Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=2[C:28]#[N:29])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][CH:32]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[C:20]([C:28]#[N:29])[CH:21]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3C#N)c2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3C#N)c2)c1
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A suspension of 3-(1-cyano-1-methylethyl)-N-[3-(2-cyano-4-nitrophenoxy)phenyl]benzamide (4.18 g, 9.80 mmol), calcium chloride (3.43 g, 29.4 mmol) and reduced iron (2.73 g, 49.0 mmol) in ethanol (70 mL)/water (7 mL) was stirred with heating at 80° C. for 16 hr. The reaction mixture was cooled to room temperature, and insoluble material was filtered off through a pad of celite and washed with ethanol. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (200 mL×2) and saturated brine (200 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (3.18 g, 82%) as a yellow oil.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([CH:26]=[CH2:27])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([NH:8][C:9]1[S:10][C:11]([CH2:26][CH3:27])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: C=Cc1sc(NC(=O)OC(C)(C)C)nc1C(=O)OCP(=O)(OCC)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1CC)OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonyl thiazole (1 mmole) and 10% Pd/C (0.5 mmole) in MeOH (5 mL) was stirred under an atmosphere of H2 (balloon) at room temperature for 15 h. Filtration and evaporation gave 2-[N-Boc(amino)]-5-ethyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid, which was subjected to Step D of Example 18 followed by Step C of Example 3 to give 2-amino-5-ethyl-4-phosphonomethoxycarbonylthiazole (18.3) as a solid. Mp>230° C. (decomp). Anal. Calcd. for C7H11N2O5PS: 31.58; H: 4.16; N: 10.52. Found: C: 31.80; H: 4.04; N: 10.18.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:33]([NH:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=4)=[O:34])[CH:17]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc(C2=C(Nc3ccc4c(c3)CCC4)C(=O)NC2=O)c1
Reactant: O=C=Nc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)Nc1cccc(C2=C(Nc3ccc4c(c3)CCC4)C(=O)NC2=O)c1
Reaction time: 72 h

Procedure:
3-(Indan-5-ylamino)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (Table A, Example A599; 0.08 g, 0.3 mmol) in dichloromethane (10 mL) was was treated with 3-fluorophenyl isocyanate (0.038mg, 0.3 mmol). The mixture was shaken on an orbital shaker for 72 hours. Saturated aqueous sodium bicarbonate (5 mL) was added, shaking continued for 5 minutes and the organic layer transferred directly onto a column of silica gel. Elution with dichloromethane gave the product as a yellow solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:21][CH2:22][CH:23]([F:47])[CH2:24][NH:25][C:26](=[O:46])[C@H:27]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:28][C:29]([O:31][CH3:32])=[O:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N+:63]([C:66]1[CH:71]=[CH:70][C:69]([S:72](Cl)(=[O:74])=[O:73])=[CH:68][CH:67]=1)([O-:65])=[O:64]>ClCCl>[Si:1]([O:18][CH2:19][C@@H:20]([N:48]([CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[S:72]([C:69]1[CH:68]=[CH:67][C:66]([N+:63]([O-:65])=[O:64])=[CH:71][CH:70]=1)(=[O:73])=[O:74])[CH2:21][CH2:22][CH:23]([F:47])[CH2:24][NH:25][C:26](=[O:46])[C@H:27]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:28][C:29]([O:31][CH3:32])=[O:30])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NCCC(C)C)C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a stirred solution of the material from Step 12 (85 mg, 0.12 mmol) in dichloromethane (1.1 mL) were added N,N-diisopropylethylamine (30 μL, 0.172 mmol) and 4-nitrobenzenesulfonyl chloride (28 mg, 0.126 mmol). The reaction mixture was stirred at room temperature overnight. Additional N,N-diisopropylethylamine (30 μL, 0.172 mmol) and 4-nitrobenzenesulfonyl chloride (6 mg, 0.03 mmol) were added, stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 85 mg of the title compound. LCMS (M+1)=947
