Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:5]2[CH:18]=[CH:19][N:20]=[C:4]2[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:5]2[CH:18]=[CH:19][N:20]=[C:4]2[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc([N+](=O)[O-])cc2)n2ccnc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)n2ccnc12
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A mixture of methyl [7-chloro-5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (0.383 g, 1.06 mmol) and SnCl2.2H2O (1.44 g, 6.37 mmol) in EtOH (5 mL) was heated at refluxing temperature for 1 hour. After cooling to room temperature, the reaction mixture was poured into sat. NaHCO3 aq. and EtOAc and the resulting white suspension was filtered through a pad of Celite. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give methyl [7-chloro-5-(4-aminobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (0.322 g, 92%).
Reaction SMILES: [C:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14](C)[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:28]1([S:34]([N:37]2[CH:41]=[C:40](I)[C:39]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[N:38]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C>[C:1]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:19][CH2:20][CH3:21].[C:28]1([S:34]([N:37]2[CH:41]=[C:40]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:39]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[N:38]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c(-c2cccnc2)n1
Reactant: C#CCCCCCCC
Solvent: CCOCC
Product: CCCCCCCC#Cc1c[nH]nc1-c1cccnc1
Product: CCCCCCCC#Cc1cn(S(=O)(=O)c2ccccc2)nc1-c1cccnc1
Yield: 80 %

Procedure:
Compound 44C was prepared following the procedure as described for the synthesis of compound 44A (see Scheme 9) using non-1-yne and 3-(1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl)-pyridine (36B). (flash chromatography with diethyl ether/PE 1/1) to afford 3-(1-phenylsulfonyl-4-non-1-ynyl-1H-pyrazol-3-yl)-pyridine (43C) as an oil (80%). (TLC diethyl ether Rf 0.44).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C[O-].[Na+].CO.[C:30](OCC)(=[O:32])C>CO.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:32][CH3:30])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: CCOC(C)=O
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(C)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of 7-methyl-5-bromo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol), 30% sodium methoxide-methanol (0.5 mL), and CuBr (0.005 g, 0.04 mmol) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-methyl-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.035 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.80 (s, 3H), 3.91 (s, 3H), 4.26 (s, 2H), 4.83 (s, 2H), 6.82 (d, 2H), 7.26 (d, 2H), 7.42 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.O=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH2:24][CH2:25][CH3:26])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: Cc1ccccc1C=O
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2C)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Br:34]>CC#N>[Br-:23].[Br:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: BrCCCOc1ccccc1Br
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccccc3Br)(CC1)CC2
Product: [Br-]
Yield: 74.3 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0472 g, 0.161 mmol) and 2-bromophenyl 3-bromopropyl ether (0.0648 g, 0.220 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0703 g, 74.8%). EI-MS m/z 507(M+) Rt (2.18 min).
Reaction SMILES: [CH:1](=[C:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[C:20]([NH2:25])[N:19]=1>C(O)(=O)C>[NH2:17][C:18]1[N:19]=[C:20]([NH2:25])[C:21]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH3:16])[NH:24][C:22]=2[N:23]=1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(C)=O
Reactant: Nc1cc(N)nc(N)n1
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)Nc2nc(N)nc(N)c2C1c1ccccc1
Temperature: 25 °C

