Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:9]=[C:10]([C@H:15]2[CH2:19][CH2:18][N:17]([C@H:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=4)[C:21]3=[O:35])[CH2:16]2)[CH:11]=[C:12]([Cl:14])[CH:13]=1>N1C=CC=CC=1.CS(C)=O>[Cl:14][C:12]1[CH:11]=[C:10]([C@H:15]2[CH2:19][CH2:18][N:17]([C@H:20]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([S:31]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)(=[O:32])=[O:33])=[CH:29][CH:30]=4)[C:21]3=[O:35])[CH2:16]2)[CH:9]=[C:8]([Cl:7])[CH:13]=1
Reactant: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized according to General Procedure 12, Method A: To a solution of 2-aminothiazole (15.9 mg, 0.16 mmol) in pyridine (0.4 mL) was added 4-[(3R,3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]benzene-1-sulfonyl chloride (25 mg, 0.05 mmol) and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DMSO, filtered and purified by reverse phase HPLC using 5%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to afford the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[C:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Reactant: CNC
Product: CCc1cc(-c2ccc(C(=O)N(C)C)s2)c(C)[nH]c1=O
Yield: 77 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and dimethylamine to afford the title compound (77% yield). LC/MS: RT 2.44 min; m/e 291 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.Cl.Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:14][CH:13]=1.O1CCN([CH2:36][CH:37]([N+:45]([O-:47])=[O:46])[CH2:38]N2CCOCC2)CC1>CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[CH2:38][CH:37]([N+:45]([O-:47])=[O:46])[CH2:36][N:19]2[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CNNCc2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])C(CN1CCOCC1)CN1CCOCC1
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CC([N+](=O)[O-])CN2Cc2ccc(OC)cc2)cc1
Yield: 85.9 %

Procedure:
To a mixed solution of toluene (8 ml) and methanol (12 ml) were added 1,2-bis(4- methoxyphenylmethyl)hydrazine dihydrochloride (0.99 g) and 1,3- dimorpholino-2-nitropropane (0.75 g). The mixture was refluxed with heating for 3 hours. The reaction solution was concentrated under a vacuum, purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby yielding 0.88 g (86%) of 1,2-bis (4-methoxyphenylmethyl)-4-nitropyrazolidine.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]#[N:15].Cl>CO.O>[NH2:15][C:14]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[NH:4][C:3]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:2]=2[N:1]=1
Reactant: N#Cc1c(Nc2cc(F)ccc2N)sc2ccccc12
Agent: Cl
Solvent: O
Solvent: CO
Product: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21

Procedure:
2-(2-Amino-5-fluoroanilino)benzo[b]thiophene-3-carbonitrile (155 g) was suspended in a mixture of methanol (250 ml) and water (200 ml) and 35% aqueous hydrochloric acid (42 ml) was added. The mixture was stirred under reflux with heating for 5.5 hours. The reaction mixture was cooled and stirred at 20° C. for 1 hour. The precipitated crystals were filtered by suction, washed successsively with water (500 ml) and isopropyl alcohol (200 ml) and dried in a drying box overnight to give 12-amino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 hydrochloride (104 g) as yellow crystals.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[H][H]>CO.[Pd]>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(N2CCN(C3CC3)CC2)cc1
Yield: 99.4 %

Procedure:
To a solution of 1-cyclopropyl-4-(4-nitro-phenyl)-piperazine (1.24 g, 5.00 mmol) in methanol (25 mL) was added Pd/C (10%, 100 mg) and trifluoroacetic acid (1.0 mL). The mixture was stirred under 1 atm of hydrogen (balloon) overnight, filtered and concentrated. To the residue was added water and 1N aq. NaOH to adjust the PH>11. The mixture was extracted ethyl acetate, and the organic layer was dried over Na2SO4, concentrated to give the title compound (1.08 g, 100%) as a brown oil. MS (ES+): m/z=218.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCCC1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(-c1cn[nH]c1)c(=O)n2C1CCCC1
Temperature: 120 °C
Yield: 65 %

