Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:21])[N:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])[C:8](=[O:20])[CH:7]=[CH:6]2.[C:22]([N:26]1[CH2:31][CH:30]=[C:29]([Sn](C)(C)C)[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([N:26]1[CH2:27][CH:28]=[C:29]([C:2]2[CH:3]=[C:4]([Cl:21])[N:5]3[C:10]([CH:11]=2)=[C:9]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[C:8](=[O:20])[CH:7]=[CH:6]3)[CH2:30][CH2:31]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N1CC=C([Sn](C)(C)C)CC1
Reactant: O=c1ccn2c(Cl)cc(Br)cc2c1-c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: CC(C)(C)N1CC=C(c2cc(Cl)n3ccc(=O)c(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
To a solution of 8-bromo-6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (Example 17, 132 mg) in THF was added 1-t-butyl-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine (process route disclosed in U.S. Pat. No. 6,809,199, 90 mg.), dichlorobis(triphenylphosphine) palladium (21 mg) and heated to reflux for 12 h. The mixture was concentrated and purified by silica gel (methylene chloride/acetone=1/2) to give title compound (57 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCNC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCC(O)C1
Yield: 24 %

Procedure:
The intermediate 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A and pyrrolidin-3-ol were reacted as described in Example 80 to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (59 mg, 24%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.65-7.50 (m, 2H), 7.35-7.05 (m, 4H), 6.50 (s, 1H), 5.05 (s, 1H), 4.45-4.25 (m, 3H), 4.15-3.85 (m, 6H), 3.75-3.65 (d, 1H), 3.45 (M, 2H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 579 (M+H)+.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>O>[N+:15]([C:12]1[CH:13]=[CH:14][C:7]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:17])=[O:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a dimethylformamide solution (30 ml) containing 2-chloro-5-nitrobenzonitrile (10 g) and phenol (5.7 g) was added sodium hydride (60% content, 2.63 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give 5-nitro-2-phenoxybenzonitrile (10.8 g), melting point: 126° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([S:22][CH3:23])=[N:20]3)=[CH:15][CH:14]=2)=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>CN(C)C=O>[CH3:23][S:22]([C:19]1[N:18]=[CH:17][C:16]2=[CH:15][CH:14]=[C:13]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=3[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[N:21]2[N:20]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(-c3ccc(C)cc3NS(C)(=O)=O)n2n1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a RB flask, N-[5-Methyl-2-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (580 mg, 1.7 mmol) and N,N-Dimethylformamide (13 mL,) were added. Resulting solution was cooled to 0° C., m-CPBA (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 431 mg, 1.75 mmol) was added in portion over 10 minutes. After 2 h, solvent was removed .The residue was partitioned with DCM and sat. NaHCO3 solution. The organic phase was separated, washed with brine, and dried over Magnesium sulfate. N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-methanesulfonamide was obtained as a yellow solid (539 mg, 89%) which was taken to the next step without further purifications. LCMS (E/I+) 365 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13].O>CS(C)=O>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:13]
Reactant: CCOC(CBr)OCC
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(Cn1ccc2ccccc21)OCC
Reaction time: 1 h

Procedure:
To a solution of 12 g of indole in 100 ml of dimethyl sulfoxide was added 6.5 g of sodium hydride at room temperature. The mixture was stirred at the same temperature for 1 hour, and 20 ml of bromoacetaldehyde diethyl acetal was added thereto, followed by further stirring at 50° C. for 1 hour. After cooling, the reaction mixture was poured into water, and the product was extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 23 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CCOCC>[CH3:24][S:25]([O:12][CH2:11][CH2:10][CH2:9][C@@H:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC[C@@H](CCCO)OC1CCCCO1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC[C@@H](CCCOS(C)(=O)=O)OC1CCCCO1
Reaction time: 4 h

Procedure:
A mixture of (4S)-4-(2-tetrahydropyranyloxy)-1-nonanol (29.2 g., 0.12 mole) and pyridine (20 ml.) is cooled to 5° by means of an ice bath. Methanesulfonyl chloride (17.2 g., 0.15 mole) is added dropwise during 20 minutes and the mixture is stirred 4 hours with ice bath cooling. The mixture is then taken up in ether, washed with 4 portions of water and with brine and dried over sodium sulfate. The ether is distilled on the rotary evaporator to leave as a residual oil crude (4S)-1-methylsulfonyloxy-4-(2-tetrahydropyranyloxy)-nonane.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[I:19]Cl.O>C(O)(=O)C>[I:19][C:10]1[C:11]([NH2:13])=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:8][CH:9]=1
Reactant: ClI
Reactant: Nc1ccnc(N2CCOCC2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(N2CCOCC2)ncc1I
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 17.8 %