Procedure:
2.2 g (10 mmol) of ethyl 2-benzylideneacetoacetate were heated under reflux for 10 hours together with 1.3 g (10 mmol) of 2,4,6-triaminopyrimidine in 25 ml of glacial acetic acid. The reaction mixture was then cooled to room temperature, and the precipitated product was filtered off with suction and recrystallized as the acetate from acetonitrile.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH2:13])=[C:11]([CH3:17])[CH:10]=1)([F:8])[C:4]([F:7])([F:6])[F:5].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH2:26]>ClCCl>[F:1][C:2]([F:18])([F:19])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH:13][C:4]([C:3]2[CH:2]=[C:24]3[C:25](=[CH:10][CH:9]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)=[O:26])=[C:11]([CH3:17])[CH:10]=1)([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: c1ccncc1
Reactant: O
Solvent: ClCCl
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
Quinoline-6-carboxylic acid (1.0 g) was dissolved in dichloromethane. N,N-dimethylformamide (300 μL) and oxalyl chloride (1.2 g) were added to this solution at room temperature and stirred for two hours followed by reflux for 20 minutes. The solvent was removed under the reduced pressure, and quinoline-6-carbonyl chloride was obtained as a crude product, which was then dissolved in dichloromethane. To this solution, 4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylaniline (1.6 g) dissolved in dichloromethane and pyridine (1.2 g) were added and stirred at room temperature for 5 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylphenyl]quinoline-6-carboxamide (2.0 g, yield 78%).
Reaction SMILES: BrC1N=C(N(CC2C=C(OCC)C=C(OC(C)C)C=2F)C2C=CC(C#N)=CC=2)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.[Br:50][C:51]1[N:52]=[CH:53][N:54]([C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:55]=1.[Si:75]([O:82][C:83]1[C:84]([F:101])=[C:85]([CH:96]=[C:97]([CH2:99][CH3:100])[CH:98]=1)/[CH:86]=[N:87]/[C:88]1[CH:95]=[CH:94][C:91]([C:92]#[N:93])=[CH:90][CH:89]=1)([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76]>>[Br:50][C:51]1[N:52]=[C:53]([N:87]([CH2:86][C:85]2[CH:96]=[C:97]([CH2:99][CH3:100])[CH:98]=[C:83]([O:82][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76])[C:84]=2[F:101])[C:88]2[CH:89]=[CH:90][C:91]([C:92]#[N:93])=[CH:94][CH:95]=2)[N:54]([C:56]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:55]=1
Reactant: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCc1cc(/C=N/c2ccc(C#N)cc2)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCOc1cc(CN(c2ccc(C#N)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Product: CCc1cc(CN(c2ccc(C#N)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Yield: 65.6 %

Procedure:
According to the procedure for the preparation of Intermediate 28.1, reaction of 4-bromo-1-triphenylmethyl-imidazole (100 mg) with Intermediate 188.4 (102 mg) afforded 130 mg of Intermediate 188.5.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([NH:18][CH:19]1[CH2:20][CH2:21][C:22](=[O:25])[CH2:23][CH2:24]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
To a stirred solution of oxalyl chloride (0.83 g) in dry dichloromethane (15 mL) at -60° C. was added dimethylsulfoxide (1.0 mL) in dichloromethane (3 mL) dropwise. The reaction mixture was stirred at -60° C. for 10 min, then N-tert-butyloxycarbonyl-trans-4-aminocyclohexanol (1.28 g) in dichloromethane (70 mL) was added over 15 min. The resulting mixture was stirred at -60° C. for a further 15 min, then triethylamine (4.2 mL) was added and the solution was allowed to warm to room temperature. The mixture was washed with water (20 mL) and this aqueous layer was extracted once with dichloromethane (20 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Drying under vacuum gave N-tert-butyloxycarbonyl-4-aminocyclohexanone (1.25 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[N:12]=CN(C)C)=[O:4].[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>O>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[CH3:1][N:2]([CH3:17])[C:3](=[O:4])[OH:5].[NH2:12][C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[OH:5]
Reactant: CN(C)C=Nc1ccncc1OC(=O)N(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)O
Product: Nc1ccncc1O

Procedure:
A mixture prepared from 4-[[(dimethylamino)methylene]amino]-3-pyridinol N,N-dimethylcarbamate (7.4 g), trifluoroacetic acid (30 mL) and water (15 mL) was refluxed for a half hour. The reaction mixture was concentrated, filtered over a pad of basic alumina (CH2Cl2, 30% ethyl acetate/CH2Cl2, ethyl acetate), recrystallized from methanol/diethyl ether, and dried under high vacuum and refluxing ethanol to yield 4.97 g of microcrystals, m.p. 159°-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=2)=[N:3][CH:4]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=2)=[CH:4][N:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc(Br)cn2)c1
Product: COc1cccc(-c2ccc(Br)nc2)c1
Yield: 43 %

Procedure:
In a schlenck tube, a mixture of 2,5-dibromopyridine (2.11 mmol, 0.500 g), 3-methoxyphenylboronic acid (2.11 mmol, 0.321 g), PdCl2dppf.DCM (0.21 mmol, 0.172 g), Cs2CO3 (6.33 mmol, 2.063 g) in a dioxane/water 4:1 mixture (14.5 ml) was heated at 100° C. for 14 hours, under argon atmosphere. The solvent was evaporated and the crude mixture was extracted between water and ethyl acetate. The solid residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 5-bromo-2-(3-methoxyphenyl)pyridine (0.242 g, yield 43%) as major product and 2-bromo-5-(3-methoxyphenyl)pyridine (0.039 g) as minor product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(O[C:14]([S-])=[S:15])C.[K+].Cl>N1C=CC=CC=1>[S:15]=[C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10]1
Reactant: CCOC(=S)[S-]
Reactant: N#Cc1ccc(O)c(N)c1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc2oc(=S)[nH]c2c1
Temperature: 0 °C
Yield: 46 %