Procedure:
To a solution of 2-amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.31 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxy late (110 mg, 1.2 equiv), dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 009 mmol), DMF (2 mL) in a 10 mL microwave vial was added potassium carbonate (3 M, 0.8 mL). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 10 min at 120° C. Once complete, the reaction was diluted with 1 N NaOH (10 mL) and EtOAc (50 mL). The EtOAc layer was washed with 3N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was submitted for chromatography purification. the title compound was obtained in (62.5 mg, 65% yield).
Reaction SMILES: C(O)(=[O:3])C.[CH:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.OO>O>[CH:5]1[C:18]2[S:17](=[O:3])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: O=S1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 83 %

Procedure:
Into 1600 g of acetic acid was dissolved 100 g (0.5 mole) of phenoxathiin, and 48.5 g (0.5 mole) of an aqueous hydrogen peroxide (35%) was added into it dropwise at room temperature. The mixture was agitated at room temperature for 7 days, and then added by 3,000 g of water to precipitate white crystals. They were collected by filtration and dried under reduced pressure to obtain the intended compound. The amount of the white crystals was 90 g and the yield was 83%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1>CO>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCN(Cc3ncc(C)cc3C)Cc3ncccc3C(C)C)c2)cc1
Agent: On1nnc2ccccc21
Solvent: CO
Product: Cc1cnc(CN(CCc2c[nH]cn2)Cc2ncccc2C(C)C)c(C)c1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-{2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine (99.1 mg, 0.19 mmol) in anhydrous MeOH (1.5 mL) was added HOBT (108.5 mg, 0.803 mmol) and the resulting mixture was stirred overnight. The mixture was concentrated and purified by radial chromatography on silica gel (1 mm plate; using 6% MeOH/CH2Cl2, followed by CH2Cl2/MeOH/NH4OH; 17:1:1) to afford COMPOUND 176 as a light brown oil (43.4 mg, 62%). 1H NMR (CDCl3) δ 1.00 (d, 6H, J=9.0 Hz), 2.07 (s, 3H), 2.21 (s, 3H), 2.86 (s, 4H), 3.09 (qnt, 1H, J=6.0 Hz), 3.77 (s, 2H), 3.84 (s, 2H), 6.70 (s, 1H}, 7.11 (m, 2H), 7.43 (d, 1H, J=7.8 Hz), 7.57 (s, 1H), 8.14 (s, 1H), 8.32 (d, 1H, J=4.7 Hz). 13C NMR (CDCl3) δ 18.2, 18.3, 23.0, 23.5, 27.8, 54.8, 57.6, 58.2, 123.0, 124.4, 130.4, 132.0, 132.6, 133.6, 134.9, 139.1, 143.6, 145.8 146.3, 153.9, 155.7. ES-MS m/z 364 [M+H]+. Anal. Calcd. for C22H29N5.0.6H2O.0.1 CH2Cl2: C, 72.69; H, 8.04; N, 19.27. Found: C, 69.46; H, 8.11; N, 18.24.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1([C:25]2[S:26][C:27]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:22]1[CH2:23][CH2:24][N:19]([C:25]2[S:26][C:27]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:28][N:29]=2)[CH2:20][CH2:21]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CCC(=O)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCC(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)s1
Yield: 24 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(2-piperazin-1-yl-thiazol-5-yl)-propan-1-one hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a light brown crystalline solid (yield 24%). MS (m/e): 466.0 (M+H+, 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:7](I)=[CH:8][C:9]([O:17][CH2:18][CH3:19])=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])=[O:4].[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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.O>[C:22]([C:7]1[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:21])[CH3:1])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(I)cc1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(C#N)cc1OCC
Temperature: 80 °C
Yield: 92 %

