Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[N:23]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[H-].[Na+].[H][H].Cl[CH2:37][O:38][CH3:39]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[N:23]=[C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[C:13]=2[C:14]([O:16][CH2:37][O:38][CH3:39])=[O:15])[N:27]=1
Reactant: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1
Reactant: [H][H]
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)cccc1Oc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
1.5 g (3.5 mmol) of 2,6-bis[(4.6-dimethoxypyrimidin-2-yl)oxy]benzoic acid was dissolved in N,N-dimethylformamide, and 0.1 g of 60% sodium hydride was added to the resultant solution with stirring. After the generation of hydrogen ceased, 0.4 g of chloromethylmethylether was added to the solution and the resultant mixture was reacted at 100° C. for 3 hours. After completing the reaction, ice water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated and washed with water. The washed ethyl acetate layer was then dried to be concentrated, and an oily product obtained thereby was subjected to column purification to obtain 1.0 g of a white crystal having a melting point of from 95° to 96° C.
Reaction SMILES: [C:1]([O:10]C)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B(F)(F)F.CC[O:18]CC.[O-]O.[C:23]1([CH:29]([CH3:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:29]([O:18][O:10][C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:31])[CH3:30]
Reactant: CC(C)c1ccccc1
Reactant: CCOCC
Reactant: COC(C)(C)c1ccccc1
Agent: FB(F)F
Agent: [O-]O
Product: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 99.8 %

Procedure:
There are loaded into a 100 ml glass flask, 30 grams of methyl cumyl ether (0.2 moles), 0.1 ml of boron trifluoride diethyl etherate and 9 grams of technical cumene hydroperoxide (0.05 moles) having the same composition as that used in Example 1. The mixture is heated to 60° C. with stirring and maintained at a pressure of 200 mmHg. After 30 minutes the conversion of the cumene hydroperoxide is 100% with a yield of 99.8% of dicumyl peroxide.
Reaction SMILES: [IH:1].[CH3:2][C:3]1([CH3:14])[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[NH:6][C:5](SC)=[N:4]1.[NH2:15][NH2:16]>C(O)C.CCOCC>[IH:1].[NH:15]([C:5]1[NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][CH2:9][C:3]([CH3:14])([CH3:2])[N:4]=1)[NH2:16]
Reactant: NN
Reactant: CSC1=NC(C)(C)CCC(C)(C)N1
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CC1(C)CCC(C)(C)NC(NN)=N1