Reaction SMILES: [Cl:1][C:2]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:3]=1[CH2:4][N:5]([CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]([CH2:20][CH2:21]CC)[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.Cl>C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:41]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:39]=[CH:38][C:3]=1[CH2:4][N:5]([CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: CCCCC(C(=O)O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Product: CCC(C(=O)O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 80 %

Procedure:
To a solution of 2-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-hexanoic acid in diethyl ether was added HCl in diethyl ether (1.0 M) to precipitate the amine salt. The suspension was filtered and dried to give the title compound as a white solid (30 mg, 80%). MS m/e 609.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][C@@H:15]1[NH:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:16]1=[O:30]>C(#N)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:20]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:16](=[O:30])[C@@H:15]2[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H]1NCCN(CCCN2CCCCC2)C1=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: C[C@H]1C(=O)N(CCCN2CCCCC2)CCN1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 83 %

Procedure:
3-(Trifluoromethyl)phenyl isocyanate (30 mg, 0.15 mmol) was added to a solution of (S)-3-methyl-1-(3-piperidin-1-yl-propyl)-piperazin-2-one (intermediate 20; 30 mg, 0.13 mmol) in acetonitrile (1 ml). The solution was heated at 60° C. for 15 min under microwave irradiation, then evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (46 mg, 86%). Colorless gum, MS (ISP)=427.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:44])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39]I)[C:22]=1[CH2:41][CH2:42][CH3:43])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:17][C:18](=[O:44])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:41][CH2:42][CH3:43])[CH3:16]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCCCOCCCCI
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCOCCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 87.1 %

Procedure:
A mixture of 1.00 g (0.0052 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.78 g (0.0052 mole) of [4-acetyl-3-[4-(4-iodobutoxy)butoxy]-2-propylphenoxy]acetic acid ethyl ester and 1.44 g (0.010 mole) of anhydrous potassium carbonate in 75 ml of anhydrous acetone was stirred at reflux for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by HPLC using 35% ethyl acetate-hexane to give 2.72 g (87% yield) of [4-acetyl-3-[4-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butoxy]butoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][N:16]2[C:21]=1I)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC>O1CCOCC1.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>[CH2:1]([O:8][C:9](=[O:23])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][N:16]2[C:21]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cccnn2c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(NC(=O)OCc1ccccc1)c1nc2cccnn2c1-c1ccccn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(3-iodo-imidazo[1,2-b]pyridazin-2-yl)-ethyl]-carbamic acid benzyl ester (3.0 g, 7.1 mmol) and 2-tributylstannanyl-pyridine (7.8 g, 21.32 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh3)4 (820 mg, 0.71 mmol) at rt. The reaction mixture was stirred overnight at 110° C. After completion of the reaction, the mixture was concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-40% acetone in hexane to provide [1-(3-pyridin-2-yl-imidazo[1,2-b]pyridazin-2-yl)-ethyl]-carbamic acid benzyl ester: LC-MS (ESI) m/z 374.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].O1CCOCC1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]=[C:21]([C:20]1[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=1)[NH:8]2
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ncnc(Cl)c1N
Solvent: C1COCCO1
Product: Clc1ccc(-c2nc3c(Cl)ncnc3[nH]2)cc1
Temperature: 100 °C

Procedure:
To a solution of 6-Chloro-4,5-diaminopyrimidine (1 g, 0.007 mol) (Example 89, step a) in 1,4-Dioxane (60 mL, 0.8 mol) was added 4-Chlorobenzaldehyde (2.2 g, 0.016 mol) and Ferric chloride (2.5 g, 0.015 mol) mixed with 28.6 g silica gel, and the mixture was heated at 100° C. for 20 hours. The reaction was cooled to 23° C., filtered and washed with 10% ethanol/ethyl acetate and concentrated. The residue was dissolved in ethyl acetate and washed with water, brine, and concentrated. The residue was triturated in diethyl ether to obtain 272 mg (10%). LC/MS: Rt=1.54 min, ES+ 265 (AA standard).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH:8]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)[C:9]#[N:10].O.[OH-].[Na+]>C1COCC1>[NH2:10][CH2:9][CH:8]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)[OH:7]