Procedure:
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-iodobenzoate (1.01 g, 2.36 mmol), zinc cyanide (0.167 g, 1.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.191 g, 0.165 mmol) were combined under nitrogen in a flame-dried Schlenk tube. Dimethylformamide (9 mL) was added and the reaction mixture was put through three freeze-pump-thaw cycles and then put under a nitrogen atmosphere and heated at 80° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the resulting mixture was extracted with diethyl ether (100 mL, 2×50 mL). The combined organic phases were washed with brine (3×50 mL) and then dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 33% ethyl acetate in hexanes) gave ethyl 4-cyano-5-dimethylsulfamoyl-2-ethoxybenzoate as an off-white solid (0.708 g, 92%). LC-MS: 327.1 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].C(N(CC)CC)C.[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[C:29](O)[CH:30]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:30]=1)[CH3:24]
Reactant: CCc1ccc(CCCOC)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCc1ccc(CCCOC)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (0.47 mL, 2.8 mmol) followed by triethylamine (0.42 mL, 3 mmol) was added to a cooled 0° C. solution of 5-ethyl-2-(3-methoxy-propyl)-phenol (0.45 g, 2.3 mmol). The reaction was stirred for 1 hour and then warmed to room temperature. The reaction was partitioned between 1 N HCl and EtOAc. The organic extracts were washed with bring, dried over Na2SO4 and concentrated to a black oil. 1H NMR (400 MHz, CDCl3): δ 1.24 (t, J=7.6 Hz, 3 H), 1.89 (m, 2 H), 2.65 (d, J=7.6 Hz, 2 H), 2.75 (t, J=7.6 Hz, 2 H), 3.35 (s, 3 H), 3.40 (t, J=7.6 Hz, 2 H), 7.07 (s, 1 H), 7.14 (d, J=8.0 Hz, 1 H), 7.23 (d, J=8.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9]C)[CH2:5][C:6]#[N:7])C.[CH3:11][C:12]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.C[O-].[Na+]>CO>[CH3:9][O:8][CH:4]([O:3][CH3:1])/[C:5](=[CH:14]/[C:13]1[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:12]=1[CH3:11])/[C:6]#[N:7]
Reactant: Cc1cccc(C=O)c1C
Reactant: CCOC(CC#N)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)/C(C#N)=C/c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) and 2,3-dimethylbenzaldehyde (2.1 g, 16 mmol) in methanol (10 mL) was added a 25-30% of sodium methoxide in methanol over 20 minutes. The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). The two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and concentrated in vacuo. The residue was then purified to give product. It was used in next step. (1.55 g, 33%); 1H NMR (600 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 2.28 (s, 3H) 3.37 (s, 6H) 5.13 (s, 1H) 7.17-7.22 (m, 1H) 7.27 (d, J=7.55 Hz, 1H) 7.39-7.45 (m, 1H) 7.79 (s, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:33])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:33])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:31]=[CH:30][C:29]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)CS3(=O)=O)cc2)CC1
Yield: 40 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (240 mg) described in Preparation Example 4 and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (650 mg) described in Preparation Example 117 and by the reaction and treatment in the same manner as in Example 1, the title compound (264 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[OH2:9]>O1CCCC1>[N:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:9])=[CH:4][CH:5]=1
Reactant: N#Cc1ccncc1
Reactant: O
Solvent: C1CCOC1
Product: NC(=O)c1ccncc1
Yield: 91.4 %

Procedure:
(0.0051 g, 0.0119 mmol) of the platinum complex, prepared as in Example 1, was stirred with 4-cyanopyridine (2.0 g, 0.019 mol) and 0.75 ml (0.042 mol) of water and 10 ml tetrahydrofuran and the mixture heated under reflux for 4 hours. After cooling the liquids were removed using a rotary evaporator to give pyridine 4-carboxamide (2.12 g) corresponding to 90% yield.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([CH:25]([CH3:45])[CH2:26][C:27]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH2:3]1.[H][H]>[Pd].CO>[OH:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:6][CH2:5][N:4]([CH:25]([CH3:45])[CH2:26][C:27]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:28]([N:30]([CH3:31])[CH3:32])=[O:29])[CH2:3]1
Reactant: [H][H]
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2ccccc2OCc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2ccccc2O)[C@H](O)C1
Yield: 63 %

Procedure:
A mixture of 2.7 parts of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[2-(phenylmethoxy)benzoyl]amino]-1-piperidinebutanamide and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in methylbenzene and the solvent was evaporated again. The residue was suspended in a mixture of 2,2'-oxybispropane and a few drops of acetonitrile. The product was filtered off and dried in vacuo at 70° C., yielding 1.3 parts (63.0%) of trans-3-hydroxy-4-[(2-hydroxybenzoyl)-amino]-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 154.3° C. (compound 77).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[F:36]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:36][C:28]1[CH:29]=[CH:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][C:27]=1[C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F

