Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1C2C(=CC=CC=2)C=CC=1S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)c1ccc2ccccc2c1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(CC(F)(F)F)c4=O)cc3)CC2)cc1
Yield: 42.4 %

Procedure:
A mixture of 17.5 parts of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-3H-1,2,4-triazol-3-one prepared as described in example XVII of U.S. Pat. No. 4,267,179, 19.5 parts of 2,2,2-trifluoroethyl 2-naphthalenesulfonate, 10.0 parts of potassium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 145° C. After cooling, water was added. The crystallized product was filtered off under pressure and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-butanone. The product was filtered off and dried, yielding 9.2 parts (42.4%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-(2,2,2-trifluoroethyl)-3H-1,2,4-triazol-3-one; mp. 208.0° C. (int. 37).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:22][CH3:23])[CH:10]=[CH:11][C:12](=[O:21])[CH2:13]4.[H][H].O.C(=O)(O)[O-].[K+]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:22][CH3:23])[CH2:10][CH2:11][C:12](=[O:21])[CH2:13]4
Reactant: [H][H]
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)C=CC(=O)C3
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A solution of 7,8-didehydro-3,14-dimethoxy-17-methylmorphinan-6-one (3) (4.30 g, 13.72 mmol) in acetic acid (80 ml) was hydrogenated over 1.72 g of Pd/C (10%) at 3 atmospheres pressure until the hydrogen uptake was complete. The mixture was filtered through Celite and the solution concentrated under reduced pressure to give a clear oil. This oil was treated with water (100 ml) and potassium bicarbonate was added until the solution became basic. The mixture was extracted with methylene chloride (3×100 ml) whereupon the organic layer was separated, dried over MgSO4 and filtered. The filtrate was concentrated under vacuum to give 4.19 g (97% theory) of the desired product as a colorless solid (m.p. 152°-156° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-])=O)[CH:10]=2)=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1ccc(C(c2ccc(F)cc2)n2ccnc2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccc(C(c2ccc(F)cc2)n2ccnc2)cc1N

Procedure:
A mixture of 6.24 parts of 4-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-2-nitrobenzenamine, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 5.6 parts of 4-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine as a residue (int. 5).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:33]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl>[N:33]1([CH2:39][CH2:40][N:41]2[C:7](=[O:9])[C:6]3[CH:5]=[C:4]([CH2:11][CH2:12][CH3:13])[S:3][C:2]=3[NH:1][C:15]2=[O:17])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCc1cc(C(=O)OC)c(N)s1
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cc2c(=O)n(CCN3CCOCC3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution (30 mL) of methyl 2-amino-5-propylthiophene-3-carboxylate (1.0 g) in methylene chloride were added triphosgene (1.8 g) and triethylamine (3.0 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-morpholin-4-ylethanamine (2.3 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (15 mL), sodium methoxide (1.0 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.5 g, 72%).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:23]([OH:26])[C:24]#[CH:25]>C(N(CC)CC)C.CN(C=O)C.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.[Cu]I>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:25]#[C:24][CH2:23][OH:26])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2s1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(C#CCO)cc2s1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
120 mg (0.30 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 11A), 10.5 mg (0.01 mmol) of PdCl2(PPh3)2 and 4.6 mg (0.02 mmol) of copper(I) iodide are dissolved in 1.5 ml of triethylamine/DMF (2:1) under argon and stirred at 60° C. for 1 h. Addition of 25.1 mg (0.45 mmol) of propargyl alcohol is followed by heating at 70° C. for a further 16 h. Cooling is followed by filtration through kieselguhr and purification by preparative HPLC, concentration and drying of the product under high vacuum. 12 mg (11% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[CH:14].O>C(N(CC)CC)C.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.[Cu](Br)Br>[C:15]1([C:13]#[C:14][C:2]2[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Reactant: C#Cc1ccccc1
Agent: Br[Cu]Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncc(C(F)(F)F)cc1C#Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, to a solution of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (the compound described in Bio. Org. Med. Chem., 9, 1715 (1999)) (163 mg) in triethylamine (1.5 mL), ethynylbenzene (82 μL), bis(triphenylphosphine)palladium dichloride (43 mg) and copper bromide (14 mg) were added. The reaction mixture was stirred for overnight at 60° C. To the reaction mixture, water was added and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (26 mg) having the following physical data.
