Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CO[C:14](=[C:21]([C:24]#[N:25])[C:22]#[N:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>C(#N)C>[NH2:25][C:24]1[C:21]([C:22]#[N:23])=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:1]([CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)CBr
Reactant: COC(=C(C#N)C#N)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1c(N)c(C#N)c(-c2ccccc2)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
tert-Butyl N-(2-aminoethyl)carbamate (10.6 g) was added to a solution of (methoxyphenylmethylene)methane-1,1-dicarbonitrile (10.4 g) in acetonitrile (350 mL), and the mixture was stirred for 10 minutes. Anhydrous cesium carbonate (65.1 g) and methyl bromoacetate (13.5 mL) were added, and the mixture was heated to reflux for 1 hour. After cooling the mixture to room temperature, it was allowed to stand, the supernatant was separated by decantation, and the solvent was distilled off under reduced pressure. The concentrated residue was combined with the solid portion remaining after decantation, ethyl acetate and water were added, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 2/1) to obtain the title compound (20.6 g, yield: 95%) as a yellow transparent oil. The NMR and ESI/MS data for this compound-are shown below.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH2:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33]>>[CH2:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:14][CH:15]=3)[CH2:20]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1

Procedure:
2-(4-n-Butyl-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt3 (0.25 mL, 1.8 mmol), and 4-(n-butyl)benzenesulfonyl chloride (140 mg, 0.60 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (165 mg, 70% yld). MS(ES+)471.1(M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)C[CH2:2]1.[OH:12][CH:13]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)/[CH:14]=[CH:15]/[C@H:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[N:17]1[CH2:23][C:24]#[C:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30].IC(C)C>CC(C)=O.CCOC(C)=O>[CH:1]([O:30][C:29](=[O:31])[CH2:28][O:27][CH2:26][C:25]#[C:24][CH2:23][N:17]1[C:18](=[O:22])[CH2:19][CH2:20][CH2:21][C@@H:16]1/[CH:15]=[CH:14]/[CH:13]([OH:12])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([CH3:11])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(C)I
Product: CC(C)OC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 0.08 h
Yield: 57 %

Procedure:
DBU (10 μL, 0.067 mmol) was added to a solution of {4-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid (16.6 mg, 0.045 mmol) in acetone (0.5 mL). After 5 min, 2-iodopropane (22.5 μL, 0.225 mmol) was added. After 18 h, the reaction mixture was diluted with EtOAc (25 mL) and washed sequentially with aqueous HCl (0.1 M, 10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 10.6 mg (57%) of the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12](=[O:14])C)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:12](=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC(=O)c1ccccc1-n1cccc1
Product: COc1ccc(CNC(=O)c2ccccc2-n2cccc2)c(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 1-(2-(1H-pyrrol-1-yl)phenyl)ethanone and 2,4-dimethoxy-benzylamine. MS (M+H, 337.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH2:11].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=1)=[O:30]
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C(NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 12 h
Yield: 46.5 %

Procedure:
A solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.14 g of 4-trifluoromethoxyphenyl isocyanate dissolved in 10 ml of toluene was heated under reflux, while stirring, for 12 hours, and the reaction mixture was then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-4-(2-(N'-(4-trifluoromethoxyphenyl)ureido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (46% yield), m.p., 125.4° C.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]([OH:10])=O.[NH3:11]>[Ni].[H][H]>[O:10]=[C:8]1[NH:11][CH:2]2[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7]1
Reactant: [H][H]
Reactant: O=C(O)CC1CCCC1=O
Reactant: N
Agent: [Ni]
Product: O=C1CC2CCCC2N1

Procedure:
Heat under reflux cis-octahydrocyclopenta[b]pyrrole [prepared by the methods of A. Bertho, et al, Chem. Ber. 92, 2218 (1959), wherein 2-oxo-cyclopentyl acetic acid is cyclized by reduction with Raney Nickel/H2 in the presence of ammonia to obtain 2-keto-octahydrocyclopenta[b]pyrrole, which is then reduced with lithium aluminum hydride in etheral solution to yield ciso-octahydrocyclopenta[b]pyrrole, or by the method of A. G. Anderson, Jr., et al, J. Org. Chem. 43, 55 (1978), discussed above] and mercuric acetate in water or up to 10% aqueous acetic acid for twenty hours or more, to obtain cis-3,3a,4,5,6,6a-hexahydrocyclopenta[b]pyrrole. Dissolve this compound in water and treat with potassium cyanide followed by 2N hydrochloric acid at 0° C. for two hours and at room temperature for approximately twenty hours to obtain 2-cyano-cis-octahydrocyclopenta[b]pyrrole. Heat this resultant compound in 6N hydrochloric acid under reflux for 6 hours followed by concentration of the reaction mixture to obtain cis-octahydrocyclopenta[b]pyrrole-2-carboxylic acid. If desired, adsorb the residue on an XAD-2 resin column and elute with methanol. Esterify by reaction with ethanol to obtain ethyl cis-octahydrocyclopenta[b]pyrrole-2-carboxylate, as a mixture of two epimers.
Reaction SMILES: Cl.C([N:5]1[C:17]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][N:13]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:14]3=[O:18])=[CH:9][C:8]=2[CH:7]=[N:6]1)(=O)C.C(OCC)(=O)C>CO>[CH3:25][C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:17]3[NH:5][N:6]=[CH:7][C:8]=3[CH:9]=2)[C:14]1=[O:18]
Reactant: CC(=O)n1ncc2cc3c(cc21)C(=O)N(c1cnccc1C)CC3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccncc1N1CCc2cc3cn[nH]c3cc2C1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 11.5 %