Procedure:
1.126 ml of ethynyl(trimethyl)silane, 55 mg of triphenylphosphine and 24 mg of palladium (2+) acetate are added to a solution of 1.169 g of 2-bromo-1-fluoro-4-nitrobenzene in 13 ml of triethylamine with stirring and under argon. After four and a half hours at a temperature of 100° C., the reaction medium is cooled and the insoluble material is filtered off through sintered glass. The filtrate is concentrated to dryness under reduced pressure. After two silica column purifications, eluent: 90/10 heptane/EtOAc then 95/5 heptane/EtOAc, 460 mg of [(2-fluoro-5-nitrophenyl)ethynyl](trimethyl)silane are obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([CH:7]([OH:15])[CH2:8][CH2:9]CS([O-])(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:17]>O1CCCC1>[NH2:17][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:15]
Reactant: [NH4+]
Reactant: O=S(=O)([O-])CCCC(O)c1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCC(O)c1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 3-phenyl-3-hydroxypropylmethanesulfonate (1.71 g, Gao, et al., J. Org. Chem., 1988, 53, 4081), tetrahydrofuran (10 mL) and 28% ammonium hydroxide (30 mL) was heated in a bomb at 65° C. for 16 hours. After cooling, the volatiles were eliminated to leave the aqueous solution which was extracted with ether. The aqueous layer was concentrated under reduced pressure, azeotroped twice with anhydrous acetonitrile and dried under vacuum to give 3-amino-1-phenyl-1-propanol (1.04 g) as a white solid: mp 92-94° C., Rf=0.1 (silica, methanol/ethyl acetate 1/1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.N[CH2:11][CH2:12][OH:13].N>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:13][CH2:12][CH2:11][N:7]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: N#Cc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Product: Nc1ccc(C2=NCCO2)cc1
Yield: 82 %

Procedure:
Using known procedures for the synthesis of cyclic imino ethers from nitriles (18,26), 4-aminobenzonitrile was treated with an excess of 2-aminoethanol (1 part nitrile/2 parts aminoalcohol) in refluxing xylene, with 3.5 wt. % zinc acetate catalyst, with all under a slow nitrogen stream. The solution was heated until no NH3 was detected in the off gas. After removal of the xylene, the crude solid product was obtained in high yield. The crude product was recrystallized from acetonitrile to obtain an 82% yield of white, crystalline 4-APOXO having mp 163-165° C., reported 158-160° C. The structure of the monomer was confirmed by FT-IR and 1H NMR. Structure of 4-APOXO is as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[S:15](=[O:17])(=[O:16])[N:14]([CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:13](=[O:24])[CH2:12]2)=[C:7]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=1.[C:37](Cl)(=[O:39])[CH3:38]>N1C=CC=CC=1.CCOC(C)=O>[CH2:26]([O:25][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N:11]1[CH2:12][C:13](=[O:24])[N:14]([CH2:18][CH2:19][Si:20]([CH3:21])([CH3:22])[CH3:23])[S:15]1(=[O:16])=[O:17])[CH2:4][C:3]1[CH:33]=[CH:34][CH:35]=[CH:36][C:2]=1[NH:1][C:37](=[O:39])[CH3:38])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3N)cc2OCc2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[4-(2-aminobenzyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (Example 4, Step A) (250 mg, 0.478 mmol) in pyridine (1.5 mL) is added acetylchloride (41 mg, 0.525 mmol). The mixture is stirred at ambient temperature for 30 min., then diluted with EtOAc and washed with 0.5N HCl, saturated NaHCO3 and brine. It is then dried over Na2SO4/MgSO4, filtered and concentrated to afford N-(2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-phenyl)-acetamide as a gum: MS (M+H)+=566.1.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 97.8 %

Procedure:
A total of 4 g (8 mmol) of 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and 6 mL (78 mmol) of trifluoroacetic acid were mixed in 60 mL of methylene chloride for 5 hrs. Methylene chloride (40 mL) was added and the organic layer was washed with 3×50 mL of saturated sodium bicarbonate followed by brine. The organic layer was dried over odium sulfate and concentrated to yield 3.1 g of solid.