Procedure:
A 10.0 g portion of 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2-methylthio-1H-1,3-diazepine, hydroiodide was dissolved in 150 ml of ethanol and 2.5 g of hydrazine was added. The mixture was refluxed 6 hours, diluted with 300 ml of ether and stored at -10° C. The solid was removed by filtration. The filtrate was concentrated to about 25 ml in vacuo, diluted with 50 ml of 2-propanol, then 200 ml of ether and stored at -10° C. The solid was collected, washed with ether and dried in vacuo at 60° C., giving 3.5 g of the desired intermediate, mp 154°-155° C.
Reaction SMILES: [CH2:1]1[O:5][CH:4]([CH:6]([OH:9])[CH2:7][OH:8])[C@@H:3]([OH:10])[CH:2]1[OH:11].[C:12](OC)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CO.C[O-].[Na+].[PH2]([O-])=O.[Na+]>>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:8][CH2:7][CH:6]([OH:9])[C@H:4]1[O:5][CH2:1][C@H:2]([OH:11])[C@H:3]1[OH:10])=[O:24]
Reactant: CCCCCCCCCCCC(=O)OC
Reactant: OCC(O)C1OCC(O)[C@@H]1O
Agent: C[O-]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
After 469 g of a 70% by weight sorbitan aqueous solution (aldehyde value of sorbitan: 6.5 ppm) and 556 g of methyl laurate were charged into a 2000 mL four-neck flask fitted with a stirring apparatus, a thermometer, and a nitrogen gas inlet, dehydration was performed at 110° C. under a nitrogen stream at normal pressure for 1 hour and further at 110° C. under a nitrogen stream at 4 kPa for 1 hour. The whole was cooled to 65° C. and, after 35.4 g of a 5% by weight sodium methoxide methanol solution and 0.44 g of sodium hypophosphite were added thereto, was heated under a nitrogen stream at normal pressure to 150° C. as a reaction temperature. After the temperature reached 150° C., the reaction was carried out under a nitrogen stream at normal pressure. At the time point when the spot of methyl laurate as a raw material disappeared on thin-layer chromatography, it was judged that the reaction was completed. The reaction time was 8 hours and, after the completion of the reaction was confirmed, the product was filtrated at 80° C. to obtain sorbitan monolaurate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole (8 g) in methanol (40 mL)/ethyl acetate (400 mL) is added palladium-on-carbon (Pd/C) (10%, 0.5 g) and ammonium formate (7.27g). The mixture is stirred at 50° C for 2 hours, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and ethyl acetate. The organic layer is washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and rotary evaporated to afford pure 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14]O)[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][Br:36])[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]
Reactant: BrC(Br)(Br)Br
Reactant: CS(=O)(=O)n1ccc2ccc(CO)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)n1ccc2ccc(CBr)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A solution of N-methanesulfonyl-6-hydroxymethylindole (340 mg, 1.51 mmol, from above) and triphenylphosphine (Ph3P) (415 mg, 1.58 mmol) in 5 ml of dry CH2Cl2 was cooled to 0° C. and a solution of carbon tetrabromide (551 mg, 1.66 mmol) in 3 ml dry CH2Cl2 was added dropwise via cannula (2 ml CH2Cl2 rinse). The reaction mixture was allowed to warm to room temperature. After 4 hr, the solvent was removed by rotary evaporation and the resultant purple oil was purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane) to give 290 mg of N-methanesulfonyl-6-bromomethylindole, a colorless oil which solidified on standing (67% yield).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[FH:20].B(F)(F)F>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:2]3[CH:10]=[CH:9][C:5]([F:20])=[CH:4][CH:3]=3)=[CH:4][CH:3]=2)=[O:11])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: Fc1ccccc1
Reactant: F
Agent: FB(F)F
Product: O=C(c1ccc(F)cc1)c1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 122.6 %

Procedure:
20.3 g of terephthaloyl dichloride, 19.2 g of fluorobenzene and 50 g of hydrogen fluoride were initially introduced into a 250 ml stainless steel autoclave and boron trifluoride was introduced under pressure at 10 bar. The autoclave was shaken for 16.5 h at room temperature. Working-up was carried out by initially evaporating the volatile components at room temperature and then at 60° to 100° C. and recrystallizing the residue from chlorobenzene in the presence of sodium carbonate. 19.76 g of 1,4-bis-(4-fluorobenzoyl)-benzene were obtained in the form of colorless crystals of m.p. 221° C. Examination by means of high pressure liquid chromatography (HPLC) gave a degree of purity of 99.5%.
Reaction SMILES: [CH2:1]([OH:3])C.[Na].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)=O>C1(C)C=CC=CC=1.O>[CH:1]([CH:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([O:14][CH2:15][CH3:16])=[O:13])=[O:3]
Reactant: CCO
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCOC=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C=O)C(=O)OCC
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Ethanol (20 cm3) was added portionwise to a suspension of finely divided sodium (10.0 g) in dry toluene (100 cm3). On completion of the addition the mixture was heated for 3.5 hours at 80° C. To the resulting yellow suspension, cooled to 20° C., was added dropwise, over a period of 1 hour, a mixture of diethyl succinate (70.0 g) and ethyl formate (35.0 g), whilst the temperature of the mixture was maintained in the range 20° to 30° C. The mixture was kept at the ambient temperature for 16 hours after which water (100 cm3) was added carefully.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1.[C:18]1(=[O:25])[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]1.C([O-])(=O)C.[NH4+:30]>C(O)C>[CH2:3]([C:4]1[NH:30][C:20]2[CH2:21][CH2:22][CH2:23][C:18](=[O:25])[C:19]=2[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH:5]=1)[CH:2]([CH3:17])[CH3:1]
Reactant: CC(C)CC(=O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC(C)CC1=CC(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Yield: 42.8 %

