Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([OH:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.[CH2:14](O)[CH3:15]>S(=O)(=O)(O)O.C(N(CC)CC)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([O:10][CH2:14][CH3:15])[C:7]([CH3:11])([CH3:12])[C:6]=2[CH:13]=1
Reactant: CCO
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC1Oc2ccc(Br)cc2C1(C)C
Yield: 86 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (5 g, 0.02 mole) was heated under reflux in ethanol (30 ml) with sulphuric acid (4 drops) for 11/2 hours. The solution was cooled, neutralised with a few drops of triethylamine and run down. The residue was redissolved in ether and the solution washed with water, dried over magnesium sulphate and the solvent removed under vacuum leaving 4.7 g (86%) title product as a buff-coloured oil. The structure was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl:26][C:27]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:28]=1[CH:29]=[CH:30][CH2:31]Cl.C(OC(C)C)(C)C>C(#N)C>[Cl-:1].[Cl:26][C:27]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:28]=1[CH:29]=[CH:30][CH2:31][N+:8]1[CH:9]=[CH:10][N:6]([CH2:5][CH:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:3]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=2[Cl:1])[CH:7]=1
Reactant: ClCC=Cc1ccc(Cl)cc1Cl
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: Clc1ccc(C=CC[n+]2ccn(CC(OCc3ccc(Cl)cc3Cl)c3ccc(Cl)cc3Cl)c2)c(Cl)c1
Product: [Cl-]

Procedure:
A mixture of 4.2 parts of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazole, 2.7 parts of 2,4-dichlorocinnamylchloride and 40 parts of acetonitrile is stirred and refluxed overnight. Upon the addition of diisopropyl ether, the product crystallizes. It is filtered off and dried, yielding 5.8 parts of 1-(2,4-dichlorocinnamyl)-3-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]-imidazolium chloride; mp. 142.2° C.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)C=CC=CC=1.C1COCC1.C([Li])CCC.[CH3:45][C:46]1[CH:61]=[CH:60][C:49]([CH2:50][O:51][C:52]2[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=2)[CH:55]=O)=[CH:48][CH:47]=1>CCCCCC.O>[CH3:45][C:46]1[CH:61]=[CH:60][C:49]([CH2:50][O:51][C:52]2[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=2)/[CH:55]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:14][CH:15]=2)=[CH:48][CH:47]=1
Reactant: c1ccc([P+](Cc2ccc(CN3CCCCC3)cc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(COc2cccc(C=O)c2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1ccc(COc2cccc(/C=C/c3ccc(CN4CCCCC4)cc3)c2)cc1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a mixture comprising triphenyl[4-(piperidinomethyl)benzyl]phosphonium bromide (1.06 g) and THF (10 ml) was added dropwise under a nitrogen atmosphere a 1.6 M solution of butyllithium in hexane (1.28 ml), and the resulting mixture was stirred for 30 minutes. To this reaction mixture was added 3-(4-methylbenzyloxy)benzaldehyde (453 mg), and the resulting mixture was stirred at room temperature for one hour, was then mixed with water (100 ml) and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was then evaporated under reduced pressure to remove the solvent. The resulting residue was subjected to purification using column chromatography (ethyl acetate/triethylamine=20/1) and to recrystallization to obtain (E)-1-[4-[3-(4-methylbenzyloxy)styryl]benzyl]piperidine (compound 97) (330 mg) as colorless crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.BrBr>ClCCl>[CH3:7][CH:6]([CH3:8])[C:5]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(C)C(=O)Cl
Reactant: c1ccsc1
Agent: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 125.3 %

Procedure:
Aluminum chloride (4.75 g, 35.7 mmol, 3 eq) was diluted in ice cold dichloromethane (30 mL). Isobutyryl chloride (4 mL, 38 mmol, 3.2 eq) in dichloromethane (30 mL) was added to the aluminum chloride suspension at 0° C., and the mixture was stirred at 0° C. for 30 minutes. Thiophene (1 g, 11.9 mmol) was added as a solution in dichloromethane (30 mL) over 10 minutes. The reaction was stirred at 0° C. for 30 minutes, then at rt for 1 h. Bromine (0.65 mL, 12.6 mmol, 1.1 eq) was added dropwise at 0° C., and the reaction mixture was slowly warmed to rt overnight. The mixture was cooled to 0° C., and was carefully quenched by the dropwise addition of water. The reaction mixture was extracted with dichloromethane, and the combined organics washed with saturated aqueous sodium bicarbonate. The combined organics were then dried over sodium sulfate, filtered, and concentrated. The crude product was purified by isco combiflash, eluting with 0-10% ethyl acetate in hexanes to afford a slightly yellow oil (2.3 g, >100%).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:56])[CH:47]([C:49]1[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=1)[OH:48].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH3:44][O:45][C:46](=[O:56])[CH:47]([C:49]1[CH:54]=[CH:53][C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:51][CH:50]=1)[OH:48]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)C(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Temperature: 91 °C
Reaction time: 5 h
Yield: 31.6 %

