Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:5][C@H:6]([NH:26]C(=O)OC(C)(C)C)[C@H:7]([OH:25])[CH2:8][NH:9][C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.FC(F)(F)C(O)=O.[ClH:45]>C(Cl)Cl.CCOCC>[ClH:45].[ClH:45].[NH2:26][C@@H:6]([CH2:5][C:4]1[CH:34]=[C:35]([F:37])[CH:36]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:25])[CH2:8][NH:9][C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)c1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)CCCCC2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CCCCC2)c1
Reaction time: 1 h

Procedure:
To 1.98 g (3.8 mmol) of compound 5 in 15 mL of CH2Cl2 is added 6.5 mL of trifluoroacetic acid. The mixture is stirred under a nitrogen atmosphere for 1 h and then concentrated. The resulting residue is taken up in ethyl acetate and washed twice with 10% Na2CO3 and once with 1 N NaHCO3. The organic layer is dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.6 g (quant.) of a pale yellow oil (free base of 6), which is generally carried on in the next step without characterization. The yellow oil may be dissolved in ether and treated with ethereal HCl to precipitate (dihydrochloride 6 as a white solid after trituration with ether: 1H NMR (CDCl3+CD3OD drop) δ 7.55 (s, 1 H), 7.45-7.15 (m, 3 H), 6.85 (m, 2 H), 6.75 (m, 1 H), 4.4 (d, J=9.5 Hz, 1 H), 3.82 (m, 1 H), 2.97 (m, 2 H), 2.81 (dd, J=8, 14 Hz, 1 H), 2.65 (m, 2 H), 2.5 (obscured by water) 2.26 (m, 1 H), 2.13 (m, 2 H), 1.79 (m, 2 H), 1.59 (m, 1 H), 1.45-1.25 (m, 3 H), 1.28 (d, J=7 Hz, 6 H); MS (CI) m/z 417.3 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:7][C:6]=1[CH3:18])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:14]([O:13][C:11](=[O:12])[NH:10][C:8]1[S:9][C:5]([CH2:3][OH:2])=[C:6]([CH3:18])[N:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid methyl ester (0.5 g) was dissolved in anhydrous THF (7 mL) and cooled to 0° C. and 1 eq of Lithium aluminum hydride (2M solution in THF) was added and stirred 1 h. Reaction was slowly warmed to RT and stirred for 6 h. Reaction was cooled to 0° C. and quenched with min amount of sat. Na2SO4 soln. White solid was filtered and washed with ethyl acetate (5 mL), filtrate was concentrated by rotavap and residue was dired in vacuum gave (5-Hydroxymethyl-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.4 g). This was used in the next reaction without further purification. 1H NMR (400 MHz, Acetone-d6) 4.6 (s, 2H), 2.1 (s, 3H), 1.5 (s, 9H).
Reaction SMILES: [N:1]1([NH:7][C:8](=O)OC(C)(C)C)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27](C=O)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[N:1]1([N:7]=[CH:8][C:27]2[CH:30]=[CH:31][C:24]([C:23]([F:33])([F:32])[F:22])=[CH:25][CH:26]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C=NN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Tert-butyl piperazin-1-yl-carbamate (403 mg, 2.0 mmol) was suspended in methylene chloride (4 ml), to which trifluoroacetic acid (1.6 ml) was added, and the mixture was stirred at room temperature for 5 minutes. To which 4-(trifluoromethyl)benzaldehyde (0.3 ml, 2.2 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into sodium hydrogencarbonate aqueous solution, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=9/1) to afford piperazin-1-yl-(4-trifluoromethylbenzylidene)-amine (432 mg, yield 84%) as a colorless crystalline powder.
Reaction SMILES: C1(=O)CCCCCCCCCCC1.[C:14]1([NH:26][CH:27]=[C:28]([C:34]([O:36]CC)=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:36][C:34]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]=12
Reactant: CCOC(=O)C(=CNC1=CCCCCCCCCCC1)C(=O)OCC
Agent: O=C1CCCCCCCCCCC1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c1O)CCCCCCCCCC2
Temperature: 25 °C