Procedure:
6N HCl (5 mL) was added drop wise to a solution of 1-acetyl-7-(4-methylpyridin-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-g]isoquinolin-8(5H)-one (I-69h: 80 mg, 0.249 mmol) in methanol (5 ml) at 0° C. and the resulting reaction mass was stirred at room temperature for 36 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mass was concentrated under reduced pressure, basified using saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (100% ethyl acetate), followed by preparative HPLC afforded 8 mg of the product (11.5% yield).
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6](O)=O>[Mn].C1CCCCC1>[C:1]1(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCCC(=O)O
Agent: [Mn]
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
The reaction was conducted in the same manner as Example A1-1 except that the manganese compound was not used. Cyclohexane was transformed into adipic acid with a transformation rate of 56% and a yield of 10%. Incidentally, cyclohexanone and cyclohexanol were formed in yields of 36% and 4%, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[C:16]([C:18]1[CH:23]=[CH:22][C:21](OB(O)O)=[CH:20][CH:19]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(OB(O)O)cc1
Reactant: N#Cc1cc(Br)c(-c2ccco2)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cc(C#N)c(N)nc2-c2ccco2)cc1
Yield: 15.4 %

Procedure:
2-Amino-5-bromo-6-(2-furyl)nicotinonitrile (20 mg, 75.7 μmol), 4-cyanophenylboric acid (30 mg, 204 μmol), dichlorobis(acetonitrile) palladium (II) (2 mg, 7.71 μmol), and a solution of 2 M aqueous potassium carbonate (150 μL, 300 μmol) in N,N-dimethylformamide (0.6 mL) was stirred at 80° C. for 14 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate and water. After filtering off the insoluble matters, the organic layer in the filtrate was concentrated. A half of the residue was purified by HPLC on a reverse phase column and using a water-acetonitrile-trifluoroacetic acid system as the elution solvent, to give the title compound (3.33 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O>C(O)=O>[ClH:13].[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH3:21])[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Agent: C=O
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Product: Cl
Temperature: 70 °C
Yield: 175 %