Reaction SMILES: [Si]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36]C(O)=O)=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.CN1CC[O:53][CH2:52]C1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:78][CH2:79][C:80]([NH:82][C@@H:83]([C:88]([OH:90])=[O:89])[C:84]([CH3:87])([CH3:86])[CH3:85])=[O:81].[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>CN(C=O)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C@@H:9]([OH:8])[CH2:10][S:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:21][CH:22]=3)[C@@H:13]2[C:31]2[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:52]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:88]([OH:90])=[O:89])[C:84]([CH3:85])([CH3:86])[CH3:87])=[O:81])=[O:53])=[CH:33][CH:32]=2)=[CH:43][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)[C@@H](NC(=O)CN)C(=O)O
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred solution of {4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (19.4 mg, 0.027 mmol) and N-methylmorpholine (9 μl, 0.082 mmol) in DMF (1 ml, dry) was added TBTU (13.0 m, 0.040 mmol) and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-methyl-D-valine (7.1 mg, 0.038 mmol) was added and the reaction mixture was stirred for 1 hour. LC-MS showed the formation of the TBDMS-ether of the title compound, M/z: 881.65 (M−1). The reaction mixture was diluted with water and EtOAc. The solution was acidified with KHSO4 (2M) to pH 3. The phases were separated and the organic phase was concentrated. The residue was dissolved in acetic acid (1 ml). Water (100 μl) and LiCl (63 mg, 1.47 mmol) were added and the reaction mixture was stirred over the weekend. The acetic acid was co-evaporated with toluene. The residue was purified with preparative HPLC on a C8 column, UV 235/285 nm. A gradient from 20 to 60% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and most of the MeCN was removed under reduced pressure. The residue was lyophilised to give the title compound. H-NMR (500 MHz, DMSO-d6): 0.89 (s, 9H), 2.92 (d, 2H), 2.97 (s, 8H), 3.82 (d. 2H), 3.98-4.07 (b, 3H), 4.31 (d, 1H), 4.53 (s, 2H), 4.72 (t, 1), 5.09 (d, 1H), 6.99 (d, 2H), 7.07-7.13 (m, 2H), 7.20 (d, 2H), 7.32-7.40 (m, 6H), 7.59 (b, 1H), 7.81 (b, 1H), 8.23 (t, 1H). M/z: 769.39 (M+1) and 767.58 (M−1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10](F)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:19])[C:5]2[C:20](=[O:23])[NH:21][S:22][C:4]1=2)[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[N:24]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:31][CH2:32]3)[C:11]=2[O:13][CH:14]([F:16])[F:15])[C:6](=[O:19])[C:5]2[C:20](=[O:23])[NH:21][S:22][C:4]1=2)[CH3:2]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCn1c2s[nH]c(=O)c2c(=O)c2cc(F)c(F)c(OC(F)F)c21
Product: CCn1c2s[nH]c(=O)c2c(=O)c2cc(F)c(N3CCN(c4ncccn4)CC3)c(OC(F)F)c21
Yield: 1.4 %

Procedure:
The same reaction as in Example 1 was carried out by using mg (1.44 mmole) of 9-ethyl-6,7-difluoro-8-difluoromethoxy-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinolin-3,4-dione and 1.9 g (11.5 mmole) of 1-(2-pyrimidinyl)piperazine to obtain 10 mg of the title compound as pale yellow powder.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33].CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[N:4]=[CH:5][C:6]([NH:9][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:7][CH:8]=1
Reactant: CN(c1ccc(N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(N(C)[C@@H]2CCN(c3ncnc4c3ccn4COCC[Si](C)(C)C)C2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