Procedure:
A solution of 10 g of the mixture of cyclododecanone and diethyl N-(1-cyclododecenyl)-aminomethylenemalonate in 25 ml Dowtherm® is added to 200 ml Dowtherm® at 250° under nitrogen, collecting distillate in a water separator. After heating for 0.5 hour the mixture is cooled to room temperature and the solvent distilled off under reduced pressure. The residual solid is triturated with ether and dried to give ethyl 5,6,7,8,9,10,11,12,13,14-decahydro-4hydroxycyclododeca[b]pyridine-3-carboxylate, m.p. 182°-90°.
Reaction SMILES: NC(C([C:12]1S[C:14]2C=CC=[CH:17][C:15]=2[N:16]=1)=O)CCCNC(N)=N.C([N:24]1CC(O)[CH2:26][CH:25]1[C:30](O)=O)(=O)C>C1COCC1.O>[CH:25]([N:24]=[C:12]=[N:16][CH:15]([CH3:14])[CH3:17])([CH3:30])[CH3:26]
Reactant: CC(=O)N1CC(O)CC1C(=O)O
Reactant: N=C(N)NCCCC(N)C(=O)c1nc2ccccc2s1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N=C=NC(C)C

Procedure:
A solid mixture of N-(4-amino-5-benzothiazol-2-yl-5-oxo-pentyl)-guanidine (0.24 g, 0.83 mmol) and 1-acetyl-4-hydroxy-pyrrolidine-2-carboxylic acid (0.14 g, 0.83 mmol) was dissolved in THF (10 mL) and water (2 mL). To the reaction mixture was then added N,N′-diisopropyl carbodiimide to yield a reaction mixture of pH 1.8 at 0° C. The pH of the reaction mixture was adjusted to about 5.5 with 8% NaHCO3. The reaction mixture was stirred at ambient temperature for 4 hours. The title compound was detected by HPLC (180 mg) and assayed by weight analysis.
Reaction SMILES: [SiH3][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].OS([O-])(=O)=O.[K+]>CO.O.[Na+].[Cl-]>[Si:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:17])=[O:2])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(=O)O[SiH3]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 3.25 g (9.02 mmol) of the bissilylated compound 6-[(tert-butyldimethyl-silyl)oxy]-hexanoic acid silyl ester in 130 ml of methanol and 44 ml of ThF is mixed with a solution of 4.4 g (31.8 mmol, 3.5 equivalents) of K2CO3 in 44 ml of H2O, and it is stirred for 1 hour at room temperature. Then, the volume of reaction solution is reduced to one-fourth in a vacuum. It is diluted with 130 ml of saturated NaCl solution and set at pH 4-5 with 1 M KHSO4 solution. It is extracted with diethyl ether. The combined organic phases are dried on MgSO4, and the solvent is distilled off in a rotary evaporator. 2.01 g (8.17 mmol) of 6-[(tert-butyldimethylsilyl)oxy]-hexanoic acid, corresponding to a yield of 90%, is obtained.
Reaction SMILES: CN(C)CCC[N:6]1[C:18]2[CH:17]=[CH:16][C:15]([CH:19]=O)=CC=2C2C1=CC=CC=2.N1CCCC([NH:28][C:29](=[O:35])[O:30]C(C)(C)C)C1.C(O)(=O)C.[BH3-]C#N.[Na+]>CCO.CO.C(Cl)Cl>[C:29](=[O:30])([O:35][CH:15]1[CH2:16][CH2:17][CH2:18][NH:6][CH2:19]1)[NH2:28]
Reactant: CN(C)CCCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)OC1CCCNC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 121.3 %

Procedure:
A 250-mL round-bottomed flask was charged with a solution of 9-(3-(dimethylamino)propyl)-9H-carbazole-3-carbaldehyde (800 mg, 2.86 mmol, 1.00 equiv) in EtOH (120 mL), tert-butyl piperidin-3-ylcarbamate (1.07 g, 5.35 mmol, 1.50 equiv), acetic acid (1.03 g, 17.17 mmol, 6.00 equiv) and NaBH3CN (720 mg, 11.43 mmol, 4.00 equiv). The resulting mixture was stirred at 40° C. in an oil bath for 16 hours. The reaction progress was monitored by TLC (DCM: MeOH=10:1). The reaction was then quenched by the addition of NaHCO3 (50 mL). The mixture was then extracted with dichloromethane (4×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50/1) affording tert-butyl 14(943-(dimethylamino)propyl)-9H-carbazol-3-yl)methyl)piperidin-3-yl carbamate as brown oil (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.O.C(OCC)(=O)C>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-Chloro-2-fluoronitrobenzene (3.5 g) was dissolved in dry dimethylformamide (25 mL) and diisopropylethylamine (3.6 mL), and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (4.2 g) were added at room temperature. The mixture was stirred at 80° C. for 1 h, then cooled to room temperature and water and ethyl acetate added. The organic layer was dried over MgSO4, filtered and evaporated, and the residue was purified by chromatography eluting with 10 to 25% ethyl acetate in hexane to afford the title compound, 6.8 g.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[C:2]1([CH2:1][CH2:8][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: CC(=O)CCc1ccccc1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
Activated Ni EnCat (0.26 g, water wet, 20 mol % Ni on substrate) was washed with MeOH three times to remove water and added to benzalacetone (0.148 g, 1 mmol) dissolved in MeOH (4 ml) in a pressure vessel. The vessel was sealed and purged twice with hydrogen then pressurised to 5-6 bar with hydrogen and the contents magnetically stirred at room temperature. Progress of reaction was carried out by GCMS analysis. After 24 h the hydrogen was vented and the Ni EnCat beads removed by filtration. The filtrate was concentrated on a rotary evaporator to give 4-phenylbutanone (0.149 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=4)[C:33]([O:35]C)=[O:34])([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:40])=[N:3]1.[OH-].[Na+].C(O)(=O)C>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=4)[C:33]([OH:35])=[O:34])([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:40])=[N:3]1
Reactant: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(C(=O)O)c4)c3)c2)n(C)n1
Yield: 66.2 %

