Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[C:18]([F:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][C:14]=2[F:22])[O:11][CH3:12])=[C:5]([OH:26])[CH:4]=1)#[N:2].Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:13]2[C:14]([F:22])=[CH:15][C:16]([O:20][CH3:21])=[CH:17][C:18]=2[F:19])[O:11][CH3:12])=[C:5]([O:26][CH2:28][C:29](=[O:30])[NH:31][CH3:32])[CH:4]=1)#[N:2]
Reactant: CNC(=O)CCl
Reactant: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)COc1cc(C#N)ccc1CNC(=O)C(OC)c1c(F)cc(OC)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide was alkylated with 2-chloro-N-methylacetamide/cesium carbonate in DMF to give (RS)-N-(4-cyano-2-methylcarbamoylmethoxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide as a colorless foam. MS 434.2 ([M+H]+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:21]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])[C:7](=[CH:19][CH:20]=1)[C:8]([O:10][CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])([O-])=O.Cl.O.[OH-].[Na+]>C1C=CC=CC=1.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:21]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])[C:7](=[CH:19][CH:20]=1)[C:8]([O:10][CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:9]
Reactant: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OCC(CC)CCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCC(CC)COC(=O)c1ccc(N)cc1C(=O)OCC(CC)CCCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
Compound 411 (2.0 g, 5.3 mmol) was dissolved in 265 ml of benzene, and then 3.2 g of purified zinc dust was added. Concentrated hydrochloric acid (9.3 ml) was added in portions. After 15 minutes of stirring at room temperature, another 3.2 g of zinc dust was added and the mixture was stirred at room temperature for 12 hours. Then 320 ml of water was added to the reaction mixture and the mixture was neutralized with 1N NaOH solution. The mixture was transferred to a separatory funnel and the benzene layer was removed. The aqueous layer was extracted with benzene. The combined benzene extracts were washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (n-hexane: acetic acid =15:1) to give 1.3 g (72.2%) of bis(2-ethylhexyl) 4-aminophthalate (compound 412).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=1)[N:5]=2.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>CS(C)=O>[CH3:24][NH:23][C:20]1[N:19]=[CH:18][C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]4)[N:3]3[CH2:25][CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Solvent: CS(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCN(S(C)(=O)=O)CC4)n(CC4CCOC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 24.9 %

Procedure:
A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]-N-methylpyrimidin-2-amine (100 mg, 0.23 mmol), N-methanesulfonylpiperazine (114 mg, 0.70 mmol), and dimethyl sulfoxide (1 ml) was stirred at 150° C. for 4 hours. The mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (32 mg, 25%) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Si]([C:16]([F:19])([F:18])[F:17])(C)(C)C.Cl>C1COCC1.[F-].[Cs+]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[C:16]([F:19])([F:18])[F:17])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cc(C(O)C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
2-Fluoro-5-formyl-benzonitrile (5 g, 33.5 mmol) and CsF (51 mg, 0.335 mmol) in THF (10 mL) were treated with TMSCF3 (4.77 g, 33.5 mmol) at room temperature for 2 hours. The reaction was then treated with 4 N HCl (5 mL) and stirred at room temperature for 30 min. The solvent was removed and the residue was partitioned between ether and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, purified by silica gel column (hexanes:ethyl acetate 3:1) to afford the title compound as colorless solid (4.5 g, 61%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:21][C:5]2[S:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[C:3]1=[O:22].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][CH:2]1[CH2:21][C:5]2[S:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]1[OH:22]
Reactant: CC1Cc2sc(-c3ccccc3)c(-c3ccccc3)c2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1Cc2sc(-c3ccccc3)c(-c3ccccc3)c2C1O
Reaction time: 8 h