To a solution of (R)—N2-methyl-N-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-pyridine-2,5-diamine (0.25 mmol) in DCM (5 mL) were subsequently added ethanesulfonyl chloride (0.3 mmol) and Et3N (0.3 mmol). The solution was stirred at the ambient temperature for 18 hours and then concentrated. The crude product was purified by preparative TLC to give the title compound in 42% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:11]([C:23]([O:25][CH3:26])=[O:24])[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+].[CH3:30]I>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:11]([C:23]([O:25][CH3:26])=[O:24])[N:10]([CH3:30])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1[nH]nc(-c2ccc(Br)cc2)c1OCc1ccc(OC)cc1
Reactant: CI
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OCc2ccc(OC)cc2)c(-c2ccc(Br)cc2)nn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-(4-bromophenyl)-4-(4-methoxybenzyloxy)-1H-pyrazole-5-carboxylate T-11 (10 g, 24 mmol) in anhydrous N,N-dimethylformamide (100 mL) cooled in an ice bath was added lithium hydroxide monohydrate (3 g, 71 mmol) and methyl iodide (10 g, 70 mmol). The reaction mixture was stirred at room temperature for 3 hours. The crude product was diluted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate. Solvent was evaporated under reduced pressure. The crude solid product was washed with hexane to afford the desired methyl 3-(4-bromophenyl)-4-(4-methoxybenzyloxy)-1-methyl-1H-pyrazole-5-carboxylate T-12 (7 g, 16 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12](SC)[NH:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)(=[O:10])=[O:9].Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=[N:25][OH:26])(=[O:10])=[O:9]
Reactant: NO
Reactant: CSC(=NS(=O)(=O)c1ccccc1Cl)Nc1nc(C)cc(C)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NC(=NO)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of 0.5 g of methyl N'-(2-chlorophenylsulfonyl)-N-(4,6-dimethylpyrimdin-2-yl)carbamimidothioate in 10 ml of tetrahydrofuran was added 0.3 g of hydroxylamine hydrochloride and 0.3 g of sodium acetate. The mixture was stirred at room temperature for 2 hours, whereupon the product was precipitated with ice-water, filtered, washed with water, and dried by suction to afford 0.3 g of the title compound, m.p. 165°-167°. NMR(CDCl3 /DMSO-d6) δ2.6 (s, 6), 6.8 (s, 1), 7.4 (m, 3), 8.2 (m, 1), 10.2 (br, 1), 12.0 (br, 1). m/e: 355 (M+).
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([S:14]([N:17]([CH2:19][CH2:20]I)[CH3:18])(=[O:16])=[O:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].C(C(C(C(S(N(CCO)C)(=O)=O)(F)F)(F)F)(F)F)(F)(F)F.S(Cl)([Cl:45])=O>C(Cl)Cl>[C:1]([C:5]([C:8]([C:11]([S:14]([N:17]([CH2:19][CH2:20][Cl:45])[CH3:18])(=[O:16])=[O:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: CN(CCI)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(Cl)Cl
Agent: CN(CCO)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCl)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
CF3(CF2)3SO2N(Me)CH2CH2I was made as follows: CF3(CF2)3SO2N(Me)CH2CH2OH was reacted with an excess of thionyl chloride in methylene chloride at 25-45° C. to give CF3(CF2)3SO2N(Me)CH2CH2Cl, which (7.1 g) was mixed with a solution of 6.0 g NaI in acetone. The resulting solution was stirred at reflux, and the conversion to CF3(CF2)3SO2N(Me)CH2CH2I was followed by GC. At 24 hours, conversion was 14 percent, and 6.0 g more NaI was added; at 3 days, conversion was 46 percent; at 6 days, conversion was 72 percent, and 6.0 g NaI was added; at 13 days, 96 percent conversion was achieved. The resulting product was precipitated with water and recrystallized from hexane to provide 6.2 g white plates with a m.p. of 80-82° C. FO2S(CF2)2O(CF2)2I was obtained from Sigma-Aldrich Chemical Company, St. Louis, Mo. C3F6O(isoC3F3O)5CF(CF3) can be prepared essentially as described by Chen et. al. in J Fluorine Chem. 65, 59 (1993). I(CF2)4I was obtained from Sigma-Aldrich Chemical Company, St. Louis, Mo. CF3(CF2)7Br was obtained from 3M Company, St. Paul, Minn., and is available from Sigma-Aldrich Chemical Company, St. Louis, Mo. Sodium acetate was obtained from Sigma-Aldrich Chemical Company, St. Louis, Mo. Dimethylsulfoxide (DMSO) was obtained from Alfa Aesar, Ward Hill, Mass. Tetrahydrofuran (THF) was obtained from EMD Chemicals, Inc., Gibbstown, N.J. p-Toluenesulfonic acid was obtained from J. T. Baker, Phillipsburg, N.J. NaHCO3 was obtained from EMD Chemicals, Inc., Gibbstown, N.J.