Procedure:
Degassed N,N-dimethylformamide (0.26 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 22.4 mg, 0.0343 mmol), 4-bromo-phenyl-hydroxy-acetic acid methyl ester (Example 154-(1); 10.5 mg, 0.0428 mmol), tetrakis(triphenylphosphine)palladium (0) (6.2 mg, 0.0054 mmol) and potassium phosphate (14.1 mg, 0.0664 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 86 to 96° C. for five hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (7.0 mg, 32%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:18]3[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=3[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:21][NH:22]2)=[CH:27][CH:26]=1
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2cc(F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5cc(F)ccc45)C(=O)NC3=O)c21
Temperature: 25 °C

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.466 g, 2.48 mmol) and (6-fluoro-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.543 g, 2.45 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (8.6 mL, 8.6 mmol) dropwise over 5 minutes. The mixture was heated at 65–70° C. for 15 h. The mixture was cooled to room temperature, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated onto flash SiO2. Flash chromatography (40% EtOAc/hex) gave the title compound as a bright orange solid which was dried under vacuum at 80–100° C. overnight (0.342 g, 39%). 1H NMR (400 MHz, DMSO-d6) 11.49 (br s, 1H), 11.08 (s, 1H), 7.49 (dd, J=6, 3 Hz, 1H), 7.30 (d, J=2.3 Hz, 1H), 7.24 (d, J=3 Hz, 1H), 6.86–7.05 (m, 4H), 6.43 (d, J=3 Hz, 1H), 6.40 (d, J=7 Hz, 1H), 3.76 (s, 3H). MS (electrospray, m/z) 360.0 (M++1), 358.0 (M−−1). HRMS 360.1161 (M++1, calcd for C21H15FN3O2 360.1148). Anal. Calcd for C21H14FN3O2: C, 70.19; H, 3.93; N, 11.69. Found: C, 69.94; H, 3.92; N, 11.59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:34])[CH3:33].FC(F)(F)C(O)=O.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of N-(2-chloro-4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (100 mg, 0.209 mmol) in DCM (3 mL) was cooled to 0° C., treated with trifluoroacetic acid (3 mL, 40.4 mmol), and the yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was treated with 2 M NH3 in MeOH and concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 2% to 10% 2M NH3.MeOH in DCM, to give N-(2-chloro-4-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (70 mg, 0.178 mmol, 58.3% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.62 (s, 1H); 13.01 (s, 1H); 9.80 (s, 1H); 9.47 (s, 1H); 8.38-8.43 (m, 1H); 8.31 (d, J=1.57 Hz, 1H); 7.54-7.60 (m, 1H); 7.47-7.52 (m, 1H); 7.07 (dd, J=7.82, 4.69 Hz, 1H); 2.88 (s, 3H); 2.07 (s, 3H). m/z (ESI, +ve ion) 394 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of ethyl 4-piperidinecarboxylate (14.71 g) and triethylamine (12.04 g) in chloroform (200 mL) was cooled to 0° C. and treated dropwise with benzyl chloroformate (17.91 g). The resulting mixture was stirred at 0° C. for 1 hour, then was warmed to room temperature and was stirred for 12 hours. The mixture was then washed (1N hydrochloric acid, brine), dried, filtered and evaporated to yield a pale yellow oil (26.4 g). The oil was purified by chromatography, with dichloromethane:methanol (95.5) as the eluent, to afford the urethane as a colorless syrup (22.15 g); NMR: 7.35 (m, 5), 5.07 (s, 2), 4.06 (q,2, J=7.0), 3.91 (broad d, 2, J=13.3), 2.95 (broad, 2), 2.53 (m, 1), 1.82 (broad d, 2, J=13.3), 1.41 (m, 2), 1.18 (t, 3, J=7.0).
Reaction SMILES: [Cl-:1].[Cr+3:2].[Cl-:3].[Cl-].[NH2:5][C@H:6]([C:12]([OH:14])=O)[CH2:7][CH2:8][C:9](O)=[O:10]>C(O)C>[NH2:5][C@H:6]([C:12]([Cl:3])=[O:14])[CH2:7][CH2:8][C:9]([Cl:1])=[O:10].[Cr:2]
Reactant: [Cl-]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: [Cr+3]
Solvent: CCO
Product: N[C@@H](CCC(=O)Cl)C(=O)Cl
Product: [Cr]
Reaction time: 3.5 h