Procedure:
A solution of 5-methyl-2,3-diphenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-4-one (6.08 g, 20 mmol) in 75 mL of ether was slowly added to a solution of LiAlH4 (0.38 g, 10 mmol) in 50 mL of ether and stirred overnight. The resulting suspension was poured into a mixture of ice and water, the organic layer was isolated, while the water layer was extracted with ether (3×50 mL). The combined organic layers were washed with water, dried over MgSO4 and evaporated off to dryness. The 5-methyl-2,3-diphenyl-5,6-dihydro-4H-cyclopenta[b]thiophen -4-ol so obtained was dissolved in 100 mL of benzene, added of 1 g of p-toluenesulfonic acid and was refluxed for 10 min. Then the reaction mixture was cooled to room temperature and treated with a saturated aqueous solution of Na2CO3. The organic phase was isolated, dried over MgSO4 and evaporated off to dryness giving the crystallized product. Yield 3.46 g (60% with respect to the starting ketone).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:33]=[N+:34]=[N-:35].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[N:34][NH:35][N:30]=3)=[CH:25][CH:24]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CCNC(=O)C(N(Cc2ccc(C#N)cc2)S(=O)(=O)c2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CCNC(=O)C(N(Cc2ccc(-c3nn[nH]n3)cc2)S(=O)(=O)c2ccc(Cl)cc2)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Rac-4-Chloro-N-(4-cyano-benzyl)-N-(5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide (80 mg, 0.18 mmol) was dissolved in dimethylformamide (1 ml). Then ammonium chloride (11 mg, 0.2 mmol) and sodium azide (13 mg, 0.2 mmol) was added and the mixture was stirred overnight at 120° C. After cooling the mixture was distributed 3 times between ethyl acetate (10 ml) and hydrochloric acid (10 ml 1N). The combined organic layers were dried and evaporated. The residue was purified on silica gel (eluent hexane/ethyl acetate) to yield 79 mg (89%). MS: m/e=506.1 (M+NH4+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH2:23][O:24][CH:25]3[CH2:30]CCC[O:26]3)=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:43].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[C:25]([O:24][CH2:23][C:20]1[S:19][C:18]([C:16]2[NH:43][C:13]([CH:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:14][CH:15]=2)=[N:22][CH:21]=1)(=[O:26])[CH3:30]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)[nH]2)s1
Temperature: 110 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (366 mg) in acetic acid (3.1 mL) was added ammonium acetate (773 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (103 mg, yield 31%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 523 (MH+).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=1[CH3:37]>N1C=CC=CC=1.CCOC(C)=O>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([O:36][C:12]2[NH:11][C:10]3[CH:18]=[C:19]([F:20])[C:7]([C:4]4[CH:5]=[CH:6][C:1]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:2][CH:3]=4)=[CH:8][C:9]=3[N:13]=2)[CH:33]=[CH:32][C:31]=1[CH3:37]
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Reactant: COC(=O)c1cc(O)ccc1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)ccc1C

Procedure:
To a solution of 7 (454 mg, 1.2 mmol) in pyridine 10 mL was added 5-hydroxy-2-methyl-benzoic acid methyl ester (412 mg, 2.4 mmol). The reaction mixture was heated to reflux for 5 days. Once the reaction was determined to be complete by TLC, the reaction mixture was diluted with EtOAc (100 mL) and washed two times with 100 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo to give a crude brown oil. The resulting oil was purified on ISCO (EtOAc/Hexanes=2/3) to give title compound 8 as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][NH:5][C:4]([C:16]([NH:18][N:19]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])=[O:17])=[CH:3]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(NC1CCCCC1)(NC1CCCCC1)=O>C(#N)C>[OH:8][C:7]1[C:2](=[O:1])[CH:3]=[C:4]([C:16]([NH:18][N:19]2[CH2:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])=[O:17])[NH:5][CH:6]=1
Reactant: O=C(NN1CCCNC1=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CC#N
Product: O=C(NN1CCCNC1=O)c1cc(=O)c(O)c[nH]1
Reaction time: 1 h

Procedure:
To a suspension of 1.71 g. (ca. 5 mmol) crude 1,4-dihydro-4-oxo-5-(phenylmethoxy)-N-(tetrahydro-2-oxo-1(2H)-pyrimidinyl)-2-pyridine-carboxamide in 22 ml acetonitrile was added 4.1 g (20 mmol) bis(trimethylsilyl)acetamide. After stirring for 20 minutes the undissolved dicyclohexylurea was filtered off and 0.85 g palladium on carbon were added to the filtrate. After the mixture had been hydrogenated for one hour, the catalyst was removed by filtration and 2.1 ml methanol and 0.1 ml acetic acid were added to the filtrate. After stirring overnight the desired product was filtered off and dried in vacuo. Yield 0.7 g, melting point 285°-290° C. (dec.).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[Cl:15][C:16]1[C:17]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]=[C:21]([O:27][CH3:28])[C:20]([O:29][CH3:30])=[N:19]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][C:16]1[C:17]([N:31]([CH2:2][CH2:3][N:4]2[C:8](=[O:9])[C:7]3=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]3[C:5]2=[O:14])[S:32]([CH3:35])(=[O:34])=[O:33])=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]=[C:21]([O:27][CH3:28])[C:20]([O:29][CH3:30])=[N:19]2
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc2cc(Cl)c(Cl)c(N(CCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)c2nc1OC
Reaction time: 48 h
Yield: 85.5 %

