Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10]CC2C=CC=CC=2)=[C:4]1[CH2:18][O:19]C)[CH3:2].[ClH:21]>>[ClH:21].[CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([OH:10])=[C:4]1[CH2:18][OH:19])[CH3:2]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Agent: Cl
Product: CCn1ccc(=O)c(O)c1CO
Yield: 73 %

Procedure:
2.0 g (7.33 mmol) 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one was dissolved in 50 ml of 4N hydrochloric acid and refluxed for 6 hours. Concentration to dryness in vacuo afforded the crude product. Recrystallisation from methanol/diethyl ether gave the pure title compound (1.1 g, 73%) as a white crystalline solid. m.p. 168-169° C.
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH:3]12[O:24][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
Benzyl 2,5-dihydropyrrole-1-carboxylate (25 g) was dissolved in chloroform (125 mL), and mCPBA (39 g) was slowly added with ice cooling. The mixture was stirred at room temperature for 1 day, then diluted with chloroform, and washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried with anhydrous sodium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=8:2-1:99) to obtain benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (18 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].O.[N+:14]([O-])([OH:16])=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-4-fluoro-5-nitrophenol (4.0 g, 17 mmol) in methylene chloride (29.5 mL), 2.0 M nitric acid in DCM (25 mL) was added and the mixture was stirred for 15 min at room temperature. The mixture was poured over cold water and extracted with methylene chloride to give the product.
Reaction SMILES: [N+:1]([C:4]1[C:5](NN)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]>CO.O.C([O-])(=O)C.[Ag+]>[N+:10]([C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)([O-:12])=[O:11]
Reactant: NNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Yield: 21.4 %

Procedure:
Silver acetate (2.0 g) was added to a solution of the crude 3,5-dinitro-pyridinyl-hydrazine (2.2 g) in a mixture of methanol:H2O (1:1, 6 ml), and the mixture was stirred at reflux overnight. Solvent was evaporated, then water and conc. NH4OH were added. The mixture was extracted with ethyl ether, the combined extracts were dried over MgSO4, concentrated and purified by column chromatography (5:1 hexane: ethyl acetate) to give the title compound (400 mg) in 21.8% yield. MS (DCI/NH3) m/e: 124 (M-46+1). 1H NMR (CDCl3, 300 MHz) δ: 9.77 (m, 2H), 9.27 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([OH:10])[N:4]=1
Reactant: CSc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 3 h
Yield: 49 %

Procedure:
2-Methylsulfanyl-pyrimidine-4,6-diol (10 g, 63 mmol) was added portion wise to a stirring solution of glacial acetic acid (25 mL) and concentrated nitric acid (10 mL) at 50° C. After 3 h, the reaction mixture was poured onto crushed ice and the product was isolated by filtration as a yellow solid (6 g, 49%). MS (ESI, negative mode): mass calcd. for C5H5N3O4S, 203.0; m/z found, 202.4 [M−H].
Reaction SMILES: ClCCl.[CH2:4]([C@H:6]1[O:8][CH2:7]1)[Cl:5].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC)(C)(C)C.CS(O)(=O)=O>[Cl:5][CH2:4][C@@H:6]([OH:8])[CH2:7][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC[C@@H]1CO1
Reactant: Oc1ccccc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O[C@H](CCl)COc1ccccc1
Reaction time: 1 h
Yield: 122 %