Procedure:
15.85 grams (0.1 Mole) of chromium chloride, 29.4 grams (0.2 Mole) of glutamic acid and 100 ml ethanol were placed into a beaker provided with a reflux condenser. The mixture was stirred and boiled at atmospheric pressure for 3.5 hours. The mixture was cooled and thereafter filtered yielding 43.8 grams of chromium glutamate chloride complex in the form of a fine blue powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9](NC(OC(C)(C)C)=O)([NH:13]C(OC(C)(C)C)=O)[C:8]1=[O:29])[CH3:6])[CH3:2].C(OC(=O)NC1CCCN(CC2NC(C3C=CC(C4C=CC(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)=CC=4)=CC=3)=CN=2)C1=O)(C)(C)C>>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH2:13])[C:8]1=[O:29])[CH3:6])[CH3:2].[CH2:1]([O:3][C:4](=[O:30])[CH:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH2:13])[C:8]1=[O:29])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1CCCC(NC(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C1=O
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: CCOC(=O)C(C)N1CCCC(N)C1=O

Procedure:
2-(3-Amino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester 2-(3-Amino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester was prepared using method 804 substituting 2-[3,3-bis(tert-butoxycarbonylamino)-2-oxo-piperidin-1-yl]-propionic acid ethyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C10H18N2O3 calculated 214.2 observed [M+1]+215.2; rt=1.21 min.
Reaction SMILES: C1C=C2C3[C:12]([C:13]([C:21]4[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=4)(C4C=CC(O)=CC=4)C2=CC=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.N1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:34]1COC[CH2:35]1>>[C:21]1([C:13]2[C:12]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: c1ccncc1
Product: c1ccc(-c2cccc3c2Cc2ccccc2-3)cc1
Yield: 75 %

Procedure:
1,2,4-trimellitic anhydride acid chloride (120 mmole) was dissolved in 60 mL of anhydrous THF. Fluorene-9-bisphenol (60 mmole) and pyridine (14.5 mL) were dissolved in another 100 mL of anhydrous THF, and then slowly and dropwise added into the 1,2,4-trimellitic anhydride acid chloride solution under nitrogen, and then completely reacted at 40° C. for 12 hours. The reaction result was filtered to remove the salt thereof, and the solvent of the filtrate was removed by a rotary evaporator to obtain a solid. The solid was washed with n-hexane and re-crystallized from acetic anhydride two times to obtain a white solid (yield=75%). The 1H NMR spectrum of the white solid is listed below: 1H NMR (CDCl3, 400 MHz, ppm): 8.77 (s, 2H), 8.69 (d, 2H), 8.14 (d, 2H), 7.82 (d, 2H), 7.43 (m, 4H). The above-mentioned reaction is represented as:
Reaction SMILES: [ClH:1].C([S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:8]/[C:7]/1=[CH:25]\[C:26]1[N:27]=[N:28][N:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:30]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CO>[ClH:1].[CH:15]1([C:13](=[O:14])[CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([SH:5])/[C:7](=[CH:25]/[C:26]3[N:27]=[N:28][N:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:30]=3)/[CH2:8]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:17][CH2:16]1
Reactant: COC(=O)Cn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)Cn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Yield: 47.1 %

Procedure:
Following a procedure similar to that described in Example 151, (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}piperidine hydrochloride (300 mg) was treated with potassium carbonate in methanol and the concentrated extract was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (130 mg, yield: 47%) as a yellow amorphous solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N[CH:8]=[N:9][C:10]1[N:14]2[CH:15]=[CH:16][C:17]3[C:22]([C:13]2=[N:12][C:11]=1[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])#N>O>[ClH:23].[ClH:23].[CH:1]([NH:4][CH:8]=[N:9][C:10]1[N:14]2[CH:15]=[CH:16][C:17]3[C:22]([C:13]2=[N:12][C:11]=1[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])([CH3:3])[CH3:2]
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1N=CNC#N
Reactant: CC(C)N
Solvent: O
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N=CNC(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropylamine (2 ml) was added to a suspension of N-cyano-N'-(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)formamidine (0.95 g) in water (1.5 ml) and the mixture was stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with water and dissolved in ethanol. To the solution was added a saturated solution of hydrogen chloride in ethanol and the mixture was evaporated in vacuo. The residual solid was washed successively with a mixture of diethyl ether and ethanol and isopropanol and then dried in a desiccator to give N-isopropyl-N'-(7-chloro-2-methylimidazo[2,1-a]isoquinolin-3-yl)formamidine dihydrochloride (0.73 g).
Reaction SMILES: [C:1]([C:6]([O:8][CH2:9][CH3:10])=[O:7])#[C:2][C:3]([O-:5])=[O:4].[Br:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[OH:20].[F-].[CH2:22]([N+](CCCC)(CCCC)CCCC)[CH2:23]CC>CC(O)C>[Br:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[O:20]/[C:1](=[CH:2]\[C:3]([O:5][CH2:22][CH3:23])=[O:4])/[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COc1ccc(O)c(Br)c1
Reactant: CCOC(=O)C#CC(=O)[O-]
Agent: [F-]
Solvent: CC(C)O
Product: CCOC(=O)/C=C(\Oc1ccc(OC)cc1Br)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Ethyl acetylenedicarboxylate (17.8 ml, 0.145 mol) was added to 2-bromo-4-methoxyphenol (Synlett p1241, 1997) (27.3 g, 0.134 mol), in anhydrous 2-propanol (55 ml) followed by the addition of a catalytic amount of tetrabutylammonium fluoride (0.4 ml, 1.0 M in THF). The solution was stirred at room temperature overnight and was then heated to reflux for 30 min. Upon cooling a precipitate formed. The solution was cooled and filtered to give diethyl (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate as a yellow solid (29.9 g, 62% yield). Note: the solid contains 10% of diethyl (2E)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate. GC/MS (EI, M+) m/z 344 and 346.
Reaction SMILES: [SH:1][C:2]1SC=[C:5]([C:7]2C=CC=[CH:9][CH:8]=2)[N:6]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:6]1[CH:5]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Sc1nc(-c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 65 °C
Yield: 145.7 %

