Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[OH:8].[OH-].[Na+].[OH-].[K+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1.O>[CH2:13]([O:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH2:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: NC1CCCCC1OCc1ccccc1

Procedure:
0.2 mol of trans-2-aminocyclohexanol are dissolved in 600 ml of xylene isomer mixture and heated to reflux. 0.2 mol of a 50% sodium hydroxide or potassium hydroxide solution in water is added dropwise to this solution over 15 minutes. In the course of this, the water which has been introduced and which forms is distilled off immediately. After the addition has ended, the water present in the reaction solution is distilled off further until a transition temperature of 140-141° C. is attained. Thereafter, 0.2 mol of benzyl chloride is added dropwise over 30 minutes and the solution is stirred further under reflux for two hours. After aqueous workup, the desired 2-benzyloxycyclohexylamine is obtained in 62% (GC area%) yield in the case of sodium hydroxide, and in 69% (GC area%) yield in the case of potassium hydroxide.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([OH:22])[CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:24].O1CCOCC1.Cl.Cl.Cl.CC1CCN(CCN2CCC(N)CC2)CC1>>[ClH:24].[ClH:24].[ClH:24].[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([OH:22])[CH2:17]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2CCC[C@@H](O)C2)CC1
Agent: CC1CCN(CCN2CCC(N)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CCN2CCC[C@@H](O)C2)CC1

Procedure:
It is prepared by BOC-cleavage of tert-butyl ester 13 (1.7 g, 5.19 mmol) with 4M-HCl in dioxane (10.4 ml, 41.52 mmol) as described for amine 7.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[CH2:18][C:17]1=[O:25]>>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[C:18]2[C:19]3[C:24](=[N:23][CH:22]=[CH:21][CH:20]=3)[NH:16][C:17]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Reactant: O=C1Cc2cccnc2N1
Product: COc1ccc(C=C2C(=O)Nc3ncccc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 7-aza-2-oxindole to give 0.25 g of 3-(3-cyclopentyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1]CN(CC)CC.[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:26][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:28][N:29]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CI>CN(C=O)C>[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:1])[CH2:32][CH2:31]2)=[N:28][N:29]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCNCC3)o2)N1OCc1ccccc1
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.5 %

Procedure:
Et3N (631 μL, 4.5 mmol) was added to a solution of crude (2S,5R)-6-(benzyloxy)-2-(5-(piperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (997 mg) in DMF (15 mL). Then, MeI (106 μL, 1.6 mmol) was slowly added at 0° C. The mixture was stirred at rt for 6 hrs then, the mixture was concentrated and purified by reverse phase column chromatography (gradient elution, 0 to 80% of acetonitrile in water) to give (2S,5R)-6-(benzyloxy)-2-(5-(4-methylpiperazin-1-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (202 mg, 34% for two steps) as a yellow solid. ESI-MS (EI+, m/z): 399.3 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][N:4]=1.S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[NH2:2][C:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:16])=[O:10])[CH2:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: NC1=NCC(C(=O)O)CC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1CCC(N)=NC1
Temperature: 25 °C
Yield: 54 %