Procedure:
To the 5-phenyl-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine compound from step 69b (262 mg) was added formalin (37%, 0.5 mL) and formic acid (0.25 mL), and the mixture was heated at 70° C. for 3 hours. The solvent was removed, and to the residue was added solid NaHCO3. When pH 7-8 was achieved, the mixture was extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH:NH4OH 100:10:0.04 to afford to give the free base of the title compound (200 mg). MS (CI/NH3) m/z 303 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.98 (m, 2H), 2.10 (m, 1H), 2.22 (m, 1H), 2.71 (m, 1H), 2.78 (s, 3H), 3.27 (m, 1H), 3.60 (m, 111), 4.18 (m, 1H), 4.47 (m, 1H), 7.46 (m, 5H), 8.10 (m, 1H), 8.30 (br s, 1H). The base was converted to the salt by treatment with HCl in THF to give the title compound. MS (CI/NH3) m/z 303 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.05-2.17 (m, 2H), 2.19-2.27 (m, 1H), 2.35-2.45 (m, 1H), 3.04 (s, 3H), 3.30 (m, 1H), 3.74 (m, 1H), 3.94 (m, 1H), 4.37 (dd, J=6.1, 11.2 Hz, 1H), 4.54 (dd, J=3.3, 11.2 Hz, 1H), 7.56 (m, 6H), 8.15 (d, J=3.0 Hz, 1H). Anal. Calcd for C17H19N2OCl.1.1 HCl: C, 59.55; H, 5.91; N, 8.17. Found: C, 59.74; H, 6.04; N, 8.14. [α]25D=+7.17° (c 1.11, MeOH).
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[C:3]=1Cl.[C:15](/[C:17](/[S-:22])=[C:18](\[C:20]#[N:21])/[S-:19])#[N:16].[Na+].[Na+].O>O1CCCC1>[O:12]=[C:11]1[C:2]2[S:19][C:18]([C:20]#[N:21])=[C:17]([C:15]#[N:16])[S:22][C:3]=2[C:4](=[O:13])[N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][N:6]12
Reactant: N#C/C([S-])=C(/[S-])C#N
Reactant: O=c1c(Cl)c(Cl)c(=O)n2n1CCCC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1=C(C#N)Sc2c(c(=O)n3n(c2=O)CCCC3)S1
Temperature: 40 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
An amount of 1 g (4.254 mmol) of 2,3-dichloro-6,7,8,9-tetrahydropyridazino[1,2-a]pyridazine-1,4-dione (II-1) is introduced in 20 ml of absolute tetrahydrofuran. Subsequently 0.869 g (4.254 mmol) of disodium (Z)-1,2-dicyanoethene-1,2-bis(thiolate) and 2 ml of water are added and the mixture is stirred at 40° C. for 18 hours. It is filtered with suction and extracted with methylene chloride and water, and the extract is dried and concentrated. Chromatography on silica gel (cyclohexane/ethyl acetate 0-100%) gives 0.5 g (99% purity, 38.3% of theory) of 5,12-dioxo-5,7,8,9,10,12-hexahydro[1,4]dithiino[2,3-d]pyridazino[1,2-a]pyridazine-2,3-dicarbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N+:17]([O-])=O)[C:14]([F:16])=[CH:15][C:10]=2[S:9][C:8]1=[O:20])=[O:5])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:17][C:13]1[C:14]([F:16])=[CH:15][C:10]2[S:9][C:8](=[O:20])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)Cn1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)sc2cc(F)c(N)cc21
Yield: 71.7 %

Procedure:
Electrolytic iron powder (0.29 g) was suspended in 5% acetic acid (2 ml), and a solution of 3-ethoxycarbonylmethyl-6-fluoro-5-nitro-2(3H)-benzothiazolone (0.31 g) in acetic acid (1 ml) and ethyl acetate (1 ml) was dropwise added thereto while heating. The resultant mixture was heated under reflux for 3 hours. The reaction mixture was subjected to filtration with celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 0.20 g of 5-amino-3-ethoxycarbonylmethyl-6-fluoro-2(3H)-benzothiazolone. m.p., 172.5°-173.5° C.
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:14][C:13]2[C:5](=[C:6]3[C:10](=[C:11]([CH3:16])[C:12]=2[CH3:15])[NH:9][C:8]([CH3:18])([CH3:17])[CH2:7]3)[CH2:4]1.Cl.[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2([CH3:19])[O:14][C:13]3[C:5](=[C:6]4[C:10](=[C:11]([CH3:16])[C:12]=3[CH3:15])[NH:9][C:8]([CH3:18])([CH3:17])[CH2:7]4)[CH2:4]2)[CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1
Reactant: CN(c1nc2ccccc2s1)C1CCNCC1
Reactant: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CI)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C)c2c(c3c1NC(C)(C)C3)CC(C)(CN1CCC(N(C)c3nc4ccccc4s3)CC1)O2
Temperature: 180 °C
Reaction time: 6 h
Yield: 56.2 %