Procedure:
To a stirred solution of 92.8 g (311 mmol, 60 wt % purity) 2-morpholin-4-yl-pyridin-4-ylamine in 1000 ml glacial acetic acid was added 76.5 g (932 mmol) sodium acetate and the mixture was then cooled to 15° C. in an ice-bath. A solution of 50.4 g (311 mmol) iodine monochloride in 200 ml glacial acetic acid was then added dropwise at a rate such that the reaction temperature remained at 10-15° C. After 40 min the addition was complete. The reaction mixture was then stirred for a further 20 min before being poured onto 1000 ml water. The mixture was concentrated in vacuo and the residue partitioned between THF/ethyl acetate (1:1) and saturated brine. 5 N aqueous sodium hydroxide solution was added until the aqueous phase was pH 14, whereupon some product precipitated. The crystals were collected by filtration to afford 16.9 g (18%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. The mother liquid phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether and the resulting crystals collected by filtration to afford a further 47.2 g (50%) of 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. The mother liquor was concentrated in vacuo and the residue was purified by flash chromatography (1/1-1/2 heptane/ethyl acetate) to afford a further 9.4 g (10%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. Meanwhile, the aqueous phase from the initial aqueous extraction was left to stand for 2 days whereupon crystals deposited. These crystals were collected by filtration to afford a further 5.2 g (5%) 5-iodo-2-morpholin-4-yl-pyridin-4-ylamine as a yellow crystalline solid. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([OH:18])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([OH:18])=[C:15]([N+:20]([O-:22])=[O:21])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)nc2sc(SCc3ccccc3)nn12
Solvent: CC(=O)O
Solvent: O
Product: O=c1c([N+](=O)[O-])c(O)nc2sc(SCc3ccccc3)nn12
Temperature: 40 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
Twenty-four (24) grams of 2-benzylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was suspended in 250 ml of acetic acid and warmed to 40° C. To this suspension, 7.9 g of fuming nitric acid was added dropwise. After the addition of the nitric acid was finished, the reaction mixture was stirred at 40° C. for 5 hours. After the reaction was finished, the reaction mixture was cooled, and water was added thereto. The deposited crystals were collected by filtration, washed with water and dried under reduced pressure. Thus 24 g of 2-benzylthio-7-hydroxy-6-nitro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 87%.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Product: CCc1cc(-c2cccc(CN3CCCC3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with pyrrolidine as described in Method A, Example 123 to give the title compound. MS: m/e=298 (M+H). 1H NMR (CDCl3, δ ppm): 7.89 (t, 1H, J=7.8 Hz); 7.77 (s, 1H); 7.61 (d, 1H, J=7.8 Hz); 7.41 (d, 1H, J=7.8 Hz); 4.43 (s, 2H); 3.80 (m, 2H); 3.07 (m, 2H); 2.66 (q, 2H, J=7.4 Hz); 2.55 (s, 3H); 2.13 (m, 4H); 1.25 (t, 3H, J=7.4 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]3[N:39]=[CH:40][N:41]=[C:15]23)[CH2:10][CH2:9]1)C1C=CC=CC=1.O1CCCC1>[C].[Pd].C(O)C>[O:20]=[C:19]1[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]2[N:39]=[CH:40][N:41]=[C:15]2[N:14]1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(Cc3ccccc3)CC2)c2ncnn12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-{[4-(1-benzylpiperidin-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (4.82 g), 10% palladium-carbon (containing water by 50%, 2.39 g), tetrahydrofuran (30 mL) and ethanol (60 mL) was stirred at room temperature for 2 days under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was purified by basic silica gel chromatography [eluent: methanol/ethyl acetate=0/100→5/95 (volume ratio)] to give the title compound as a colorless amorphous compound (2.97 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([C:26](=[O:27])[C:25]3[C:24]([F:23])=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2ccc(Cl)c(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3,4-Dichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3,4-dichlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:18]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:28])[CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[Cl:29][C:30]1[C:31]([F:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:12]([Si:9]([CH3:11])([CH3:10])[O:8][CH2:7][CH2:6][C:5]([CH3:17])([CH3:16])[CH2:4][CH:3]1[CH2:2][NH:1][CH:33]([C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([Cl:29])[C:31]=2[F:38])[C:18]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC(CN)C1C(=O)Nc2cc(Cl)ccc21
Reactant: O=Cc1cccc(Cl)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 130 °C
Yield: 6.1 %

Procedure:
To a solution of racemic 3-[1-aminomethyl-5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one (1.5 g, 3.5 mmol) in toluene (30 mL) was added 3-chloro-2-fluoro-benzaldehyde (Oakwood) (0.56 g, 3.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (67 mg, 0.35 mmol). The reaction mixture was heated at 130° C. for 2 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and aqueous NaHCO3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give rac-(2′S,3′S,4′S)-4′-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (0.12 g, 6%)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:5]2[NH:6][C:7]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.Cl>C(O)(=O)C>[NH2:18][C:16]1[C:5]2[NH:6][C:7]([NH:12][CH:13]([CH3:14])[CH3:15])=[N:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=[C:2]([Cl:1])[CH:17]=1
Reactant: CC(C)NC1=NS(=O)(=O)c2cc(Cl)cc([N+](=O)[O-])c2N1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)NC1=NS(=O)(=O)c2cc(Cl)cc(N)c2N1
Reaction time: 12 h
Yield: 49.5 %