Procedure:
N-(2-bromoethyl)phthalimide (1.73 g, 6.81 mmol) was added to a refluxing mixture of N-(6,7-dichloro-2,3-dimethoxy-quinoxalin-5-yl)-methanesulphonamide (2.00 g, 5.68 mmol) and potassium carbonate (1.88 g, 13.63 mmol) in acetone (100 ml) under nitrogen. After 48 hours, further N-(2-bromoethyl)phthalimide (1.73 g, 6.81 mmol) was added and refluxing continued for 18 hours. After cooling the mixture was concentrated under reduced pressure and the residue dissolved in dichloromethane. The resulting solution was washed twice with 1N sodium hydroxide solution, water and brine and then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexane:ethyl acetate) to afford N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide as a pale yellow solid (2.55 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=3[O:28][CH3:29])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: CCCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: CCCCNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-butyl-cinnoline-3-carboxamide (100 mg, 0.31 mmol) and 2,5-dimethoxyphenyl boronic acid (112.6 mg, 0.62 mmol) according to Method A to afford a white solid (96.3 mg, 82%). 1H NMR (300.132 MHz, CDCl3) δ 8.54 (t, J=4.7 Hz, 1H), 7.86 (dd, J=7.6, 2.2 Hz, 1H), 6.96 (t, J=3.0 Hz, 1H), 6.96 (s, 1H), 6.93 (d, J=1.9 Hz, 1H), 7.76-7.68 (m, 2H), 3.79 (s, 3H), 3.64 (s, 3H), 3.48 (q, J=6.6 Hz, 2H), 1.61 (quintet, J=7.2 Hz, 2H), 1.43 (sextet, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H). MS APCI, m/z=381.2 (M+H). HPLC 2.83 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([SH:8])[N:4]=1.[H-].[Na+].Cl[C:12]1[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([S:8][C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=2)[N:4]=1
Reactant: N#Cc1nccnc1Cl
Reactant: CSc1nc(S)ns1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nc(Sc2nccnc2C#N)ns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(methylthio)-1,2,4-thiadiazole-3-thiol (328 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 2 hr.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[S:30])[O:9][CH2:10]/[CH:11]=[C:12](\[CH3:29])/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:28])/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:27])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])C=1.C(C/C(/C)=C/CC/C(/C)=C/[CH2:48][OH:49])/C=C(/CCC=C(C)C)\C.O1C=CC=C1CN=C=S>>[O:49]1[CH:48]=[CH:6][CH:5]=[C:4]1[CH2:3][NH:7][C:8](=[S:30])[O:9][CH2:10]/[CH:11]=[C:12](\[CH3:29])/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:28])/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:27])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=S)Nc1cccnc1
Agent: S=C=NCc1ccco1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=S)NCc1ccco1
Yield: 23 %