Procedure:
A solution of 5-methyl-1-(3-nitrophenyl)-1-hexen-3-one (2.52 g), 1,3-cyclohexanedione (1.22 g) and ammonium acetate (1.88 g) in ethanol (65 mL) was stirred at reflux for 7.5 hours. After removal of the solvent, the residue was chromatographed (ethyl acetate/hexane 2:1) to yield the title compound (1.51 g) as a yellow solid; mp 158°-160° C.; NMR: 0.81 (d,3, J=5.8, CH3), 0.86 (d,3, J=5.8, CH3), 1.77-1.97 (m,5, CH2, CH), 2.10-2.23 (m,2, CH2), 2.46 (m,2, CH2), 4.59(d,1,J=4.8, CH), 4.64 (d,1, J=5.8, CH), 7.53 (m,1, Ar), 7.65 (m, 1, Ar), 7.97 (m,2, Ar), 8.49 (s,1, NH); MS: m/z=326(M). Analysis for C19H22N2O3 : Calculated: C, 69.92; H, 6.79; N, 8.58; Found: C, 70.03; H, 6.81; N, 8.54.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[CH:6][N:5]2[C:27]=1[CH3:28].[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][CH2:30]1>CC(C)=O>[CH2:19]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[CH2:11][NH:10][C:9]1[C:4]2[N:5]([C:27]([CH3:28])=[C:2]([CH3:1])[N:3]=2)[CH:6]=[C:7]([C:21]([NH:23][CH2:24][CH2:25][O:26][C:29](=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:22])[CH:8]=1)[CH3:20]
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Reactant: O=C1CCC(=O)O1
Solvent: CC(C)=O
Product: CCc1cccc(C)c1CNc1cc(C(=O)NCCOC(=O)CCC(=O)O)cn2c(C)c(C)nc12
Yield: 227.9 %

Procedure:
2,3 dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-hydroxyethyl-imidazo[1,2-a]pyridine-6-carboxamide (250 mg, 0.263 mmol) and succinic anhydride (100 mg, 1.00 mmol) were added to 7 ml of acetone. The mixture was refluxed for 48 h. The presiptated product was filtered off and washed with acetone and ether to give 288 mg (91%) of the title compound.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[C:8](=O)[C:7]2=[O:17].Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22]>>[OH2:3].[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[O:3][CH3:2])[C:7](=[O:17])[C:8](=[N:19][NH:20][C:21]([NH2:23])=[O:22])[C:9]2=[O:15]
Reactant: COc1cc2c(=O)c(=O)c(=O)c2cc1OC
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Product: COc1cc2c(=O)c(=NNC(N)=O)c(=O)c2cc1OC

Procedure:
5,6-dimethoxyindan-1,2,3-trione, monohydrate, semicarbazide hydrochloride
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:13]1[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.O>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:16]([O:15][C@@H:14]1[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:25][C@H:13]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 85.2 %