Procedure:
To a stirred suspension of 7-chloro-3-isopropylamino-5-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide (200 mg; 0.63 mmol) and zink (200 mg; 3.06 mmol) in acetic acid (20 ml) was added 36% hydrochloric acid (0.3 ml). The mixture was stirred for 12 hr. After filtration and concentation in vacuo the crude product was purified by column chromatography eluting with ethyl acetate:ethanol (9:1). Concentration of the appropriate fractions produced 90 mg of the title compound; m.p. >230° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN
Reactant: Cc1ncccc1OCCCCl
Solvent: CO
Product: CNCCCOc1cccnc1C
Temperature: 100 °C
Yield: 61 %

Procedure:
The 3-chloro-1-(2-methyl(3-pyridyloxy))propane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and the mixture was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated to give 1.19 g (61.0%) of an oil.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C-:17]#[N:18].[Na+]>C(OCC)C.O.Cl>[C:17]([CH:2]([OH:1])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)#[N:18]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CC(O)C#N)CC1
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (60 g) in diethylether (150 mL) were added a solution of sodium cyanide (32.4 g) in water (100 mL) and concentrated hydrochloric acid (55 mL) by small portions at 0° C. The reaction system was stirred for 4 hr, and the organic layer was washed with brine, dried, and concentrated to give the title compound (67.0 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:10]2)=[CH:5][CH:4]=1.C(Br)C.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[CH2:25]([O:24][P:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:10]2)=[CH:5][CH:4]=1)([O:27][CH2:28][CH3:29])=[O:30])[CH3:26]
Reactant: CCOC(=O)c1nn(-c2ccc(CBr)cc2)nc1C
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Product: CCOC(=O)c1nn(-c2ccc(CP(=O)(OCC)OCC)cc2)nc1C
Reaction time: 3 h

Procedure:
155.6 g of 2-(p-bromomethyl-phenyl)-4-methyl-5-carboethoxy-2H-1,2,3-triazole in 430 ml of triethyl phosphite are heated to 150° C. in the course of 21/2 hours and the mixture is kept at this temperature for 3 hours, with stirring, ethyl bromide distilling off. The reaction mixture is evaporated under a waterpump vacuum. The residual dark viscous oil is dissolved in 300 ml of methylene chloride and, after the addition of bleaching earth, the solution is filtered to give a clear filtrate and 300 ml of hexane are added to the filtrate. The resulting mixture is then concentrated to 200 ml and cooled to 0° to 5° C. and the product which has crystallised out is filtered off with suction and dried in vacuo. This gives 56.6 g of 2-(p-diethylphosphonomethyl-phenyl)-4-methyl-5-carboethoxy-2H-1,2,3-triazole of the formula ##STR59##
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH2:31][CH2:32][CH3:33]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[O:28][N:29]=[C:30]([CH2:31][CH2:32][CH3:33])[N:27]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCCC(=N)NO
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Product: CCCc1noc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=469 [M+H]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:18]1[C:19](C2C=CC=CC=2)=[C:20]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=2C2C=CC=CC=2)[CH:21]=[CH:22][CH:23]=1>CN1CCCC1=O>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([S:14][C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([S:24][C:20]4[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=4)[CH:30]=3)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cccc(Sc2cccc(Cl)c2-c2ccccc2)c1-c1ccccc1
Reactant: Sc1cccc(Sc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: c1ccc(Sc2cccc(Sc3cccc(Sc4ccccc4)c3)c2)cc1
Temperature: 210 °C

Procedure:
436 g of m-phenylmercapto thiophenol and 78 g of potassium hydroxide were dissolved in 500 ml of N-methyl-2-pyrrolidone, then 376 g of m-chlorophenyl phenylsulfide was added and the resultant mixture was heated to 170° C. After removing the water content, 20 g of cuprous chloride was added and heated to 210° C. and maintained at that temperature for 10 hours while stirring. After the reaction was over, the product was treated by the method as in Example Z-1 and bis(m-phenylmercaptophenyl)sulfide was obtained as a fraction at 255° C.-265° C./5 Torr by vacuum distillation.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Br:43][C:44]1C=[CH:48][CH:47]=[CH:46][C:45]=1CBr>>[Br:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:15]=1[CH2:14][N:12]1[N:11]=[C:9]2[N:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:6]=[C:7]([N:16]3[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]3)[C:8]2=[N:13]1
Reactant: BrCc1ccccc1Br
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3Br)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-(bromomethyl)benzene and isolated as colorless gum (6.9 mg, 37%). MS (m/e): 451.3 (MH+).