Procedure:
2-Amino-3,4,5,6-tetrahydropyridine-5-carboxylic acid HCl (1 g, 5.6 mmol) was suspended in anhydrous methanol (100 ml), and thionyl chloride (0.5 ml, 7 mmol) was added dropwise with stirring at room temperature. The resulting solution was refluxed overnight and then evaporated to dryness in vacuo. The resulting crude white solid was recrystallized from methanol/ether to give white crystals 589 mg (54%) mp 177-179.C, identified as product by 300 MHz nmr and ir 1733 cm-1. Calculated: C 43.64, H 6.8, N 14.55; found: C 43.63, H 6.75, N 14.56.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([OH:15])CO)[C:8]([C@@H:16]([N:18]1[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]1=[O:28])[CH3:17])=[CH:7]2.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:15])[C:8]([C@@H:16]([N:18]1[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]1=[O:28])[CH3:17])=[CH:7]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1C(O)CO)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1cc2cccc(Cl)c2nc1C=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-((S)-1-(8-chloro-2-(1,2-dihydroxyethyl)quinolin-3-yl)-ethyl)isoindoline-1,3-dione (170 mg, 0.43 mmol) in THF (4.0 mL) and water (1.0 mL) was added sodium periodate (91.6 mg, 0.43 mmol). The reaction was stirred at room temperature for 3 hours and then it was diluted with water (50 mL). The separated aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated in vacuo to give (S)-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-quinoline-2-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ ppm 10.36 (1H, s), 8.59 (1H, s), 7.89-7.91 (1H, m), 7.82-7.86 (3H, m), 7.71-7.73 (2H, m), 7.57-7.61 (1H, m), 6.67 (1H, q, J=7.0 Hz), 2.00 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH:9]([C:13]1[CH:14]=[N:15][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:18]=1)[CH2:10][CH2:11][CH3:12])[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH:9]([C:13]1[CH:14]=[N:15][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:18]=1)[CH2:10][CH2:11][CH3:12])=[CH2:6])[CH3:2]
Reactant: CCCC(c1ccc(NC(=O)C(C)(C)C)nc1)C(C(=O)O)C(=O)OCC
Agent: C=O
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: C=C(C(=O)OCC)C(CCC)c1ccc(NC(=O)C(C)(C)C)nc1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of 2-{1-[6-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-butyl}-malonic acid monoethyl ester (712 mg, 1.95 mmol) in THF (6.5 mL) at 0° C. formaldehyde (37% in water, 0.3 mL) was added within 5 min. Stirring was continued for 10 min, then piperidine (0.26 mL, 2.63 mmol) was added dropwise within 10 min. The mixture was allowed to warm up overnight to room temperature. After 14 h the mixture was concentrated under reduced pressure to one third of its volume, then ether and water were added (15 mL each). After 2 min vigorous stirring the layers were separated, the aqueous was extracted with ether and the combined organic layers were washed with water, 4% citric acid, water and brine. Drying and concentration under reduced pressure gave 2-{1-[6-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-butyl}-acrylic acid ethyl ester (550 mg, 85%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: Cc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(C)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 64.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) was obtained. melting point: 110-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[Cl-].[OH:13][NH3+:14].C([O-])(=O)C.[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:14][OH:13])[CH2:6][CH2:5]2
Reactant: [NH3+]O
Reactant: O=C1CCc2cc(Br)ccc21
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1CCc2cc(Br)ccc21
Reaction time: 8 h
Yield: 95.2 %

Procedure:
5-Bromoindan-1-one (5.0 g) was dissolved in methanol. Hydroxylammonium chloride (2.5 g) and sodium acetate (2.9 g) were added to the solution at room temperature, and then stirred overnight. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was filtered and separated, and then the solvent was evaporated off under reduced pressure to obtain 5-bromo-N-hydroxyindan-1-imine (5.1 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=S)[NH2:2].NC1C=CC([C@H](C)C(OC)=[O:26])=CC=1.[O-]C#N.[Na+]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:26])[NH2:2]
Reactant: COC(=O)[C@@H](C)c1ccc(N)cc1
Reactant: COC(=O)[C@@H](C)c1ccc(NC(N)=S)cc1
Agent: N#C[O-]
Agent: [Na+]
Product: COC(=O)[C@@H](C)c1ccc(NC(N)=O)cc1

Procedure:
Following the same procedure described for (S)-methyl 2-[4-(carbamothioylamino)phenyl]propanoate and starting from methyl (2S)-2-(4-aminophenyl)propanoate (98 mmol) and sodium cyanate (128 mmol), after workup (S)-methyl 2-[4-(carbamoylamino)phenyl]propanoate was isolated as white solid (59%). 1H-NMR (CDCl3): δ 8.90 (bs, 1H, CONH), 7.55 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.50 (bs, 2H, CONH2), 3.75 (m, 1H), 3.60 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[CH2:8](Br)[CH:9]=C.[CH3:12]COCC>>[CH2:1]([C:2]1([CH3:12])[CH2:6][CH2:5][CH2:4][C:3]1=[O:7])[CH:8]=[CH2:9]
Reactant: CC1CCCC1=O
Reactant: CCOCC
Reactant: C=CCBr
Product: C=CCC1(C)CCCC1=O

