixture is concentrated. The residue is washed with methanol to give disodium 2-[[N-(chloroacetyl)glycyl]amino]malonate (0.65 g).