Procedure:
A mixture of 3-amino-4-hydroxybenzonitrile (50 mg, 0.37 mmol) and potassium O-ethyl-xanthate (65 mg, 0.41 mmol) in pyridine (0.75 mL) was heated at reflux for 2 h. After cooling, the mixture was poured into ice-water. Then concentrated hydrochloric acid (0.2 mL) was added. The solid was collected, washed with water and dried to give 2-thioxo-2,3-dihydrobenzooxazole-5-carbonitrile 30 mg (46%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[S:8]([O-:11])([O-:10])=[O:9].[Na+].[Na+].[OH2:14]>>[S:8]([CH:2]([CH2:3][C:4]([OH:14])=[O:5])[C:1]([OH:6])=[O:7])([OH:11])(=[O:10])=[O:9]
Reactant: O=S([O-])[O-]
Reactant: O=C1C=CC(=O)O1
Reactant: O
Agent: [Na+]
Product: O=C(O)CC(C(=O)O)S(=O)(=O)O
Reaction time: 1 h

Procedure:
As described for compound G/d, 50 parts of fatty acid-β-naphtholbenzyl oxethylation product (b) are reacted with 9.5 parts of maleic anhydride and a solution of 12.8 parts of anhydrous sodium sulfite in 109 parts of water. When the reaction mixture has become clear, it is stirred for 1 hour.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([OH:24])=C[C:20](=[O:25])[NH:19][C:18]=3[S:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:26]N1C(=O)CCC1=O.I[Si](C)(C)C.[CH2:39]([Cl:41])Cl>>[Cl:26][C:16]1[S:17][C:18]2[NH:19][C:20](=[O:25])[C:39]([Cl:41])=[C:22]([OH:24])[C:23]=2[C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: O=c1cc(O)c2c(-c3ccc(OCc4ccccc4)cc3)csc2[nH]1
Reactant: ClCCl
Reactant: O=C1CCC(=O)N1Cl
Agent: C[Si](C)(C)I
Product: O=c1[nH]c2sc(Cl)c(-c3ccc(O)cc3)c2c(O)c1Cl
Reaction time: 18 h
Yield: 34 %

Procedure:
To a suspension of 50 mg (0.14 mmol) of 3-(4-benzyloxy-phenyl)-4-hydroxy-7H-thieno[2,3-b]pyridin-6-one from Example 7D in 2 mL of CH2Cl2 was added 38 mg (0.28 mmol) of N-chlorosuccinimide. The suspension became a homogeneous solution, and was stirred open to the air while the solvent was allowed to evaporate to dryness over two days. The residue was redissolved in 2 mL of CH2Cl2, and 100 μL (0.72 mmol) of iodotrimethylsilane was added. After 18 h, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (5 mL) and extracted with 5% NaHSO3(aq.) (1×2 mL) to discharge the 12 color, then with brine (1×2 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via reverse phase HPLC (0 to 70% CH3CN/0.1% aq. TFA gradient) to give 16 mg (34%) of a solid as the titled compound. MS (ESI) m/e 327.8, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 6.79 (m, 2H) 7.15 (m, 2H) 9.54 (s, 1H) 10.84 (s, 1H) 12.40 (bs, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].[S:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[N:24]=[CH:23]1>CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:27]([C:25]3[N:24]=[CH:23][S:22][CH:26]=3)=[O:28])[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: O=C(O)c1cscn1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)c2cscn2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 42.2 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol) and 4-thiazolecarboxylic acid (39 mg, 0.30 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (138a) to obtain 51.6 mg of the title compound as a colorless solid (42%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([C:18]#[N:19])(C)C.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CC#N>[N:1]1([C:7]2[C:8]([C:18]#[N:19])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1cccc(N2CCCCC2)c1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1N1CCCCC1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A mixture of 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl 1′-oxide (1.30 g, 7.30 mmol), trimethylsilyl cyanide (1.45 g, 14.6 mmol) and triethyl amine (1.47 g, 14.6 mmol) in dry CH3CN (25 mL) was heated at reflux for 16 h, yielding a red solution. The reaction mixture was then cooled to room temperature, and saturated aqueous NaHCO3 (20 mL) was added. After concentrated under reduced pressure the mixture was extracted with CH2Cl2 (4×30 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2) to afford 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonitrile as a pale yellow solid (1.26 g, 92%). 1H NMR (CDCl3) δ 1.58-1.66 (m, 2H), 1.75-1.83 (m, 4H), 3.21 (t, 4H, J=5.7 Hz), 7.34-7.38 (m, 2H), 8.19-8.22 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[CH2:21][OH:22])=[CH:17][CH:18]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[C:6]([C:10]([O:22][CH2:21][CH:20]=[CH:19][C:16]3[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=3)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: OC/C=C/c1ccccc1
Reactant: O=C(Cl)c1cccc2nnsc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC=Cc1ccccc1)c1cccc2nnsc12
Temperature: 0 °C