Procedure:
In a manner similar to that described above under "B", 2-methylcyclopentanone (6.6 g, 0.067 mole) and allyl bromide (9.24 g, 0.07 l mole) treated in anhydrous ether under nitrogen with sodium tert.-amylate (0.07 mole), worked up as above and purified by distillation, yield 2-allyl-2-methylcyclopentanone as a colourless oil, b.p. 69°-72° C/12 mm νCHCl3 /max 1733, 925 cm-1, nmr (CDCl3) δ 1.05 (s), 4.85-6.15 (m).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:17]([CH3:16])[CH2:22]1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(N2CCOCC2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 100 mL round-bottom flask was charged with 2-fluoro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.82 mmol, 1.00 equiv), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (0.840 g, 4.20 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.40 g (93% yield) of tert-butyl (2R)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 394 [M+H]+.
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:17][CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:16])=[CH:13][CH:12]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CCOC(O)C(F)(F)F
Product: O=C(NC(O)C(F)(F)F)c1ccc(Cl)cc1

Procedure:
Trifluoroacetaldehyde ethyl hemiacetal and 4-chlorobenzamide were processed as in Example 1A to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[CH3:16][N:17]([CH3:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:27])[C:18]1[CH:23]=[CH:22][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=2)=[CH:20][CH:19]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Product: CN(C)c1ccc(Nc2ccc3c(c2)C(C)(C)OC(=O)N3C)cc1

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-dimethylaminophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+(326).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=O)[CH2:11]Cl)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14]([SH:17])[CH2:15][SH:16].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:10]1[S:16][CH2:15][CH2:14][S:17][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: SCCS
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C1=CSCCS1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22.3 %

Procedure:
A solution of ethyl 2-methoxyimino-3-oxo-4-chlorobutyrate (41.4 g.) in dried chloroform (100 ml.) was added dropwise over 1 hour at 20° C. to a mixture of ethane-1, 2-dithiol (20.6 g.), triethylamine (21 g.) and dried chloroform (60 ml.). After stirring for 2.5 hours at 18° to 21° C., the mixture was adjusted to pH 1.0 with 10% hydrochloric acid. The chloroform layer was separated, washed with water (100 ml.×3), dried over magnesium sulfate and concentrated to dryness under reduced pressure at 40° C. The residue was dissolved in toluene (300 ml.), p-toluenesulfonic acid (3 g.) was added thereto and the resulting mixture was refluxed for 3 hours with removal of water. The reaction mixture was cooled to ambient temperature and an insoluble material was filtered off. The filtrate was concentrated under reduced pressure at 40° C. The residue was dissolved in ethyl acetate (300 ml.). The solution was in turn washed with a saturated aqueous solution of sodium bicarbonate (3 times) and water (twice), dried over magnesium sulfate and concentrated to dryness under reduced pressure at 40° C. to give yellow oil. The oil was subjected to column chromatography on silica gel (1 kg) and eluted with benzene. The eluate was concentrated under reduced pressure at 40° C. The residue was washed with diisopropyl ether and dried to give white crystals of ethyl 2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetate (syn isomer) (11 g.), mp. 65° to 67° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:13]=[C:14]([O:19][CH3:20])[C:15]([NH2:18])=[N:16][CH:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([O:19][CH3:20])[C:15]([NH:18][S:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])=[N:16][CH:17]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccc(C)s1