Procedure:
Benzyl alcohol (0.57 mL, 5.5 mmol) was added to a solution of β-D-ribofuranose-1,2,3,5-tetraacetate (1.59 g, 5 mmol) and zinc chloride (681.4 mg, 5 mmol) in ethyl acetate (8 mL), and the mixture was stirred with heating to 60° C. for 2 hours. After cooling the mixture to ambient temperature, water (2 mL) was added to the resulting solution, for layer separation. The resulting organic layer was washed twice with aqueous 7% sodium hydrogen carbonate solution (2 mL) and subsequently concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography, to recover the desired 1-O-benzyl-β-D-ribofuranose-2,3,5-triacetate (1.56 g; yield of 85.1%) as a colorless solid. Melting point: 65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][NH:11][C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1[NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])[C:5]#[N:6].[H-].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]([C:12]1[C:15](=[O:16])[C:14](=[O:17])[C:13]=1[NH:18][C:19]([CH3:22])([CH3:23])[CH2:20][CH3:21])[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)(C)Nc1c(NCc2ccc(C#N)cc2Cl)c(=O)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(N(Cc2ccc(C#N)cc2Cl)C(C)=O)c(=O)c1=O
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A solution of 3-chloro-4-{[2-(1,1-dimethyl-propylamino)-3,4-dioxo-cyclobut-1-enylamino]-methyl}-benzonitrile (0.829 g, 2.50 mmol, Example 76) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (5 mL) was treated with sodium hydride (0.066 g, 2.75 mmol) and stirring was continued for 15 minutes. Acetic anhydride (0.281 g, 2.75 mmol) was added. After stirring 40 minutes at room temperature, solvent was removed and the residue was partitioned between ethyl acetate and brine, and the brine fraction was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with dilute, aqueous sodium carbonate solution, with brine and dried (anhydrous sodium sulfate). Removal of solvent gave a yellow solid that was chromatographed (gravity, chloroform) on silica. The appropriate fractions were freed of solvent and the foamy residue was solidified by addition-rotoevaporation of hexane (twice). Recrystallization (twice) of the solid from acetone-hexane gave 513 mg of the title compound as a white solid: mp 150.5°-151.0° C. (softens 149.5° C.); 1H NMR (DMSO-d6) δ7.90-9.22 (broad hump, 1H), 8.10 (s, 1H), 7.84 (m, 1H), 7.51 (d, 1H), 5.29 (br s, 2H), 2.16 (s, 3H), 1.71 (q, 2H), 1.35 (s, 6H), 0.85 (t, 3H) ppm. IR (KBr): 3300, 3080, 2230, 1790, 1720, 1680 cm-1. MS (m/z) 373/375 (M+). HPLC indicates a major component (>99%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]#[N:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([OH:18])C.O>>[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH:10]=[C:11]([C:14]([NH2:15])=[O:18])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1=CCN(c2ncccc2F)CC1
Reactant: CCO
Solvent: O
Product: NC(=O)C1=CCN(c2ncccc2F)CC1
Yield: 100 %

Procedure:
3′-Fluoro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carbonitrile 20 (10.0 g, 49.2 mMol) was dissolved in ethanol:water (2:1, 150 mL) with stirring and heating. PtH(PMe2O)2(PMe2OH) (50 mg, 0.025 mol %) was added and the solution stirred under reflux for 2 h. LC/MS showed the reaction to be 100% complete after this time. The cooled solution was evaporated to dryness in vacuo to leave a white solid. The solid was filtered through a flash pad of silica gel to remove the catalyst to give the title compound as a white solid (10.9 g, 100%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH2:26])=[O:25])#[CH:16]>C(N(CC)CC)C.CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11]([O:10][C:8](=[O:9])[NH:7][C:5]1[CH:6]=[C:2]([C:16]#[C:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([NH2:26])=[O:25])[S:3][CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccccc1NC(N)=O
Reactant: CC(C)(C)OC(=O)Nc1csc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1csc(C#Cc2ccccc2NC(N)=O)c1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
To a degassed solution of 2-bromo-4-(N-tert-butyloxycarbonylamino)thiophene (261 mg, 0.94 mmol, 1 eq), 1-(2-ethynylphenyl)urea (200 mg, 1.5 eq), and triphenylphosphine (6.2 mg, 0.025 eq) in anhydrous triethylamine (2 mL) and DMF (0.5 mL) was added bis(triphenylphosphine)palladium(II) dichloride (66 mg, 0.1 eq) and copper(I) iodide (18 mg, 0.1 eq). The mixture was stirred and heated at 80° C. for 30 minutes, then cooled to room temperature and diluted with ethyl acetate. It was washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (EtOAc-Hex from 1;100 to 1:1) to yield tert-butyl[5-({2-[(aminocarbonyl)amino]phenyl}ethynyl)-3-thienyl]carbamate as a yellow oil (194 mg) which was converted to a foam after dried in vacuo.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:11]1([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1NC1CCCCC1
Yield: 85.9 %

