Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:32]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][N:33]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([C:19]2[CH:18]=[N:17][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[N:33][CH:34]=1
Reactant: Brc1ccc(I)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)nc1
Temperature: 90 °C
Yield: 97 %

Procedure:
A mixture of 1-phenyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1H-benzo[d]imidazole (Compound 16) (12 mmol), 2-iodo-5-bromo pyridine (6.816 g, 24 mmol), Pd(PPh3)4 (0.69 g, 0.6 mmol) and K2CO3 (3.3 g, 24 mmol) in dioxane/water (100 mL/20 mL) was degassed and heated at 90° C. for 20 hours. The whole was allowed to cool to RT, white precipitate formed. After filtration, a solid (Compound 17) was collected (5.0 g, in 97% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11](Br)[CH2:12][CH3:13])=[CH:5]2.[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]([N:15]=[N+:16]=[N-:17])[CH2:12][CH3:13])=[CH:5]2
Reactant: CCC(Br)c1cc2cc(F)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(N=[N+]=[N-])c1cc2cc(F)ccc2[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of 5-fluoro-indolyl-3-propylbromide (10.67 g, 41 mmol) and sodium azide (3.9 g, 60 mmol) in anhydrous N,N-dimethylformamide (60 ml) was allowed to stir at 60° C. for 18 hours. The mixture was poured into water (150 ml), extracted with methylene chloride (3×150 ml), washed with water (3×100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under vacuurml Chromatography (30% ethyl acetate-hexanes) afforded 8.10 g (89%) of product as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]([OH:21])=O)[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].CCN(C(C)C)C(C)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:19]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18]
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
N-propylphosphonic acid anhydride, cyclic trimer (50 wt % solution in EtAc) (8.57 ml, 14.68 mmol) was added at room temperature in one portion to a stirred solution of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (2 g, 5.65 mmol), DIPEA (4.9 mL, 28.2 mmol) and morpholine (0.543 mL, 6.2 mmol) in DCM (14 mL). The mixture was stirred at room temperature for 1 h then water (1 mL) was then added. The reaction mixture was stirred for 15 mins and extracted with DCM. The combined organic layers were washed with water; the organic layer was washed with brine, dried over magnesium sulfate and concentrated to afford 8-bromo-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (1.90 g, 79%) as a beige solid. Mass Spectrum: m/z [M+H]+=423.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[CH2:12](I)[CH3:13]>CC(C)=O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1)[CH3:13]
Reactant: CCI
Reactant: c1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 90.2 %

Procedure:
10 grams (0.0846 moles) of 7-azaindole (Aldrich (trademark)) were dissolved in 200 mL of reagent grade acetone at room temperature and treated with 10 grams (0.178 moles) of powdered KOH. After~2-3 minutes, 67 mL (0.846 moles) of ethyl iodide was added over a period of 5-10 minutes and the reaction mixture was stirred at room temperature for 30-40 minutes. Thin layer chromatography (TLC) using 95% methylene chloride/5% ethyl acetate showed complete consumption of the starting material and formation of a single less polar product. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and methylene chloride (350 mL). The organic layer was separated and washed with water and brine and dried (sodium sulfate). Concentration of the organic extract in vacuo gave a yellow-brown oil which was purified on a silica gel column eluting with methylene chloride/ethyl acetate (95%/5%). A total of 11.15 grams (90%) of pure final product (light yellow oil) was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:14]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl.Cl>[O:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH:14]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]1
Reactant: COC(=O)C1CC(O)CCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)C1CC(=O)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml flask, flamed dry under N2 was added CH2Cl2 (65 mL) followed by oxalyl chloride (5.2 mL, 59.6 mmol). After cooling the reaction mixture to −78° C., dimethyl sulfoxide (8.4 mL, 118.4 mmol) was added, followed by 1-benzyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate, 13b, (8.6 g, 29.2 mmol) in CH2Cl2 (65 mL). The reaction was allowed to stir at −78° C. for 45 min. To the mixture was added triethylamine (24.4 mL, 175.1 mmol) and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2 and 1N HCl. The layers were separated and the aqueous phase was re-extracted with CH2Cl2. The combined organic phases were washed with water, dried over MgSO4, filtered and evaporated to dryness. The crude was purified by silica gel chromatography (30-50% EtOAc/hexanes) to give the desired product, 13c.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)([O-])=O.[CH3:20][C:21]([Mg]Br)=[CH:22][CH3:23].[Cl-:26].[NH4+]>O1CCCC1>[ClH:26].[CH3:20][C:21]1[NH:1][C:4]2[C:5]([N:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:11]3)=[CH:6][N:7]=[CH:8][C:9]=2[C:22]=1[CH3:23]
Reactant: [Cl-]
Reactant: CC=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1ccncc1N1CCc2ccccc2C1
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)cncc2c1C
Product: Cl
Reaction time: 0.33 h
Yield: 19.5 %