Procedure:
To a mixture of N′,N′-disalicylidene ethylenediaminatocobalt(II) (138 mg, 0.425 mmol) and dichloromethane (10 ml) was added methanesulfonic acid (3 μl, 0.510 mmol) and the reaction system was stirred for 1 hour while being filled with air. The reaction solution was evaporated to dryness under reduced pressure to give a crude blackish (dark) brown cobalt (III) complex. Thereto was added tert-butylmethyl ether (4 ml) to disperse the crude cobalt (III) complex and then thereto were added (S)-epichlorohydrin (2.00 ml, 25.5 mmol, optical purity 99% e.e.) and phenol (2.00 g, 21.3 mmol) in order. The mixture was stirred for 24 hours under nitrogen atmosphere at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (20 ml), the solution was washed with a 6% aqueous sodium hydroxide solution (10 ml) and a saturated sodium chloride solution (10 ml) in order, and the organic layer was condensed under reduced pressure to give crude (S)-1-chloro-3-phenoxy-2-propanol (4.85 g). This crude compound (4.85 g) was dissolved in isopropanol (10 ml) and thereto was added a 24% aqueous sodium hydroxide solution (4.50 g, 25.5 mmol) under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (50 ml) and the solution was washed with water (20 ml), a saturated aqueous ammonium solution (20 ml) and a saturated aqueous sodium chloride solution (20 ml) in order. The organic layer was condensed under reduced pressure to give crude (R)-glycidylphenyl ether (3.24 g). Quantitative analysis by gas chromatography and optical purity measurement by HLPC were conducted on the compound. As a result the subject compound, (R)-glycidylphenyl ether (3.07 g, 96.1%) was produced with optical purity at. 99% e.e.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21](O)=O)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:21]([CH2:20][C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[N:10]=[CH:11][CH:12]=[CH:13]4)=[N:9][N:8]=2)[N:7]=1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To a suspension of (6-chloro-pyridazin-3-yl)-hydrazine (1.62 g, 11.2 mmol) and 6-quinoline acetic acid (2.1 g, 11.2 mmol) in dichloromethane (150 mL) at ambient temperature was added dicyclohexylcarbodiimide (2.3 g, 11.2 mmol). After stirring at room temperature for 4.5 hours the formed precipitate was filtered off, washed with dichloromethane and dried in vacuo to return quinolin-6-yl-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide which also contained dicyclohexylurea. This mixture was then taken up in acetic acid (250 mL) and heated for 4 hours at 50° C. After such time the mixture was concentrated onto silica gel in vacuo and purified via flash column chromatography (SiO2, CH2Cl2:CH3OH 100:0-97:3) to return the title compound as a white solid (3.35 g, 11.1 mmol, 99% yield). Analytical data presented in Table 1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:9]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([NH:9][NH:8][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Product: CC(C)(C)OC(=O)NNC1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (2.50 g) and tert-butyl hydrazinecarboxylate (3.47 g) in methanol (10 mL) was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in THF (25 mL), acetic acid (4.3 mL) and sodium borohydride (0.525 g) were added thereto, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.34 g).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4C(O)=O)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:9]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C(Br)C(C1C=CC([C:48]2[NH:49][C:50]3N(CC4CCCCC4)C(=O)N(CC4CCCCC4)C(=O)[C:55]=3[N:56]=2)=CC=1)Br)C>CN(C)C=O.ClCCl>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[CH:23][CH:24]=[C:25](/[CH:11]=[CH:15]/[C:16]([N:49]5[CH:50]=[CH:55][N:56]=[CH:48]5)=[O:17])[CH:26]=4)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[C:9]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Reaction time: 18 h