Procedure:
4-(2-(4-Phenyl)thiazolyl)thio-1-nitrobenzene: A solution of 2-mercapto-4-phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluoro-4-nitrobenzene (2.3 mL, 21.7 mmoles) followed by K2CO3 (3.18 g, 23 mmol), and the mixture was heated at approximately 65° C. overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The solid residue was triturated with a Et2O/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) Rf 0.49; 1H-NMR (CDCl3) δ 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4](C)=[CH:3]1.I([O-])(=O)(=O)=[O:12].[Na+].[OH2:17]>[Ru]=O.CC(C)=O>[O:17]=[C:4]([CH3:3])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2]([OH:1])=[O:12]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)CC(C)(C)CC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
There was added 0.15 part of solid ruthenium oxide to a solution of 2.8 parts of isophorone and 2.5 parts of sodium periodate in about 200 parts of acetone to 40 parts of water. The resulting yellow solution was stirred while 5 parts of sodium periodate, 50 parts of water and 20 parts of acetone was added over an hour. The resulting suspension was stirred 48 hours at room temperature then filtered through Celite. The resulting filtrate was then extracted with methylene chloride. The organic phase was extracted with CHCl3. Acidification of the base washings provided 2 parts, or a 63% yield of 5-keto-3,3-dimethylhexanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)(Cl)(Cl)Cl>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][Br:17])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1cc(Br)ccc1CBr
Yield: 55.3 %

Procedure:
5.0 g of 2-chloro-4-bromotoluene are dissolved in 120 ml of CCl4. 4.3 g of NBS and 1.6 g of AIBN are added. The mixture is heated at reflux for 15 hours, water is added, the two phases are separated and then extraction is carried out with CH2Cl2. Purification is carried out by chromatography on a silica column eluted with petroleum ether. 3.8 g of liquid are obtained.
Reaction SMILES: [H-].[K+].[C:3]1([CH:13]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[N:23][C:17]=3[N:16]3[CH:24]=[CH:25][CH:26]=[C:15]3[C:14]2=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C1COCC1>[CH3:28][N:29]([CH3:33])[C:30]([O:27][C:14]1[C:15]2[N:16]([CH:24]=[CH:25][CH:26]=2)[C:17]2[N:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][C:13]=1[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[O:31]
Reactant: CN(C)C(=O)Cl
Reactant: O=C1c2cccn2-c2ncccc2OC1c1cccc2ccccc12
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)OC1=C(c2cccc3ccccc23)Oc2cccnc2-n2cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a suspension of potassium hydride (0.281 g, 2.45 mmol, 35% in oil) in anhydrous THF (5.0 mL) was added the the (±)-6-(1-naphthyl)pyrrolo[1,2-d]pyrido[3,2-b][1,4]oxazepin-7(6H)-one (800 mg, 2.45 mmol) dissolved in anhydrous THF (5 mL). The reaction mixture was stirred at rt for 2 h, and then dimethylcarbamoyl chloride (0.303 g, 2.82 mmol) was slowly added. After stirring for 12 h at 30° C., the solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed (dichloromethane and hexane 1:3) to give the PBOX-13 in 78% yield. IR (neat) 1725 cm−1; 1HNMR (CDCl3) δ 2.61 (s, 3 H), 2.70 (s, 3 H), 6.44 (m, 2 H), 7.10 (m, 2 H), 7.41-7.59 (m, 4 H), 7.62-7.90 (m, 3 H), 8.12 (m, 1 H), 8.25 (m, 1 H).