Procedure:
2-(4-Nitropyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (2.0 g, 7.835 mmol) prepared in Preparation 2 was dissolved in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 9.4 ml) was added at −78° C. to the solution, which was then stirred for 20 minutes at the same temperature. 10 ml of 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (100 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (methylene chloride/methanol=10/1 (v/v)), dissolved in 5 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered to give the titled compound as a white solid (850 mg, 19.5%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.CCCCCCC.[C:20](OCC)(=[O:22])[CH3:21]>ClCCl>[F:1][C:2]1[C:7]([CH2:8][CH2:21][CH2:20][OH:22])=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(F)c(C=O)c1O
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1ccc(F)c(CCCO)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.46 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde in 50 ml of dichloromethane there was added 10 g of (triphenyl phosphoranilidene)acetic acid ethyl ester while cooling on ice. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a silica gel column and elution was performed with heptane-ethyl acetate=3:1. The eluate was concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate, 1 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of THF, and then 2 g of lithium borohydride was added while cooling on ice and the mixture was stirred overnight at room temperature. After adding 1N hydrochloric acid to the reaction mixture while cooling on ice, extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.78 g) as a solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:11]([C:13]1[CH:14]=[C:15]([NH:19][CH:20]([C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:21]([O:23][C@@H:24]2[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:22])[CH:16]=[CH:17][CH:18]=1)[CH3:12]>CCOC(C)=O>[Cl-:1].[CH2:11]([C:13]1[CH:14]=[C:15]([NH:19][CH:20]([C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:21]([O:23][C@@H:24]2[CH:29]3[CH2:28][CH2:27][N+:26]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:31][CH2:30]3)[CH2:25]2)=[O:22])[CH:16]=[CH:17][CH:18]=1)[CH3:12]
Reactant: O=C(CCl)c1ccccc1
Reactant: CCc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Solvent: CCOC(C)=O
Product: CCc1cccc(NC(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccc(OC)nc2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
2-Chloro-1-phenylethanone (143 mg, 0.93 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(3-ethylphenylamino)-2-(6-methoxypyridin-3-yl)acetate (C74) (366 mg, 0.93 mmol) in EtOAc (3 ml), and the resulting reaction was stirred at room temperature overnight. The solvent was evaporated, and the crude product was purified by preparative HPLC (Eluent: CH3CN/H2O) to obtain (3R)-3-(2-(3-ethylphenylamino)-2-(6-methoxypyridin-3-yl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (69.3 mg, 13.6% yield over two steps).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>>[S:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccsc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccsc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with thiophene-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(thiophen-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([O:12][CH3:13])[C:4]=1OC.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C.[C:27](=[O:30])([O-])[O-].[K+].[K+]>O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]([O:30][CH3:27])=[CH:7][C:8]=1[NH2:9]
Reactant: COc1ccc([N+](=O)[O-])c(SC)c1OC
Reactant: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(SC)cc1OC

Procedure:
A reaction mixture was prepared containing 68.7 g. of 3-methylthio-4-nitroveratrole, 261 g. sodium dithionite (Na2S2O4), 1500 ml. of ethanol and 2250 ml. of water. The reaction mixture was heated at reflux temperature for about 1 hour and then cooled. The reaction mixture was then made basic with potassium carbonate and the resulting alkaline solution concentrated in vacuo to one-half its original volume. The aqueous solution was extracted twice with 2 l. portions of ether. The ether extracts were combined, dried, and the ether removed therefrom by evaporation in vacuo. The solid residue, comprising 2-methylthio-4,5-dimethoxy aniline formed in the above reaction, was recrystallized from a benzene-hexane solvent mixture to yield 33.6 g. of crystalline material melting at 69°-72° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]#[N:20])=[CH:8][CH:7]=1.[N:22]([Sn](C)(C)C)=[N+:23]=[N-:24]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[NH:24][N:23]=[N:22][N:20]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2CCC#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2nnn[nH]2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 139.6 %