Procedure:
Prepared by the method of Example 1 using 5-methylthiophenesulphonyl chloride and 5-chloro-3-methoxy-2-pyrazinamine.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][C:17](=S)[C:12]=2[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:2][CH3:3].CC(C)=[O:24]>CI.O>[O:24]=[C:17]1[CH:16]=[C:15]([C:19]([OH:21])=[O:20])[O:14][C:13]2[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]3[C:10](=[CH:11][C:12]1=2)[CH2:9][CH2:8][CH2:7][CH2:6]3
Reactant: CC(C)=O
Reactant: CCCc1c2c(cc3c(=S)cc(C(=O)O)oc13)CCCC2
Solvent: O
Solvent: CI
Product: CCCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10-propyl-6,7,8,9-tetrahydro-4-thioxo-4H-naphtho[2,3-b]pyran-2-carboxylic acid (0.025 g), methyl iodide (3 drops), acetone (10 ml) and water (4 drops) was stirred in the dark at ambient temperature for 2 days. Concentration of the reaction mixture in vacuo gave a brown solid which on crystallisation from acetone gave the title compound as a light-yellow solid, mp 245°-8°.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].[CH3:38][O:39][C:40]1([CH3:54])[C:44]2[CH:45]=[CH:46][C:47](Br)=[CH:48][C:43]=2[S:42](=[O:51])(=[O:50])[C:41]1([CH3:53])[CH3:52]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:47]1[CH:46]=[CH:45][C:44]2[C:40]([O:39][CH3:38])([CH3:54])[C:41]([CH3:53])([CH3:52])[S:42](=[O:50])(=[O:51])[C:43]=2[CH:48]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC1(C)c2ccc(Br)cc2S(=O)(=O)C1(C)C
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: COC1(C)c2ccc(C#Cc3cc(Cl)ccc3OCC(=O)OC(C)(C)C)cc2S(=O)(=O)C1(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-bromo-2,2,3-trimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-3-yl methyl ether (Intermediate 250), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)(O)[CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:38][S:35]([C:32]1[CH:33]=[CH:34][C:29]([C:21]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=2)=[CH:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)=[CH:30][CH:31]=1)(=[O:36])=[O:37]
Reactant: COc1cnc2c(c1)cc(C(O)(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cnc2[nH]c(C(=CC3CCCO3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 38 %

Procedure:
A solution of 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-ethanol (184 mg, 0.33 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo and the residue was washed with methanol to afford 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-furan-2-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (50 mg, 64.1%) as a light yellow solid: LC/MS m/e calcd for C21H22N2O4S [M+H]+ 399.48, observed 399.3.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])CCC.[C:22](=[O:24])=[O:23].Cl>C(OCC)C.CCCCCC>[F:10][C:4]1[C:5]([C:22]([OH:24])=[O:23])=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1cc(F)c(-c2ccccc2)c(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1c(F)c(F)c(F)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a dry argon atmosphere, a stirred solution of 2,3,4,6-tetrafluoro-[1,1'-biphenyl] (23.0 g, 0.102 mole) in 400 ml of diethyl ether was cooled to -65°. During a 11/4 hour period 63.4 ml of a 1.6M solution of n-butyl lithium in hexane was added to the reaction mixture, which was then stirred at -65° for 23/4 hours. During a one hour period, freshly crushed dry ice (750 g) was added to the mixture. The stirred reaction mixture was then allowed to warm to room temperature. The mixture was cooled; 400 ml of 6N aqueous hydrochloric acid was added and the resultant mixture stirred vigorously for two hours. The mixture was poured into a separatory funnel, the aqueous phase separated and extracted with three 300 ml portions of diethyl ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid residue. The solid was recrystallized from toluene:n-heptane (1:1) to give 2,4,5,6 -tetrafluoro-[1,1'-biphenyl]-3-carboxylic acid (mp, 189°-190.5°).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:2]1.Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=2)[O:18][C:17](=[O:26])[CH:16]=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[O:18][C:17](=[O:26])[CH:16]=2)=[O:11])[S:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: O=c1cc(CCl)c2ccc(O)cc2o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: O=C(CCCC[C@@H]1CCSS1)OCc1cc(=O)oc2cc(O)ccc12
Temperature: 80 °C
Yield: 24.9 %

Procedure:
To a room temperature solution of (R)-(+)-1,2-dithiolane-3-pentanoic acid (2.66 g, 12.9 mmol) and 4-Chloromethyl-7-hydroxy-2H-chromen-2-one (1) (2.40 g, 11.4 mmol) in anhydrous benzene (160 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.8 mL, 25 mmol) in one portion. The reaction mixture was heated to 80° C. (oil bath temperature) for 1 h, cooled to room temperature, then quenched with aqueous 15% citric acid (200 mL). The resulting suspension was filtered, and the collected insoluble material was suspended in acetone (100 mL), sonicated for 60 s, then filtered onto a bed of silica gel (˜10 g). The suspension-sonication-filtration step was repeated a second time. Concentration of the filtrate under reduced pressure followed by flash column chromatography (1% MeOH in CH2Cl2) provided the desired product as a pale yellow powder (1.08 g, 25%).