Procedure:
Similar to the preparation of 38a, the reaction of alcohol 1 with 2-furanylmethyl isothiocyanate afforded the desired compound 38b in 23% yield (55 mg) as a viscous oil. Column (EtOAc/Hexane); TLC Rf: 0.65 (20% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3): δ 7.35 (s 1H), 6.35 (m, 1H), 5.15 (m, 3H), 5.04 (d, 0.4H), 4.95 (d, 0.6H), 4.75 (d, 0.6H), 4.42 (d 0.4H), 2.14-1.94 (m, 12H), 1.73 (s, 3H), 1.68 (s, 3H), 1.60 (s, 9H); LCMS: MS (m/z): 430.2 (M+H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([C:14]1[N:15]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:46]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:45]=[N:44][N:43]=3)=[CH:32][CH:31]=2)[C:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]([C:19](OCC)=[O:20])[N:18]=1)[CH2:12][CH3:13].C(OCC)(=O)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[OH:20][CH2:19][C:17]1[N:18]=[C:14]([CH2:11][CH2:12][CH3:13])[N:15]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:46]([C:47]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[N:45]=[N:44][N:43]=3)=[CH:34][CH:35]=2)[C:16]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
10 ml of a 1.5M solution of diisobutylaluminum hydride in toluene were added dropwise at -20° C. under an atmosphere of nitrogen to a solution of 4.27 g of diethyl 2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-4,5-dicarboxylate [prepared as described in step (a) above] in 50 ml of tetrahydrofuran. The resulting mixture was allowed to stand at 0° C. for 16 hours and then mixed with ethyl acetate and with a saturated aqueous solution of ammonium chloride; it was then stirred at room temperature for 1 hour. The resulting precipitate was filtered off, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The crystalline residue was washed with diisopropyl ether, to give 4.03 g of the title compound, melting at 135°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[C:5](O)=[O:6].C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:57]([N:64]1[CH2:69][CH2:68][CH:67]([NH2:70])[CH2:66][CH2:65]1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O>[CH2:57]([N:64]1[CH2:69][CH2:68][CH:67]([NH:70][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)=[C:2]([Cl:1])[CH:3]=2)[CH2:66][CH2:65]1)[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: COc1ccc(CN2CCC(Oc3ccc(C(=O)O)cc3Cl)CC2)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCC(Oc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a stirred mixture of 3-chloro-4-(1-(4-methoxybenzyl)piperidin-4-yloxy)benzoic acid in anhydrous dimethylformamide (0.5 mL) was added triethylamine (0.03 g, 0.30 mmol), 1-hydroxybenzotriazole hydrate (0.02 g, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.03 g, 0.15 mmol) and 1-benzylpiperidin-4-amine (0.03 mg, 0.15 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=15/1/0.05) to afford N-(1-benzylpiperidin-4-yl)-3-chloro-4-(1-(4-methoxybenzyl)-piperidin-4-yloxy)-benzamide as a white solid (0.01 g, 18%). 1H-NMR (CDCl3, 300 MHz): δ 7.76 (m, 1H), 7.60 (m, 1H), 7.30 (m, 7H), 6.94 (m, 1H), 6.87 (m, 2H), 5.83 (d, J=7.2 Hz, 1H), 4.52 (m, 1H), 3.97 (m, 1H), 3.80 (s, 3H), 3.54 (s, 4H), 2.86 (m, 4H), 2.11 (m, 8H), 1.58 (m, 4H); LCMS: >98%; MS (ESI): 548.2 (M+1), 546.2 (M−1).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([C:27]3[NH:28][CH:29]=[CH:30][CH:31]=3)[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)[CH3:8])=[CH:3][CH:2]=1.O.[OH-].[Li+]>>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([C:27]3[NH:28][CH:29]=[CH:30][CH:31]=3)[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[CH3:8])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccc3)cc2)cc1)c1ccc[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=NOCCOc1ccc(CC(C(=O)O)c2ccc[nH]2)cc1)c1ccc(-c2ccccc2)cc1
Yield: 85.7 %

Procedure:
Reaction and post-treatment were carried out according to Example 10 using 167 mg of ethyl 3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy]ethoxy]phenyl]-2-pyrrolylpropionate obtained in Example 13 and 42 mg of lithium hydroxide monohydrate to obtain 135 mg of the desired compound as crystals.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[C:30](OCC)(=[O:32])C.Cl>[Cu]Br.C[O-].[Na+].CO>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]([CH3:29])=[C:2]([O:32][CH3:30])[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: CCOC(C)=O
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: [Cu]Br
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: COc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 58.2 %

Procedure:
A mixture of N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (250 mg, 0.545 mmol) obtained in Example 35, copper(I) bromide (78 mg, 0.545 mmol), ethyl acetate (88 mg, 1.00 mmol), and 28% sodium methoxide-methanol solution (20 mL) was refluxed with heating for 6 hours. 1 N Hydrochloric acid was added to the reaction solution and the product was extracted with diisopropyl ether. The extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from hexane-ethyl acetate to obtain 130 mg (yield: 58%) of the title compound. Melting point: 191-193° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Li]CCCC.CN([CH:17]=[O:18])C>CCOCC>[Br:8][C:6]1[CH:7]=[C:2]([CH:17]=[O:18])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dibromopyridine (1.0 eq.) in Et2O (0.1M) at −78° C. was added n-BuLi (1.05 eq.). The mixture was stirred for 30 min at −78° C. then DMF (3.0 eq.) was added. The final mixture was warmed to rt, stirred for 3 h, quenched using saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 4:1) afforded the title compound as an oil.