Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].Br[CH2:14][C:15]1[C:16]([CH2:21]Br)=[CH:17][CH:18]=[CH:19][CH:20]=1>C(O)C.C(OCC)C>[CH2:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][C:3]1([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9]
Reactant: BrCc1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)C1(C(=O)O)Cc2ccccc2C1

Procedure:
Sodium (3.7 g) was dissolved in 80 ml of ethyl alcohol, followed by the addition of 150 ml of diethyl ether. Diethyl malonate (12.5 ml) was added followed by 20 g of α,α'-dibromo-o-xylene in 150 ml of diethyl ether with overhead stirring. The reaction was heated to reflux for 5 hours. The reaction was cooled, filtered, and the solvent was removed under vacuum. The residue was treated with a potassium hydroxide solution (20 g in 125 ml of water) and heated to reflux for 15 hours. The reaction was then cooled and rinsed with 200 ml of diethyl ether. The aqueous phase was acidified with 30% hydrochloric acid. The precipitate was collected and dried under vacuum over Drieruite for 5 hours to yield 8.86 g of indan-2,2-dicarboxylic acid.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[C:9]([I:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:14])[C:5]([CH3:13])=[N:6]2.[CH2:23]1[CH2:29][S:26](=[O:28])(=[O:27])[O:25][CH2:24]1>>[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:4]1([CH3:14])[C:3]2[C:7](=[CH:8][C:9]([I:12])=[C:10]([I:11])[C:2]=2[I:1])[N+:6]([CH2:24][CH2:23][CH2:29][S:26]([O-:28])(=[O:27])=[O:25])=[C:5]1[CH3:13])([OH:22])=[O:21]
Reactant: CC1=Nc2cc(I)c(I)c(I)c2C1(C)CCCCCC(=O)O
Reactant: O=S1(=O)CCCO1
Product: CC1=[N+](CCCS(=O)(=O)[O-])c2cc(I)c(I)c(I)c2C1(C)CCCCCC(=O)O
Yield: 42 %

Procedure:
600 mg (0.94 mmol) of 6-(4,5,6-triiodo-2,3-dimethyl-3H-3-indolyl)hexanoic acid was heated with 600 mg (4.7 mmol) of 1,3-propane sultone at 100° C. for 40 minutes. The raw product was column purified (Silica gel 60, 0-40% methanol-chloroform) to give 300 mg of 3-[3-(5-carboxypentyl)-4,5,6-triiodo-2,3-dimethyl-3H-1-indoliumyl]-1-propane sulfonate: 7.39 (1H, s, arom.), 4.31 (2H, m, NCH2), 3.27 (3H, s, CH3), 2.34-2.02 (2H, m, CH2), 2.19 (2H, t, CH2CO), 1.98-1.65 (4H, m, CH2), 1.31 (3H, s, CH3), 1.43-1.00 (4H, m, (CH2)3), 0.62-0.35 (2H, m, CH2).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH2:12][CH3:13].Cl.N1C=CC=CC=1>O>[CH2:11]([C:4]1[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2])[CH2:12][CH3:13]
Reactant: CCCc1c(OC)cccc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCc1c(O)cccc1O
Temperature: 180 °C
Reaction time: 7.5 h
Yield: 133.1 %

Procedure:
A mixture of solid 1,3-dimethoxy-2-propylbenzene (33.70 g, 190 mmol) and solid pyridine hyrochloride (150 g, 1.30 mol) were warmed to 180° C. After 7.5 hours, the reaction was cooled to 110° C. and 50 mL of H2O was added slowly. After the reaction cooled to room temperature, it was diluted with 100 mL of water and extracted several times with EtOAc. The EtOAc extract was washed once with 2N HC1 and then dried over MgSO4. Filtration and solvent removal gave 38.5 g of an orange solid. The product was purified by recrystallization from dichloromethane providing 11.86 g (41%) of yellow crystals.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24](O)=[O:25])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][NH2:28].C1COCC1>>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([NH:28][CH3:27])=[O:25])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1