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[N:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1>>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:16][C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1ccncc1
Product: Cc1ccc(C=Cc2ccncc2)cc1

Procedure:
By the procedure described in Ex. 1, 4-tolualdehyde (12.6 g) and 4-picoline (9.3 g) were reacted to obtain 4-(4-methylstyryl) pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][C@H:13]3[CH2:15][C@H:16]([N:18]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:17][C@H:12]3[CH2:11][O:10]2)=[CH:5][CH:4]=1.NN>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:14][C@H:13]3[CH2:15][C@H:16]([NH2:18])[CH2:17][C@H:12]3[CH2:11][O:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](N4C(=O)c5ccccc5C4=O)C[C@@H]3O2)cc1
Agent: NN
Solvent: CCO
Product: COc1ccc(C2OC[C@@H]3C[C@@H](N)C[C@@H]3O2)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-1H-isoindole-1,3(2H)-dione (390. mg, 1.03 mmol), EtOH (11.3 mL) and hydrazine (0.0362 mL, 1.13 mmol) was stirred at 90° C. for 18 h. The resulting mixture was purified via silica gel chromatography eluting with a gradient of 10 to 50% MeOH in DCM. LC/MS: Rt=1.08 min, ES− 250. (AA standard).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][NH:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1[C:24]([O:26]CC)=O>C(Cl)Cl.CO>[NH:14]1[CH:15]=[CH:16][N:12]=[C:13]1[CH2:17][N:18]1[C:19]2[CH:23]=[CH:22][NH:21][C:20]=2[C:24](=[O:26])[NH:9][C:10]1=[S:11]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1[nH]ccc1NCc1ncc[nH]1
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2ncc[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Benzoyl isothiocyanate (0.19 mL, 1.41 mmol) was added to a stirred solution of ethyl 3-[(1H-imidazol-2-ylmethyl)amino]-1H-pyrrole-2-carboxylate (0.3 g, 1.28 mmol) in CH2Cl2 (4 mL) and methanol (2 mL) and the mixture was stirred at r.t. for 1 h. The solvent was evaporated in vacuo and the residue was dissolved in ammonia (7N in methanol, 7 mL) and heated at 80° C. for 1 h. The crude product was filtrated and purified by preparative HPLC, obtaining 0.110 g, (35%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]4[CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-(tetrahydro-2-furanylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44-1.67 (m, 1 H), 1.80-1.89 (m, 3 H), 2.90 (s, 3 H), 3.19-3.29 (m, 2 H), 3.34-3.41 (m, 1 H), 3.53-3.61 (m, 1 H), 3.64-3.71 (m, 1 H), 3.77-3.87 (m, 1 H), 3.97-4.08 (m, 1 H), 4.14 (s, 2 H), 4.35 (t, J=6.18 Hz, 2 H), 7.10-7.18 (m, 2 H), 7.26 (t, J=5.76 Hz, 1 H), 7.40 (dd, J=8.14, 5.48 Hz, 2 H), 8.11 (s, 1 H), 8.55 (s, 1 H), 10.39 (t, J=5.97 Hz, 1 H), 17.10 (s, 1 H); ES+ MS: 519 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:16][CH3:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:6]([O:8]C)=O.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH2:22][C:6]([C:5]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:8])[CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Product: COc1cc(C(O)(Cc2cccc(F)c2)Cc2cccc(F)c2)cc(OC)c1C(C)C
Yield: 70 %

Procedure:
This material was prepared in 70% yield from the methyl 3,5-dimethoxy-4-i-propylbenzoate and 3-fluorobenzyl bromide using the same method as described in example 1(b). 1HNMR (CDCl3, ppm): δ 1.29 (d, J=7.1 Hz, 6H), 1.85 (s, 1H), 3.07 (d, J=13.3 Hz, 2H), 3.29 (d, J=13.3 Hz, 2H), 3.56 (qint, J=7.1 Hz, 1H), 3.72 (s, 6H), 6.42 (s, 2H), 6.7-7.2 (m, 8H).