Procedure:
A mixture of 2-fluoronitrobenzene (5.0 g, 35.4 mmol), cyclohexylamine (4.5 ml, 39.0 mmol) and potassium carbon-ate (17.1 g, 124 mmol) in acetonitrile (100 ml) was heated at reflux for 2 days. The mixture was diluted with EtOAC, washed with water then brine, dried and partially concentrated in vacuo. The solid which precipitated was collected and washed with hexane to yield the title compound (6.7 g, 86%).
Reaction SMILES: O=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH:35]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH2:35]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@@H:4]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-oxopiperidine-1,2,3-tricarboxylate of step 1n (850 mg) in toluene (10 mL) was added dropwise a solution of Ph3P═CH2 (0.25M in toluene/THF (3:1), 9.1 mL) at −10° C. The mixture was stirred and allowed to warm to RT during a period of 2 h. The mixture was diluted with ethyl acetate (75 mL) and washed with brine (3×25 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was flash chromatographed on silica gel column to afford 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-methylenepiperidine-1,2,3-tricarboxylate (546 mg). MS (ESI): 488.1 (M+Na+); 366.1 (M+H+−COO(t-Bu)).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]([C@H:43]([CH3:48])[C:44]([O:46][CH3:47])=[O:45])[S:6]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[C:11]([F:42])[CH:10]=1)(=[O:8])=[O:7].[CH2:49]1[N:54]2[CH2:55][CH2:56][N:51]([CH2:52][CH2:53]2)[CH2:50]1>CC#N>[Br-:1].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([C:20]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:18]([S:17][CH2:16][C:12]3[C:13]([F:15])=[CH:14][C:9]([S:6]([N:5]([CH2:4][CH2:3][CH2:2][N+:51]45[CH2:56][CH2:55][N:54]([CH2:53][CH2:52]4)[CH2:49][CH2:50]5)[C@H:43]([CH3:48])[C:44]([O:46][CH3:47])=[O:45])(=[O:8])=[O:7])=[CH:10][C:11]=3[F:42])=[N:22][CH:21]=2)([CH3:25])[CH3:24])=[CH:27][C:28]=1[O:33][CH3:34]
Reactant: C1CN2CCN1CC2
Reactant: COC(=O)[C@@H](C)N(CCCBr)S(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Solvent: CC#N
Product: COC(=O)[C@@H](C)N(CCC[N+]12CCN(CC1)CC2)S(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Product: [Br-]
Temperature: 60 °C
Yield: 0.1 %

Procedure:
To a solution of (R)-methyl 2-(N-(3-bromopropyl)-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate (110 mg, 0.14 mol) in MeCN (3 mL) was added DABCO (20 mg, 0.18 mol.). The reaction flask was heated at 60° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Recrystallization of the residue from DCM/Et2O (1:5) gave (R)-1-(3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluoro-N-(1-methoxy-1-oxopropan-2-yl)phenylsulfonamido)propyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide (118 mg, 99%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, 2H), 7.17-7.18 (d, 1H), 7.11 (s, 1H), 6.82-6.87 (m, 2H), 6.48-6.55 (m, 4H), 4.51-4.55 (q, 1H), 3.86-3.92 (q, 2H), 3.75 (s, 3H), 3.70 (s, 3H), 3.63-3.66 (t, 8H), 3.38-3.43 (m, 2H), 3.22-3.24 (t, 6H), 2.15-2.34 (m, 2H), 1.52 (s, 6H), 1.50 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)=[C:4]([F:10])[CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: CCOC(OCC)OCC
Product: Fc1cc(Br)ccc1C1OCCO1
Yield: 100 %

Procedure:
4-bromo-2-fluorobenzaldehyde (9.4 g, 46.3 mmol), ethylene glycol (13.2 mL), triethyl orthoformate (6.6 mL) and p-toluenesulfonic acid (0.09 g, 0.473 mmol) were stirred in DCE (50 mL) at 80° C. for 2.5 hours. Room temperature was attained and the solution was washed successively with saturated NaHCO3, H2O and brine, dried over MgSO4 and concentrated in vacuo to give 11.4 g of product (pale yellow oil, 100%). 1H NMR (CDCl3) δ 7.41 (t, J=8.1 Hz, 1H), 7.30 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (dd, J=9.6, 1.8 Hz, 1H), 6.02 (s, 1H), 4.13 (m, 2H), 4.04 (m, 2H).