Procedure:
A 50 ml THF solution of methyl 3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoate (228 mg, 0.41 mmol) and 0.5M NaOH (6.6 ml, 3.28 mmol) was stirred at room temperature for 3 hours. The reaction was quenched with acetic acid (0.188 ml, 3.28 mmol) and rotary evaporated to remove the THF solvent. The aqueous solution was partitioned between EtOAc and dilute HCl/brine mixture, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated to white solid foam. The solid was combined with impure product from another lot (14 mg) and recrystallized from EtOAc/hexane to give the title compound as a white solid (147 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[N:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[C:17]1[N:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1.[Cl-].[NH4+]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:10]=[C:9]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)[S:8][C:7]=12
Reactant: Clc1ccnc2ccsc12
Reactant: Brc1ccc(CCN2CCOCC2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccnc2cc(-c3ccc(CCN4CCOCC4)cn3)sc12
Temperature: 0 °C
Yield: 101.4 %

Procedure:
To 7-chlorothienopyridine (0.81 g, 4.8 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 2.1 mL, 5.1 mmol), dropwise. The mixture was allowed to warm to 0° C. then zinc chloride (1.0 M in diethyl ether, 4.8 mL, 4.8 mmol) was added. The mixture was stirred and warmed to room temperature. Bromide 175 (1.0 g, 3.7 mmol) and tetrakis(triphenylphosphine)palladium (0.85 g, 0.74 mmol) in THF (75 mL) were added dropwise, and the resultant mixture was heated to reflux for 2 h. It was then cooled and ammonium chloride (2.0 mL) was added, and the mixture was concentrated. The residue was partitioned between water and ethyl acetate, resulting in a thick precipitate. This was isolated by suction filtration and triturated with ethyl acetate, to provide title compound 176 (1.35 g, 100% yield, crude) as a yellow solid. LRMS (M+H): 360.4
Reaction SMILES: C(S)C.[H-].[Li+].[C:6]1([CH2:12][CH2:13][CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([O:23]C)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>CN(C)C=O>[OH:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH:14]([CH2:13][CH2:12][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:18][C:17]=2[CH:19]=1
Reactant: COc1ccc2c(c1)CC(CCc1ccccc1)O2
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCS
Product: Oc1ccc2c(c1)CC(CCc1ccccc1)O2
Yield: 98 %

Procedure:
Ethanethiol (62 gm; 1 mole) was added dropwise to lithium hydride (8 gm; 1 mole) in dimethylformamide (700 mL) under nitrogen atmosphere. 2-(2-phenylethyl)-5-methoxy-2,3-dihydrobenzofuran, E4, (126 gm; 500 mmoles) in dimethylformamide (200 mL) was then added in one portion and the mixture brought to reflux for 3 hours. The mixture was poured into 1N hydrochloric acid and extracted with diethyl ether. The ether layer was separated and backwashed with water twice, dried over MgSO4, filtered and concentrated in vacuo to obtain 123 gm (98%) of 5-hydroxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E5, m.p. 56°-58° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2Br)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>COCCO.O.[Cu]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[S:18][CH:19]=[CH:20][C:21]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2sccc2Br)CC1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2noc3ccsc23)CC1
Temperature: 65 °C
Reaction time: 6 h
Yield: 49.5 %