Procedure:
To a solution of (E)-3-{4-[1-(2-cyano-ethyl)-pyrrolidin-2-yl]-phenyl}-acrylic acid methyl ester (1.0 g, 3.5 mmol) in xylene (35 mL) was added azidotrimethyltin (1.09 g, 5.30 mmol) and the reaction solution was stirred at 130° C. for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in an aqueous sodium hydroxide solution, washed with ethyl acetate, and neutralized with 1 N hydrochloride. A yellow oil was separated from the aqueous layer which was extracted with methylene chloride:ethanol (4:1) several times. The organic layers were combined with the yellow oil, dried over sodium sulfate, filtrated and concentrated in vacuo to give 1.6 g of a yellow oil, which was used to the next step without further purification. LCMS (m/z): 328.0 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[CH3:14][NH:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19]>>[CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:16]([NH:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: CNCc1ccc(CSCCN)o1
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])NC)o1

Procedure:
A mixture of 2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethanamine (0.9 g) and N-methyl-1-methylthio-2-nitro-etheneamine was heated at 100°-120° for 30 mins under water pump pressure. The residue was purified by column chromatography (silica/methanol:0.88 ammonia) to give N-[2-[[[5-(methylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine which was crystallised from acetonitrile m.p. 106°-108° (0.65 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].[NH:32]1[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]1>CC(O)C.CCOC(C)=O>[Br:10][C:11]1[C:12]([N:32]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
DIPEA (73 μL, 0.42 mmol) was added to a solution of 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 25.2, 123 mg, 0.3 mmol) and (R)-pyrrolidin-3-ol (31.4 mg, 0.36 mmol) in iPrOH (300 μL) in a vial, which was sealed and heated at 140° C. for 1 h. After cooling at RT, the RM was diluted with EtOAc, washed with brine, dried over Na2SO4 and the solvent evaporated off under reduced pressure to give a residue which was triturated with iPr2O, filtered and dried to afford the title compound as a white crystalline powder. HPLC (Condition 4) tR=5.9 min, UPLC-MS (Condition 3) tR=1.21 min, m/z=464.1 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][P:4](=[O:11])([O:8]CC)[O:5]CC.[N:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.[ClH:24]>O>[Cl-:24].[Cl-:24].[P:4]([CH2:3][CH2:2][N+:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N+:21]([CH2:2][CH2:3][P:4]([OH:5])([OH:8])=[O:11])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([OH:11])([OH:8])=[O:5]
Reactant: c1cc(-c2ccncc2)ccn1
Reactant: CCOP(=O)(CCBr)OCC
Reactant: Cl
Solvent: O
Product: O=P(O)(O)CC[n+]1ccc(-c2cc[n+](CCP(=O)(O)O)cc2)cc1
Product: [Cl-]

Procedure:
Diethyl 2-bromoethylphosphonate (25 g) and 4,4' bipyridine (7.35 g) in 125 mLs of water are refluxed for three days. An equal volume of concentrated hydrochloric acid is added and reflux continued for several hours. The solution is concentrated to 120 mLs by atmospheric distillation and 550 mL of isopropanol are added dropwise with stirring while chilling the mixture in an ice bath. The solid which forms is collected by vacuum filtration and washed with cold isopropanol to yield 1,1'-bisphosphonoethyl-4,4'-bipyridinium dichloride. (1H NMR (D2O) 9.1(d), 8.5(d), 4.2(m), 2.0(m) ppm; 13C NMR(D2O) 151, 147, 128, 58, 30 ppm; 31P NMR(D2O) 17.8 (s) ppm; IR (KBr) 3112, 3014, 1640, 1555, 1506, 1443, 1358, 1281, 1175, 1112, 1020, 936, 816, 485 cm-1.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1([C:11]2[O:12][C:13](I)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19]([O-:21])=[O:20].[Na+].COC(=O)CCS([O-])=O.[Na+]>[Cu]I>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1([C:11]2[O:12][C:13]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)o2)CC1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: COC(=O)CCS(=O)[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1(c2ccc(S(C)(=O)=O)o2)CC1