Reactant: N#CC(O)c1ccsc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCC(O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of LAH (8.7 g, 225 mmol) in dry THF (300 mL) was added a solution of hydroxy-thiophen-3-yl-acetonitrile (12.5 mL, 90 mmol) in dry THF (50 mL) dropwise at 0° C. under nitrogen atmosphere. Then the mixture was warmed to 25° C. and stirred overnight. After cooling to 10° C., H2O (8.7 mL) was added to the solution, followed by NaOH solution (8.7 mL, 15%), then H2O (26 mL). The reaction mixture was filtered and the filtration was concentrated to dryness to afford crude 2-amino-1-thiophen-3-yl-ethanol. (Yield 12.9 g, crude).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]2[NH:18][CH:17]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23][CH2:22]3)=[O:20])[CH2:16][S:15]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:30]1([CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([C:19]([CH:17]3[CH2:16][S:15][CH:14]([CH:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[NH:18]3)=[O:20])[CH2:22][CH2:23]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C2NC(C(=O)N3CCN(CCCc4ccccc4)CC3)CS2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CSC(C2CCCNC2)N1)N1CCN(CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
1-[2-(1-tert-Butoxycarbonyl-3-piperidinyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine (430 mg) was dissolved in 3 ml of dichloromethane, followed by addition of 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 60 ml of saturated aqueous solution of sodium hydrogen carbonate, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 280 mg of 1-(3-phenylpropyl)-4-[2-(3-piperidinyl)thiazolidin-4-ylcarbonyl]piperazine. This compound was dissolved in 8 ml of ethyl acetate, and 1 ml of 4N hydrogen chloride solution in dioxane was added. After 30 minutes of stirring, the resultant solid was collected by filtration and dried to give 200 mg of 1-(3-phenylpropyl)-4-[2-(3-piperidinyl)thiazolidin-4-ylcarbonyl]piperazine trihydrochloride. Melting point 174°-178° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)=[CH:6][C:5]2[O:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[C:3]1=[O:25].[CH3:26][NH:27][CH3:28]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:27]([CH3:28])[CH3:26])=[CH:10][CH:9]=2)=[CH:6][C:5]2[O:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[C:3]1=[O:25]
Reactant: Cn1c(-c2ccc(CBr)cc2)cc2onc(-c3ccccc3)c2c1=O
Reactant: CNC
Solvent: Cc1ccccc1
Product: CN(C)Cc1ccc(-c2cc3onc(-c4ccccc4)c3c(=O)n2C)cc1

Procedure:
A mixture of 21.2 g. of the product of Example 4, containing 62% of 5-methyl-3-phenyl-6-(p-bromomethylphenyl)-isoxazolo[4,5-c]pyridin-4(5H)-one 0.0332 mole of bromo compound) and 7.2 g. (0.160 mole) dimethylamine in 300 ml. toluene is stirred overnight at room temperature. The mixture is filtered and the solid washed with toluene and the solvent evaporated in vacuo. The resulting solid is dissolved in methylene chloride and treated with 2N hydrochloric acid, the precipitate is then filtered, washed with water and ether. The solid is then dissolved in methylene chloride and 2N sodium dioxide and the organic phases separated and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 5-methyl-3-phenyl-6-(p-[dimethylaminomethyl]phenyl)-isoxazolo[4,5-c]pyridin-4(5H)-one; m.p. 159°-161° C.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:10][CH2:11][CH2:12][OH:13].C>C(OC(C)C)(C)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[Cl:17])[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)c(Cl)c1
Solvent: CC(C)OC(C)C