Procedure:
A slurry of (E)-4-[(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid (from part (a) of this example, 0.50 g) in anhydrous N,N-dimethylformamide (10 mL) was heated briefly to near reflux under nitrogen. N,N′-Carbonyldiimidazole (Aldrich, 0.211 g) was then added to the pale yellow slurry, which thinned and turned orange as a gas evolved. Within minutes the slurry turned a bright yellow and thickened as a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow solid was washed with dichloromethane (30 mL), and dried at 40° C. to provide (E)-1,3-bis(cyclohexylmethyl)-8-[3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl]-9H-purin-2,6(1H,3H)-dione as a yellow powder (0.32 g). A mixture of this sample (0.32 g), nonaethylene glycol monomethyl ether (from part (a) of example 10, 0.277 g) and anhydrous potassium carbonate (0.170 g) in acetonitrile (10 mL) was refluxed for 20 h. Chloroform (50 mL) was added and the solution was washed with 1N HCl, (20 mL). The organic layer was washed with brine, dried (magnesium sulfate), and eluted from a silica gel column with 10% methanol-chloroform. Evaporation of solvents left yellow waxy solid which was reprecipitated from ethyl acetate-hexanes. The yellow waxy solid precipitate was filtered and dried to (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid nonaethylene glycol methyl ether ester (0.355 g, 65%); 1H-NMR (DMSO-d6) δ: 8.24 (d, J=8.4, 2,2 CH), 8.06 (d, I=8.6, 2, 2 CH), 4.40 (m, 2, CH2O), 3.90 (d, J=7.3, 2, CH2N), 3.75 (m, 4, CH2N and CH2O), 3.70-3.40 (m, 32, 16 CH2), 3.19 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:13]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:33].Cl.O1CCOCC1>CO>[ClH:33].[O:31]=[C:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][N:14]1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@H]1CCCN(C2CCNCC2)C1=O)OCc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A flask was charged with (S)-tert-butyl 3-(benzyloxycarbonylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-B; 5.0 g, 12 mmol), CH2Cl2 (50 mL), and methanol (5 mL), 4N HCl in dioxane (29 mL, 116 mmol) was added and the reaction stirred overnight. The reaction was concentrated to afford crude (S)-benzyl 2-oxo-1,4′-bipiperidin-3-ylcarbamate hydrochloride (4.3 g, 100%) which was taken forward without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:13]([CH3:16])([O-:15])=[O:14]>>[N+:13]([CH:16]=[CH:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccco1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1ccco1
Yield: 53 %

Procedure:
2-Furaldehyde (18.2 g, 190 mmol) and ammonium acetate (13 g, 169 mmol) were added to nitromethane (169 mL) and the mixture was heated to reflux for 45 min. The solution was concentrated and dichloromethane (250 mL) was added. The dichloromethane solution was washed with water (2×250 mL), dried over sodium sulfate, and filtered to obtain the crude product. Purification by column chromatography (silica gel, ethyl acetate/heptane=1/10 to 2/3) afforded pure 2-(2-nitrovinyl)-furan (14 g, 53.0%) as a yellow powder (M.P. 71-74° C.). 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.78 (d, 1H, J=13.2 Hz), 7.59 (m, 1H), 7.52 (d, 1H, J=13.5 Hz), 6.90 (d, 1H, J=3.6 Hz), 6.58 (m, 1H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 146.90, 146.67, 134.93, 125.51, 120.12, 113.46.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[N:11]=[C:12]([Br:19])[C:13]2[N:14]([CH:16]=[CH:17][N:18]=2)[CH:15]=1>ClCCl>[Br:1][C:16]1[N:14]2[CH:15]=[C:10]([Br:9])[N:11]=[C:12]([Br:19])[C:13]2=[N:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: ClCCl
Product: Brc1cn2c(Br)cnc2c(Br)n1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (1.81 g, 10.15 mmol) was added to a solution of 6,8-Dibromo-imidazo[1,2-a]pyrazine (2.0 g, 10.15 mmol) in dichloromethane (40 ml). The reaction was stirred at room temperature over night then diluted with dichloromethane (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (2×50 ml) and brine (50 ml). The organic layer was dried (MgSO4), filtered and concentrated in vaccuo. The product, 3,6,8-Tribromo-imidazo[1,2-a]pyrazine was obtained as a pink solid (2.77 g), sufficiently pure to be used in subsequent reactions.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+:38]>>[K+:38].[CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([O-:30])=[O:29])=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [K+]
Agent: [OH-]
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)[O-]

Procedure:
To the oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline (2.72 g, 5 m mole) 0.1 N potassium hydroxide (50 ml) was added and the thus produced solution was freeze-dried to obtain an amorphous powder of dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline potassium salt (2.8 g).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)(O)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O)(=O)=O.CO>ClCCCl.[Pd]>[N:1]1([CH2:6][CH:7]2[CH2:8][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][CH:17]=3)[CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1(c2ccc(CN3CCCC3)cc2)CC(CN2CCCC2)C1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: ClCCCl
Product: c1cc(C2CC(CN3CCCC3)C2)ccc1CN1CCCC1
Temperature: 25 °C