Procedure:
2-[3-Cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)-phenyl]-N-methylacetamide (154 mg) is prepared from [3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]acetic acid (186 mg, 0.5 mmol) and 1 M solution of methylamine in THF (0.5 ml, 0.5 mmol) following the general procedure K.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]([CH3:48])[C:14]([N:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:20]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[C:19]([CH3:37])[N:18]=[C:17]1SCC1C=CC(OC)=CC=1)=[O:15]>ClCCl.C(OCC)(=O)C>[CH3:48][N:13]([CH3:12])[C:14]([N:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:20]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[C:19]([CH3:37])[NH:18][C:17]1=[O:6])=[O:15]
Reactant: COc1ccc(CSC2=NC(C)=C(C(=O)OC(C)C)C(c3cccc([N+](=O)[O-])c3)N2C(=O)N(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperoxybenzoic acid (3 eq, 2.5 mmol, 424 mg) was added to a solution of (+)-3,4-dihydro-3-[(dimethylamino)carbonyl]-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester in dry dichloromethane (8.2 ml) at 0° C. under a nitrogen atmosphere. The reaction was stirred overnight at room temperature, and a precipitate formed. The mixture was diluted with ethyl acetate (15 ml) and washed with 1N hydrochloric acid (twice), 1N sodium hydroxide (twice) and water. The combined organic layers were dried over magnesium sulfate, filtered, and reduced in vacuo to afford an oil, 390 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)NOC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
4-Chlorobenzoyl chloride (1.10 mL, 8.57 mmol) is added slowly to a solution of ethyl hydroxycarbamate 6 (1.00 g, 9.52 mmol) and triethylamine (1.19 mL, 8.57 mmol) in diethyl ether (30 mL) at 0° C. then stirred at room temperature for 30 min. The reaction is quenched with HCl (1 M; 10 mL) then water (100 mL) is added and extracted with diethyl ether (100 mL). The organic layer is washed with sat. NaHCO3 (50 mL), water (50 mL), dried with MgSO4 and concentrated. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 9:1 then 8:2) to yield 7 (1.54 g) as an off-white solid. M.p. 79° C. (determined by differential scanning calorimetry, sharp onset); FTIR (neat, cm−1) 3210, 3094, 2990, 1765, 1708, 1588, 1495, 1487, 1473, 1443, 1401, 1368, 1298, 1283, 1249, 1235, 1177, 1121, 1107, 1090, 1054, 1016, 996, 876, 852, 771, 747, 728, 681; 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 8.02 (dt, J=2.1, 8.7 Hz, 2H), 7.46 (dt, J=2.1, 8.7 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.1, 156.6, 140.9, 131.3, 129.1, 125.2, 63.0, 14.3; HRMS (ES+) m/z calcd for C10H10ClNO4 (M+Na)+ 266.0191, found 266.0199.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Oc1ccc(C#Cc2ccncc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C(#Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1

Procedure:
A mixture of 4-(2-(pyridin-4-yl)ethynyl)phenol (335 mg, 1.72 mmol), 2-(chloromethyl)quinoline hydrochloride (385 mg, 1.8 mmol), and cesium carbonate (2.2 g, 6.87 mmol) was stirred in dimethylformamide (8 mL) at 65° C. for 3 h. Water (20 mL) was added and the mixture was extracted with dichloromethane (3×15 mL). The organic layers were dried, concentrated, and the residue chromatographed on silica eluted with a gradient of 10% to 80% ethyl acetate-hexanes giving 450 mg (78%) of a yellow solid. 1H NMR (CDCl3, 400 mHz) δ 8.56 (m, 2H), 8.20 (d, 1H, J=8.7 Hz), 8.08 (d, 1H, J=8.3 Hz), 7.82 (d, 1H, J=7.9 Hz), 7.74 (ddd, 1H, J=8.4, 7, 1Hz), 7.63 (d, 1H, J=8.7 Hz), 7.55 (ddd, 1H, J=8, 7, 1 Hz), 7.47 (m, 2H), 7.35 (m, 2H), 7.01 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 337 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][CH2:10][O:11][C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCCc1cc(F)cc(F)c1
Product: CN1c2cc(OCCc3cc(F)cc(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(3,5-difluorophenyl)ethanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[C:34](B(O)O)=[C:33]([CH3:38])[O:32][N:31]=1.C(O)C>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.C1(C)C=CC=CC=1>[CH3:19][CH:18]([O:17][C:16](=[O:21])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:34]3[C:30]([CH3:29])=[N:31][O:32][C:33]=3[CH3:38])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:22])[CH2:6]1)[CH3:20]
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC(=O)OC(C)C)CC1C
Reactant: Cc1noc(C)c1B(O)O
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: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3c(C)noc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 38 %

Procedure:
A flask was charged with 1-methylethyl (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol), potassium carbonate (74.9 mg, 0.542 mmol), 3,5-dimethyl-4-isoxazolylboronic acid (45.8 mg, 0.325 mmol), and tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) then filled with ethanol (1 mL) and toluene (1 mL) and the resulting mixture was refluxed under nitrogen for 20 h. tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) was then added and the mixture refluxed for 40 h then cooled to room temperature and partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and the aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 66% AcOEt in Hexanes) gave 1-methylethyl[(cis)-1-acetyl-6-(3,5-dimethyl-4-isoxazolyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (42 mg, 0.103 mmol, 38%) as a colourless solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][C:2]=1S.S(Cl)(Cl)=O.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:2]2[O:3][C:4]3[C:9]([N:1]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Sc1nc2cccnc2o1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cccnc3o2)CC1
Temperature: 60 °C
Yield: 19.1 %