Product: NS(=O)(=O)OCCOc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by the procedures of Example 4228 from sulfamoyl chloride and to 2-(3,4-dichlorophenoxy)ethanol. The tan colored solid obtained was dissolved in isopropyl ether and the solution treated with charcoal and filtered through Celite®. The filtrate was evaporated under reduced pressure and the solid residue was recrystallized from isopropyl ether to give the title compound, mp 84°-85° C., in 19% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:29])[CH2:27][NH2:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:28][CH2:27][CH2:26][NH2:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (m, 2 H), 7.65-7.50 (m, 2 H), 7.42-7.30 (m, 2 H), 7.28-7.16 (m, 1 H), 6.10-5.95 (m, 1 H), 5.09 (brs, 2 H), 3.64-3.42 (m, 2 H), 3.15-2.98 (m, 2 H), 2.84 (s, 2 H), 2.35 (s, 3 H), 1.20 (s, 2 H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][NH:14][CH2:15][CH2:16][CH:17]=[C:18]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=2.Cl.C(N(CC)CC)C.[C:41]([O:45][C:46]([NH:48][CH2:49][C:50]([OH:52])=O)=[O:47])([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])O.[Na+]>ClCCl>[CH:23]1[C:24]2[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:18](=[CH:17][CH2:16][CH2:15][N:14]([CH3:13])[C:50](=[O:52])[CH2:49][NH:48][C:46](=[O:47])[O:45][C:41]([CH3:42])([CH3:43])[CH3:44])[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: CNCCC=C1c2ccccc2CCc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCC=C1c2ccccc2CCc2ccccc21)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
281 mg (1.47 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 281 mg (1.47 mmol) of nortriptyline hydrochloride and 0.40 ml (2.87 mmol) of triethylamine were added to 251 mg (1.44 mmol) of t-butoxycarbonylglycine in 10 ml of dichloromethane, and they were stirred at room temperature overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=4:1) to obtain the title compound.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1.[B:29](OC)([O:32]C)[O:30]C.Cl>O1CCCC1>[C:13]1([B:29]([OH:32])[OH:30])[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
An excess of 1.6 M n-BuLi in hexane (50 mL, 80 mmol) was added to a solution of 1-bromopyrene (20.4 g, 72.6 mmol) in 500 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C. Trimethyl borate (10.4 g, 100 mmol) was added dropwise; the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (150 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the residue was crystallized (n-hexane) to give the pyren-1-ylboronic acid 12.5 g as a yellow solid (70%)
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]#[N:23]>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[N:1]=[C:22]([NH2:23])[C:21]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[CH:4]2
Reactant: COc1ccccc1CCC#N
Reactant: COc1cccc(C=O)c1N
Product: COc1ccccc1Cc1cc2cccc(OC)c2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-3-methoxybenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [OH:1][C:2]([CH2:4][C:5]1[C:6](=[O:17])[CH2:7][CH:8]([O:10]C2CCCCO2)[CH:9]=1)=[O:3].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25]=1[O:1][C:2]([CH2:4][C:5]1[C:6](=[O:17])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:3]
Reactant: O=C(O)CC1=CC(OC2CCCCO2)CC1=O
Reactant: Oc1ccc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC1=CC(O)CC1=O)Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 g of 2-Hydroxycarbonylmethyl-4-tetrahydropyranyloxy-2-cyclopenten-1-one (21 mmol) obtained from Example 5, 2-naphthol (4.7 g, 32 mmol), dichloromethane (50 ml), and 0.2 g 4-(dimethylamine)pyridine were added together to a 50 ml dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (7 g, 34 mmol). The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with 20 ml of diluted hydrochloride solution, water, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The crude product was dissolved in 30 ml acetone and 6 ml water, further added with 0.3 g p-toluenesulfonic acid and stirred overnight. Upon completion of the reaction, acetone was evaporated and the reaction mixture was diluted with ethyl acetate and washed with an aqueous sodium bicarbonate solution and a brine solution. The organic liquid was subjected to the previous work-up procedure, including dehydration, filtration, and evaporation, and purification by chromatography on silica gel to obtain the title compound as white solid. MP: 81° C. (4.2 g, 71%) 1H-NMR (CDCl3/TMS): δ 7.82 (m,2H), 7.78 (d, 1H), 7.55 (m,2H), 7.46 (m,2H), 7.21 (dd, 1H), 5.04 (m, 1H), 3.56 (s, 2H), 2.89 (dd, 1H), 2.38 (dd, 1H), 1.60 (brs, 1H).