Procedure:
To a stirring solution of 3-pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol (Example 210, General procedure B, Step D) (0.10 g, 0.32 mmol) in 1,2-dichloroethane (3.2 mL) was added methanesulfonic acid (0.31 g, 3.2 mmol). The reaction was then heated to 65 □C (oil bath) for 30 minutes. The reaction was then cooled to room temperature and transferred to a Parr bottle. To this crude solution was added 5 mL of MeOH, 10% Pd/C (100 mg), and then the reaction vessel was pressurized to 45 psi with H2. After 30 min the reaction was purged with N2, filtered through a pad of celite, and concentrated under reduced pressure. Purification of this material was accomplished flash column chromatography using a 15 g ISCO column, pre-packing material on silica, eluting with a gradient of 20%–45% MeOH/CH2Cl2 with 0.1% NH4OH. The product containing fractions were collected and concentrated to give the title compound as the (0.97 mg) as the bis-methanesulfonic acid salt.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[C:4]([CH3:9])[C:5]([F:8])=[CH:6][CH:7]=1.[CH3:11][N:12](C=O)C>ClCCl.[C-]#N.[Zn+2].[C-]#N.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:10][C:3]1[C:4]([CH3:9])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: CN(C)C=O
Reactant: Cc1c(F)ccc(Br)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1c(F)ccc(C#N)c1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
3-Bromo-2-chloro-6-fluorotoluene (7.0 g, 31 mmol), zinc cyanide (3.7 g, 31 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.81 g, 1.56 mmol) was added to a flask under argon atmosphere. Dry DMF (35 mL) was added and the reaction mixture was stirred under argon at 120° C. The reaction was monitored by GC-MS and full conversion was observed after 2 hours. The mixture was diluted with dichloromethane (300 mL), washed with water (100 mL) and 4% magnesium sulfate solution (100 mL), dried over magnesium sulphate, filtered, and evaporated to give a clear oil. The product was further purified by column chromatography on silica gel using n-heptane/ethyl acetate (9:1) giving a white solid (3.79 g, 71%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24]>CN(C)C=O.O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([N:9]([CH2:25][C:23]([Cl:22])=[CH2:24])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(Cl)CCl
Reactant: N#CNc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cl)CN(C#N)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
N-(3-(trifluoromethyl)phenyl)cyanamide (18.6 g) was dissolved in N,N-dimethylformamide (DMF) (93.0 g), to which powdered potassium carbonate (20.7 g) and potassium iodide (1.7 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (13.3 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 1 hour. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 25.8 g of N-(3-(trifluoromethyl)-phenyl)-N-(2-chloro-2-propenyl)cyanamide as an oil (99% yield in appearance). The percentage areas of gas chromatography and liquid chromatography were 98% and 99%, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:20][Si:19]([C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)([CH3:22])[CH3:21]
Reactant: C#Cc1ccc(C)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.1 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.64 g (0.0054 mole) of 4-methylphenylacetylene, 1.50 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.011 g (0.0058 mmole) of CuI, 0.103 g (0.146 mmole) of bis(triphenylphosphine)palladium(II)dichloride in 10 ml of THF and 10 ml of triethylamine. The brown solution turned to an orange-yellow suspension when solid started to form. The mixture was stirred at room temperature under nitrogen for 3 days. It was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 25 ml of chloroform and the solution was washed two times with water (15 ml each) and then dried over anhydrous MgSO4, filtered and concentrated, 1.43 g (quantitative yield) of solid was obtained. 1HNMR indicated ˜10% of by product present. The solid product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].C1(C)C=CC=CC=1.[OH-:32].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:32])[CH3:2]
Reactant: [OH-]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 120 °C
Reaction time: 38 h
Yield: 88.9 %

Procedure:
To a 100 mL volume four-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (6.57 g), toluene (16.7 g), benzyltrimethylammonium chloride (0.16 g), and sodium hydroxide (2.86 g) were added under a nitrogen atmosphere, and stirred at 120° C. for 38 hours. Then, water (24.2 g) was added at room temperature. The organic layer was removed, and the aqueous layer was mixed with 3.5 w/w % of hydrochloric acid (20 g) at the same temperature, and filtered. The residue was washed with water (12 g) and dried to give 4.8 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).