Procedure:
To oxazolo[5,4-b]pyridine-2-thiol (1.0 g, 6.57 mmol, 1.0 equiv) was added thionyl chloride (14.1 g, 8.6 mL, 118.3 mmol, 18.0 equiv) and anhydrous DMF (0.56 g, 0.56 mL, 7.23 mmol, 1.1 equiv) and the reaction mixture heated to reflux for 30 min. The solvent was removed under reduced pressure and the crude oil azeotroped twice with xylene to remove excess thionyl chloride. To the crude reaction product was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.97 g, 9.86 mmol, 1.5 equiv) in anhydrous DMF (5 mL) and the solution heated to 60° C. for 18 h. The solution was concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with ethyl acetate/hexane (1:1) to give 0.40 g (19%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.34 (s, 9H), 1.26-1.40 (m, 2H), 1.84-1.92 (m, 2H), 2.82-2.95 (m, 2H), 3.67-3.76 (m, 1H), 3.82-3.84 (m, 2H), 7.13 (t, J=7.0 Hz, 1H), 7.52 (dd, J=7.0 Hz, J=1.8 Hz, 1H), 7.79 (dd, J=7.0 Hz, J=1.8 Hz, 1H), 8.23 (d, J=7.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:25]([O:29][C:30](=[O:43])[N:31]=[C:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])SC)([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:43])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCOC(Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2-ethoxypropanoic acid (20 mg, 0.061 mmol) and tert-butyl-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate (18.6 mg, 0.064 mmol) were mixed in 0.3 ml DMF. Triethylamine (25.5 ml, 0.183 mmol) was added. The mixture was then cooled in an ice-bath. Mercury (II)chloride (18 mg, 0.066 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water (1 ml) and ethyl acetate (0.5 ml) were added and then hydromatrix (ca. 0.5 g) was added. After a while, the mixture was filtered. The filtrate was evaporated to dryness. Chromatography of the residue on an ISOLUTE column (SI, 500 mg/3 ml) using ethyl acetate/heptane (10:90, then 25:75, and then 50:50) as eluant gave 15.4 mg, yield 44% of the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([O:18][CH3:19])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:2]2[C:7]([C:8]([NH:10][C:11]3[C:12]([O:18][CH3:19])=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1
Reactant: COc1nccc(C)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Product: COc1nccc(C)c1NC(=O)c1cccnc1NC1CC1
Temperature: 110 °C
Yield: 86 %

Procedure:
2-Chloro-N-(2-methoxy-4-methyl-3-pyridinyl)-3-pyridinecarboxamide (0.55 g, 2 mmol) was placed in a sealed tube containing cyclopropylamine (0.5 mL, 7 mmol) and heated to 110° C. overnight. Removal of the cyclopropylamine by rotary evaporation followed by flash chromatography of the residue on silica gel (1:1 EtOAc:hexanes) gave the desired compound in 86% yield (0.51 g). m.p.: 151°-152° C. (Recrystallized from heptane).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]1[O:14][CH:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCO.N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:14])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccc(C2CO2)cc1
Reactant: c1c[nH]cn1
Solvent: CCO
Solvent: c1ccncc1
Product: OC(Cn1ccnc1)c1ccccc1
Yield: 35.2 %

Procedure:
A solution of 17.6 g (0.258 mol) of imidazole in 100 mL of absolute EtOH was treated with 0.6 mL (4.0 mmol) of pyridine and refluxed for 25 minutes. This was then treated dropwise with a solution of 31.06 g (0.258 mol) of styrene oxide and the solution heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in Et2O and washed with H2O. A solid separated which was collected and dissolved in warm CHCl3 /EtOAc. The organic phase was washed with saturated NaCl and dried over MgSO4. Treatment of the filtrate with charcoal, filtering, and concentrating to 1/3 volume caused a solid to separate. There was collected 17.09 g (35% yield) of the product as a white solid, mp 146-148° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 189 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].C(N(CC)CC)C.[C:19](=S)=[S:20]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:19]([SH:20])=[N:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=O)c1cccc(N)c1
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cccc(-c2nnc(S)o2)c1

Procedure:
3-Aminobenzhydrazide (5.76 g) was dissolved in ethanol (40 mL), and triethylamine (4.8 mL) and carbon disulfide (2.1 mL) were added to the solution. The mixture was heated under reflux for 4 hrs. The solvent was evaporated, and water was added. The precipitated solids were collected by filtration to give the title compound (5.06 g) as a pale-yellow powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH3:11].[Cl:12][C:13]1[CH:34]=[CH:33][C:16]([CH2:17][NH:18][C:19]([C:21]2[C:22]([OH:32])=[C:23]3[CH:29]=[C:28]([CH2:30][OH:31])[S:27][C:24]3=[N:25][CH:26]=2)=[O:20])=[CH:15][CH:14]=1>CN(C=O)C.O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19]([C:21]2[C:22](=[O:32])[C:23]3[CH:29]=[C:28]([CH2:30][OH:31])[S:27][C:24]=3[N:25]([CH2:8][CH2:9][O:10][CH3:11])[CH:26]=2)=[O:20])=[CH:33][CH:34]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C