Procedure:
Add to a stirring solution of 4-[(3-bromo-thiophen-2-yl)-hydroxyimino-methyl]piperidine-1-carboxylic acid tert-butyl ester (Example 21b) (25 g., 64.2 mmol) in 2-methoxyethanol (200 mL), a solution of potassium hydroxide (7.2 g, 128.4 mmol) in water (20 mL). Heat the reaction to 60° C. and then add copper powder (1.25 g). Stir at 60-70° C. for 6 h and then at ambient temperature overnight. Pour the reaction mixture into water (500 mL) and extract with EtOAc (3 times). Concentrate to a dark residue and purify by column chromatography over silica gel (heptane/EtOAc, 4:1) to provide 9.8 g (50%) of a white solid.
Reaction SMILES: [C:1]1([C:7]2([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[I:22](O)(=O)(=O)=O.II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C.O>[I:22][C:4]1[CH:3]=[CH:2][C:1]([C:7]2([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])[CH2:8][CH2:9]2)=[CH:6][CH:5]=1
Reactant: O=C(N1CCCC1)C1(c2ccccc2)CC1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(N1CCCC1)C1(c2ccc(I)cc2)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 531.2 %

Procedure:
1-[(1-phenylcyclopropyl)carbonyl]pyrrolidine (0.75 g, 3.49 mmol) was dissolved in glacial acetic acid (14 ml) and treated successively with concentrated sulfuric acid (0.4 ml), water (1.5 ml), periodic acid (184 mg, 0.8 mmol), and iodine (379 mg, 1.49 mmol). This mixture was then stirred at 60° C. for 6 hours and then allowed to cool to room temperature. The reaction mixture was poured into a 10% aqueous solution of sodium metabisulfite and extracted into ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulphate and evaporated under reduced pressure to give a yellow oil (1.45 g) which was added to a 20 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (0.62 g, 52%).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N:12]1([C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1cnc2ccccc2n1
Reactant: C1CNCCN1
Product: c1ccc2nc(N3CCNCC3)cnc2c1

Procedure:
2-(1-Piperazinyl)quinoxaline is prepared from 2-chloroquinoxaline by reaction with piperazine in a manner similar to the preparation of 2-(1-piperazinyl)quinoxalines described in British Pat. No. 1,440,722, issued June 23, 1976 and assigned to Merck & Co. The preparation of 2-chloroquinoxaline is described at Gowenlock et al., J. Chem Soc. 1945: 622.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[C:7]([N+:12]([O-])=O)=[CH:6][CH:5]=1.[CH2:15]([OH:17])C>O.[Fe]>[Cl:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][CH:15]=[O:17])=[CH:6][CH:5]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1nc(Cl)ccc1NC=O
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
Iron (11.9 g) and ammonium chloride (22.7 g) were added to a solution of 6-chloro-2-methoxy-3-nitropyridine (10.0 g, CAS: 40851-91-0) in ethanol (130 mL) and water (52 mL). The reaction solution was stirred at 80 to 90° C. for one hour and 20 minutes and then left to cool to room temperature. The reaction solution was filtered through celite and washed with ethanol. Then, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with THF (26 mL). The THF solution was added dropwise to a mixed solution of formic acid (20.1 mL) and acetic anhydride (20.1 mL) at room temperature. Then, the reaction solution was stirred for one hour. Ice water (120 mL) was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were washed with water and then air-dried to obtain 5.85 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1I.C(N(CC)CC)C>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[C:2][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:32])([F:31])[F:22])[CH:4]=2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: FC(F)(F)c1ccccc1I
Reactant: C#Cc1cccc(NC(=O)Cc2ccc(O)c(OC)c2)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3C(F)(F)F)c2)ccc1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of N-(3-ethynylphenyl)-4-hydroxy-3-methoxypheny-acetamide (the compound of Example 19) (200 mg), 1-trifluoromethyl-2-iodobenzene (280 mg), copper (I) iodide (19 mg), bis(triphenylphosphine)palladium (II) dichloride (70 mg), triethylamine (1 g) and acetonitrile (3 ml) is heated with stirring at 50° C. under argon atmosphere for 18 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (120 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[C:30]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](O)=[O:43])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:32][C:30]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](=[O:43])[NH:2][CH:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:23]=[CH:22][C:13]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: COC(=O)C(N)Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)C1CCCN1C(=O)OC(C)(C)C
Reaction time: 10 h
Yield: 32.1 %

Procedure:
A solution of 5[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzylidene]thiazolidin-2,4-dione hydrochloride (2.5 g, 5.76 mmol) and N-Boc-pyrolidin-2-carboxylic acid (1.238 g, 5.76 mmol) in dimethyl formamide (25 ml) was stirred for 60 minutes at 0° C. N,N′-Dicyclohexylcarbodiimide (1.423 g, 6.91 mmol) was added to it and stirring was continued for 10 h at ambient temperature. Water (200 ml) was added to the reaction mixture and stirred for 15 minutes. Ethyl acetate (200 ml) was added to the reaction mixture and stirring continued for another 15 minutes. The organic layer was separated, washed with water (75 ml), dried over anhydrous sodium sulphate and concentrated to afford the crude product, which was purified by column chromatography to furnish the required product (1.1 g, yield 32.4%).