Procedure:
[1-(5-Methanesulfonyl-furan-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester is prepared from [1-(5-iodo-furan-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.500 g, 1.43 mmol) according to the copper (I) iodide-mediated coupling procedure described in Example 19; however, sodium methanesulfinate is used as coupling partner instead of sodium 3-methoxy-3-oxopropane-1-sulfinate.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:15])[NH:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:5]1=[O:16])[CH:2]=[CH2:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27](OCC)(=[O:33])[C:28](OCC)=[O:29]>CN(C=O)C.C1COCC1>[OH:33][C:27]1[C:28](=[O:29])[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[N:7]2[CH2:8][CH2:9][N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:16])[C:6]=12
Reactant: C=CCN1CCN(C(=O)NC(C)C)CC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(2-propenyl)-4-(N-2-propylcarbamoyl)-2-piperazinone (8.0 g, 35 mmol) in DMF (80 mL) at 0° C. was added lithium bis(trimethylsily)amide (40 mL of a 1.0 M solution in THF, 40 mmol). Diethyl oxalate (5.84 g, 40 mmol) was added and the mixture was stirred for 1 h at 0° C. More lithium bis(trimethylsily)amide was added (35 mL of a 1.0 M solution in THF, 35 mmol) and the mixture was stirred for 1 h at 0° C., and then at ambient temperature for 18 h. The reaction was quenched by the addition of 0.5 N aqueous HCl to pH 3 and the solvents were removed in vacuo. The residue was vigorously stirred in methanol-water, and the precipitate was collected by filtration and dried in vacuo to give the title compound. HPLC RT=2.72 min (Method A); ES MS (M+H)=280; 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 5.80 (ddt, 1H), 5.29 (d, J=17 Hz, 1H), 5.22 (d, J=10 Hz, 1H), 5.05 (septet, J=7 Hz, 1H), 4.10 (d, J=7 Hz, 2H), 3.94 (t, J=7 Hz), 3.58 (t, J=7 Hz, 2H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[C:13](#[N:16])[CH:14]=[CH2:15].C(O)(=O)C>O>[C:13]([CH2:14][CH2:15][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:16]
Reactant: C=CC#N
Reactant: Nc1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N#CCCNc1cccc(C(=O)O)c1
Temperature: 5 °C

Procedure:
200.0 g of 3-aminobenzoic acid in 2 l of water were admixed with 53.2 g of sodium hydroxide. At 30° C., 126.6 g of acrylonitrile were added dropwise, and the mixture was then heated under reflux for 22 hours. The mixture was then cooled to 5° C. and acetic acid was added (pH=5) and the precipitate which had formed was filtered off with suction and washed with water.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[Na+].[CH2:11](Cl)[CH2:12][OH:13].[CH2:15]([OH:17])[CH3:16]>>[OH:13][CH2:12][CH2:11][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:16][CH2:15][OH:17]
Reactant: Oc1ccccc1O
Reactant: OCCCl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: OCCOc1ccccc1OCCO
Reaction time: 0.5 h

Procedure:
Pyrocatechol [3] (55.0 g, 0.50 mol) was added to a solution (500 mol) of sodium hydroxide (50.5 g, 1.26 mol) in ethanol under purging with nitrogen, and the resultant mixture was refluxed under stirring with a mechanical stirrer for 30 minutes. Ethylene chlorohydrin (96.5 g, 1.20 mol) was dropped into the mixture in 1 hour. After refluxing overnight, the reaction was judged to have been completed. Ethanol was distilled off and chloroform (1.5 l) was added to the residue. The chloroform layer was extracted with an aqueous NaOH solution while the removal of an unreacted matter was confirmed by UV spectroscopy (seven times each with 20 ml of the aqueous NaOH solution for 500 ml of the chloroform layer until no change had been observed in the absorption at around 275 nm in the UV spectrum even when the alkaline aqueous layer turned acidic after the completion of the extraction). Chloroform was distilled off under reduced pressure to obtain the compound [4].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:24]1([CH2:30][CH2:31][S:32][CH:33]([C:37](O)=[O:38])[C:34](O)=[O:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[OH:38][C:37]1[CH:2]=[C:1]([C:4]2[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=2)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:3][C:34](=[O:35])[C:33]=1[S:32][CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CCOC(=O)COc1cccc(C(C)=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using ethyl (3-acetylphenoxy)acetate (2.00 g, 9.00 mmol), trimethyl silyltriflate (4.18 mL, 21.62 mmol), triethylamine (5.01 mL, 36.00 mmol), methylene chloride (23 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 116°-119° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, 3H), 2.77 (t, 2H), 3.05 (t, 2H), 4.89 (d, 2H), 6.80 (s, 1H), 7.20 (m, 7H), 7.44 (m, 2H).