Procedure:
Potassium carbonate (5.0 g) and bromoethylmethyl ether (5.0 g) are added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (11.4 g, prepared as described in U.S. Pat. No. 6,239,142) in anhydrous DMF (350 mL). The reaction mixture is stirred at room temperature for 18 b. The mixture is diluted with water (600 mL) and filtered. The resulting white powder is dried in a vacuum oven to afford 8.44 g of the title compound as a white solid. Physical characteristics. M.p. 193° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.58, 8.65, 7.37, 7.29, 5.82, 4.70, 4.54, 4.47, 3.76, 3.24. HRMS (FAB) m/z 407.0836 (M+H)+. Anal. Found: C, 55.81; H, 4.71; N, 6.90; Cl, 8.58, S, 7.81.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:32])=[O:31]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (120 mg, 0.36 mmol) in DCM (6 ml), were sequentially added triethylamine (79 μl, 1.08 mmol) and methanesulfonyl chloride (33.4 μl, 0.43 mmol). The reaction was stirred at RT for 3 hours, and then the volatiles were evaporated. The crude was taken up with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude was triturated with Et2O to obtain (R)-quinuclidin-3-yl 2-(methylsulfonamido)-2-phenylacetate (38.9 mg; 32% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:17]#[N:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC([O-])(C)C.[K+].Br[CH2:26][CH2:27][CH2:28][Cl:29]>CN(C)C=O>[Cl:29][CH2:28][CH2:27][CH2:26][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][C:5]=1[CH:11]([C:17]#[N:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: ClCCCBr
Reactant: CCOC(=O)C(C#N)c1ccc(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc(OC)c(OC)c1CCCCl

Procedure:
124.5 g (0.5 mol) of ethyl 3,4-dimethoxyphenylcyanoacetate in 160 ml of abs. dimethylformamide were added at 15°-20° while stirring to a suspension of 84.5 g (0.753 mol) of potassium tert-butylate in 300 ml of abs. dimethylformamide. After one hour 83.5 ml of 1-bromo-3-chloropropane were slowly added dropwise, whereby the temperature amounted to 15°-20°. After 16 hours the reaction mixture was evaporated in a high vacuum. The residue was partitioned between ether and an aqueous saturated ammonium chloride solution. The combined organic extracts were dried and evaporated under reduced pressure. The oily residue was distilled in a high vacuum, whereby 145.7 g of ethyl [γ-chloropropyl-3,4-dimethoxyphenyl]cyanoacetate were obtained, b.p. 195°-201°/80 Pa.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5](O)=[O:6].O=P(Cl)(Cl)Cl.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([N:22]=[N+:23]=[N-:24])=[O:6]
Reactant: O=C(O)c1ccc(N2CCOCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: [N-]=[N+]=NC(=O)c1ccc(N2CCOCC2)c(F)c1

Procedure:
This compound may be prepared from (14) in a one pot reaction utilizing POCl3 in DMF (Vilsmeier complex) and NaN3 following the literature procedure of Sridhar et al. (Syn. Comm. 2003, 33, 607-611).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.C=[PH3].[CH:14]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)=[CH:15][CH2:16][CH2:17][CH2:18][CH3:19]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH:14]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:1])=[CH:23][CH:22]=1)=[CH:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC=COc1ccc(C=O)cc1
Reactant: [Li]CCCC
Agent: C=[PH3]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCCCCC
Product: C=Cc1ccc(OC=CCCCC)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 200 ml three-necked flask in a nitrogen atmosphere, anhydrous diethyl ether (150 ml), methyltriphenylphosphonium bromide (7.5 g, 21 mmol) and a 1.6N solution of n-butyllithium in hexane (13.1 ml, 21 mmol of n-butyllithium) were charged and stirred at room temperature for 5 hours to prepare methylenephosphorane. To the reaction mixture, a solution of 4-(1-hexenyloxy)benzaldehyde (4.08 g, 20 mmol) in anhydrous diethyl ether (20 ml) was dropwise added over 3 minutes. After heating the reaction mixture under reflux for one hour and removing solids by filtration, hexane (150 ml) was added to a filtrate, and an organic phase was washed with water (150 ml×3), followed by evaporating volatile components off to obtain 4-(1-hexenyloxy)styrene (3.0 g) of the formula: ##STR5##