Procedure:
A suspension of 1,6,7,8-tetrahydro-2-(iodomethyl)-2,4,5,7,7-pentamethyl-2H-furo[3,2-e]indole (372 mg, 1.0 mmol), N-methyl-N-(4-piperidinyl)-1,3-benzothiazole-2-amine hydrochloride (427 mg, 1.5 mmol) and potassium carbonate (485 mg, 3.5 mmol) in N,N-dimethylacetamide (2 mL) was stirred at 180° C. for 6 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane-ethyl acetate 10:1), and recrystallized from ethyl acetate-hexane to obtain 276 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8]([CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.F[C:19]1[CH:20]=[C:21]([C:26]#[C:27][CH2:28]Br)[CH:22]=[C:23](F)[CH:24]=1.[Cl-:30].[NH4+]>C1COCC1>[Cl:30][C:24]1[CH:23]=[CH:22][C:21]([C:26]#[C:27][CH2:28][C:11]2([S:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)(=[O:10])=[O:9])[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:20][CH:19]=1
Reactant: Cc1cccc(S(=O)(=O)C2SC(=O)NC2=O)n1
Reactant: [Cl-]
Reactant: Fc1cc(F)cc(C#CCBr)c1
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(S(=O)(=O)C2(CC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
N-butyl lithium (2.5M in hexanes, 2.77 mL, 6.93 mmol) was added to a solution of 5-(6-methyl-pyridine-2-sulfonyl)-thiazolidine-2,4-dione, [(V), from Example 90, 0.92 g, 3.38 mmol] in dry THF (30 mL) at -78° C. under a dry N2 atmosphere over a twenty minute period. A solution of [3-(4-chlorophenyl)-prop-2-ynyl]-BROMIDE [(IX), from Example 21, 3.53 g, 15.4 mmol] in dry THF (10 mL) was added over a 20 min period. The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was added to saturated aqueous ammonium chloride (80 mL) and extracted with ethyl acetate (2×300 mL). The extracts were washed with water, dried (brine), concentrated and purified by flash chromatography (gradient 97:3 to 93:7 CH2Cl2 :isopropanol) to provide a sticky solid which triturated with petroleum ether (90 mL): benzene (2 mL) to provide the title compound as a off-white solid (0.55 g, 39%): mp 104°-106° C.: NMR (DMSO, d 6): δ13.1 (broad s, 1H, NH), 8.10 (t, J=7.8 Hz, 1H, pyH), 7.95 (d, J=7.7 Hz, 1H, pyH), 7.71 (d, J=7.7 Hz, 1H, pyH), 7.45 (d, J=8.8 Hz, 2H, ArH), 7.35 (d, J=8.7 Hz, 2H, ArH), 3.86 (d, J=17.4 Hz, 1H, CH2), 3.72 (d, J=17.4 Hz, 1H, CH2), 2.57 (s, 3H, CH3); MS(EI): 420 (MI, 3%), 265 (12%), 263 (38%), 194 (25%), 192 (70%), 149 (40%), 93 (100%); Anal. Calc. for C18H13ClN2O4S2 : C, 51.37; H, 3.11; N, 6.66; Found: C, 50.99; H, 3.05; N, 6.58.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:13][CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC[C@@H]1CCCC[C@@H]1c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC[C@@H]1CCCC[C@@H]1c1ccccc1
Reaction time: 2 h
Yield: 50.5 %

Procedure:
A solution of 2-(cis-2-phenylcyclohexyl)ethanol (3 g.) in methylene chloride (6 ml.) was added rapidly to a stirred suspension of pyridinium chlorochromate (4.8 g.) in methylene chloride (6 ml.). The mixture was stirred for 2 hours and diluted with ether (75 ml.). The supernatant solution was decanted from the black tar and filtered through diatomaceous earth. The residual tar was washed thoroughly with ether. The combined ethereal filtrate and washings were evaporated. The pale yellow oil obtained, was purified by flash chromatography on silica eluting with hexane/ether (2:1 v/v) to give (cis-2-phenylcyclohexyl)acetaldehyde (1.5 g.) as a semi-solid; NMR (CDCl3): 1.1-2.35 (10H, m), 2.4-2.7 (1H,m), 2.75-3.0 (1H,m), 7.0-7.4 (5H,m) and 9.3 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Cl.[NH2:25][C@H:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([NH2:29])=[O:28]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:25]([C@H:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([NH2:29])=[O:28])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: NC(=O)[C@H](N)c1ccccc1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H](c1ccccc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2 g, 0.01 mol), methanol (20 mL, 0.5 mol), triethylamine (3 mL, 0.02 mol) and (R)-2-amino-2-phenylacetamide hydrochloride (2.3 g, 0.012 mol) and the reaction heated at 50° C. for 3 hours. The starting material disappeared and the solvent was removed under reduced pressure and the residue purified by flash chromatography (40 g silica gel, 0-10% MeOH/DCM) to yield the product as a brown solid. MS m/z=324.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:24][O:25]/[N:26]=[C:27]1/[C@@H:28]([NH2:33])[CH2:29][CH2:30][CH2:31][CH2:32]/1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][O:25]/[N:26]=[C:27]1/[C@@H:28]([NH:33][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[O:21])[CH2:29][CH2:30][CH2:31][CH2:32]/1
Reactant: CO/N=C1\CCCC[C@@H]1N
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C1\CCCC[C@@H]1NC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To a solution of 0.050 g 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid in 2.0 ml dimethylformamide was added 0.030 g (S)-2-amino-cyclohexanone-(E)-O-methyl-oxime hydrochloride, 0.053 g TBTU and 0.097 g N,N-diisopropyl ethyl amine and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under high vacuum and the residue was purified by chromatography on silica gel with a gradient of heptane to ethyl acetate to yield 0.045 g of the title compound as colorless oil. MS (EI): 465.1 (M+H).