Procedure:
3 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in 25 ml of dichloromethane are added dropwise at 15° C., with cooling and stirring, to a solution of 2.3 g of cinnamic alcohol, 3.5 g of triethylamine and a spatula tip of 4-dimethylaminopyridine in 13 ml of dichloromethane, the mixture is stirred for 16 hours at room temperature, ice-water is added, and the aqueous phase is extracted with dichloromethane. The extracts are washed with water, dried over Na2SO4 and concentrated by evaporation. The solid residue is triturated with a small amount of diethyl ether, yielding the title compound with a melting point of 70°-72° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[Cl:38])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[Cl:38][C:32]1[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=1[N:30]1[C:18](=[O:19])[C:11]2[C@H:12]3[C:15]([CH3:17])([CH3:16])[C@:9]([CH3:8])([CH2:14][CH2:13]3)[C:10]=2[N:29]1[CH3:27]
Reactant: CN(Nc1cc(Cl)ccc1Cl)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1cc(Cl)ccc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.6 %

Procedure:
Triethylamine (440 μL, 3.2 mmol) was added to solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 329 mg, 1.5 mmol) in 1,2-dichloroethane (4 mL) over 1 min. Then a solution of N′-(2,5-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (300 mg, 1.03 mmol) in 1,2-dichloroethane (8 mL) was added over 2 min. The reaction mixture was stirred at room temperature for 15 min and then heated in an oil bath at 50° C. for 30 min. An additional portion of N′-(2,5-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (290 mg, 1.0 mmol) in 1,2-dichloroethane (4 mL) was added and the mixture was heated in an oil bath at 50° C. for 1.5 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 1 h. The reaction mixture was allowed to cool, silica gel was added, the solvent was evaporated and the mixture was purified using an ISCO 40 g column, eluting with 60-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated successively with methanol and diethyl ether, and then dried under high vacuum at 95° C. to give (4R,7S)-2-(2,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (24 mg, 37%) as a pale yellow solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].O=[C:9]([CH2:21][CH2:22][CH3:23])[CH:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>C(O)(=O)C>[O:6]=[C:5]1[C:7](=[C:9]([CH2:21][CH2:22][CH3:23])[CH:10]=[CH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[S:1][C:2](=[S:3])[NH:4]1
Reactant: CCCC(=O)C=Cc1ccc(C(=O)O)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCC(C=Cc1ccc(C(=O)O)cc1)=C1SC(=S)NC1=O

Procedure:
A mixture of 0.73 g (0.0055 mol) of rhodanine, 1.09 g (0.005mol) of 4-(3-oxo-hexen-1-yl)benzoic acid, 0.39 g (0.005 mol) of ammonium acetate and 10 ml of toluene was heated under reflux for 5 hours. After cooling, acetic acid was added to the reaction mixture and the precipitate was recovered by filtration. The precipitate was recrystallized from chloroform-methanol to give 0.10 g of the isomer A of the desired 4-[3-(4-oxo-2- thioxo-5-thiazolidinylidene)-1-hexen-1-yl]benzoic acid. To the filtrate was added water and the resulting mixture was extracted with chloroform (100 ml×3). The chloroform layer was washed three times with water and then once with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, chlorform : methanol=10:1) to give 0.10 g of the isomer B of the desired product.