Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C(B(CC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.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>[F:10][C:3]1[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: CCB(CC)c1cccnc1
Reactant: Nc1ccc(F)c(Br)c1F
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: C1CCOC1
Solvent: O
Product: Nc1ccc(F)c(-c2cccnc2)c1F
Temperature: 25 °C
Yield: 7 %

Procedure:
A mixture of 3-bromo-2,4-difluorophenylamine (prepared according to the procedure described in EP-A-0184384) (12.5 g, 60 mmol), diethyl(3-pyridyl)borane (10.6 g, 72 mmol) and potassium carbonate (16.6 g, 120 mmol) in tetrahydrofuran (150 mL) and water (50 mL) was degassed with nitrogen for 15 min. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol) and the reaction was heated at reflux for 4 days. The mixture was cooled to ambient temperature and the majority of the tetrahydrofuran removed on a rotary evaporator. The residue was diluted with water (250 mL), extracted with ethyl acetate (300 mL), the organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with isohexane (containing 1% triethylamine) on a gradient of ethyl acetate (10-50%) afforded 2,4-difluoro-3-(pyridin-3-yl)phenylamine as a cream-coloured solid (5.8 g, 7%): δH (400 MHz, CDCl3) 3.69 (2H, br), 6.72-6.88 (2H, m), 7.39 (1H, dd, J 8 and 5), 7.80 (1H, d, J 8), 8.62 (1H, dd, J 5 and 1), 8.72 (1H, s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH:11]([NH:17][C:18](OCC)=[O:19])[CH:10]([CH2:23][C:24]3[CH:29]=[CH:28][C:27](Cl)=[C:26](Cl)[CH:25]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH2:34]([NH:37][S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])[C:35]#[CH:36].[CH2:44](N(CC)CC)C.O>O1CCOCC1.[Cu]I>[CH2:23]([CH:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:36]#[C:35][CH2:34][NH:37][S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])[CH:8]=2)[CH2:13][CH2:12][CH:11]1[NH:17][C:18](=[O:19])[CH3:44])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#CCNS(=O)(=O)CCC
Reactant: CCN(CC)CC
Reactant: CCOC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Solvent: O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)NCC#Cc1ccc2c(c1)C(Cc1ccccc1)C(NC(C)=O)CC2

Procedure:
7-Acetamido-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (100 mg, 0.234 mmol; prepared in analogy to 8-(3,4-dichlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate, example 29), N-(prop-2-ynyl)propane-1-sulfonamide (75 mg, 0.468 mmol), palladium tetrakistriphenylphosphine (54 mg, 0.047 mmol), copper(I) iodide (35.6 mg, 0.187 mmol) and triethylamine (65 μL, 0.468 mmol) in dioxane (3 mL) were heated under reflux for 16 h. Water (15 mL) was added and the mixture extracted with dichloromethane (3×20 mL). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 56 mg (0.132 mmol, 57%).
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.CC#N.C(Cl)(Cl)(Cl)Cl.[OH2:26]>C(OCC)(=O)C>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1)([OH:1])=[O:26]
Reactant: O
Reactant: CC(C)(C(N)=O)c1ccc(-c2ccco2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C(N)=O)c1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionamide (reference example 26) (124 mg, 0.5 mmol) in CH3CN/CCl4/H2O (7 mL, 2/2/3) is added NaIO4 (420 mg, 2 mmol) followed by RuCl3 (H2O)(3 mg). The resulting mixture is stirred vigorously for 1.5 h, then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated to give 100 mg of the title compound as an orange solid. 1H NMR (CD3OD) d 1.58 (s, 6H), 7.50 (d, J=8 Hz, 2H), 7.98 (d, J=8 Hz, 2H). MS (EI) m/z 208 (M+H).
Reaction SMILES: O.[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[NH:14]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:15]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C>[NH:14]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@H:15]([C:26]([NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10])=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
2.00 equivalents water and 1 equivalent Arg (Mw=174.2) were mixed with DMF and stirred at room temperature until a solution was obtained. 1.03 equivalents of Z-Trp-OSu (Mw=435.45; purity=98%) were dissolved in DMF and poured in the arginine solution. Stirring was then continued at room temperature for at least 5 hours. After checking the termination of the reaction by HPLC, the reaction mixture was precipitated by adding slowly cold acetonitrile (0±5° C.) and kept at this temperature for at least 30 minutes before filtration. The precipitate was washed 3 times with a mixture of CH3CN/IPE(Isopropylether) (1/1) and then 2 times with IPE. The solid was then dried in vacuo at 45° C. A white solid was finally obtained.
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:13]=[CH:14][C:15]3[S:19][CH:18]=[C:17]([CH3:20])[C:16]=3[C:21]=2[CH:22]=[O:23])[N:4]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+]>CC(C)=O.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:21]([C:22]([OH:25])=[O:23])=[C:16]3[C:17]([CH3:20])=[CH:18][S:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C=O)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
0.6 g of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-4-formyl-3-methylbenzothiophene was dissolved in 80 ml of acetone. While stirring the solution at room temperature, 0.6 g of potassium permanganate dissolved in 10 ml of water was dropwise added thereto over a period of 15 minutes, and the mixture was further stirred at room temperature for 4 hours. It was then concentrated under reduced pressure to remove acetone, and then a saturated sodium bicarbonate aqueous solution was added thereto to make the mixture alkaline. The mixture was extracted with ethyl acetate, and then the aqueous layer was precipitated with 10% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain 0.47 g (yield: 76%) of the desired compound.
Reaction SMILES: [NH:1]([CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12](=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:16][CH:17]=1
Reactant: O=C(O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1CCCC(c2ccc(Cl)cc2)N1c1ccccc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
(2)-(a) A solution of 17.8 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid in a mixed solution of 290 ml of toluene and 13.9 g of pyridine was cooled to -3° C. and stirred. To this solution was added 10 ml solution of 5.1 ml of thionyl chloride in toluene dropwise over 1 hour. After stirring at -3° C. for 1 hour and at room temperature for 1.5 hours, the reaction mixture was poured into ice-water. The toluene layer was washed with diluted hydrochloric acid, a saturated aqueous sodium chloride solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried and treated with activated charcoal. After removal of charcoal and the solvent, the residual solid was recrystallized from isopropyl ether to give 16.4 g of 6-(4-chlorophenyl)-1-phenyl-2-piperidone as colorless prisms.
Reaction SMILES: [P:1]([O:10]CCCl)([O:6]CCCl)[O:2]CCCl.[CH3:14][N:15]1[C:19](=[O:20])[N:18]([CH3:21])[CH2:17]P1(=O)OCCCl>C(O)(=O)C.O>[CH3:17][N:18]([CH2:21][P:1](=[O:2])([OH:6])[OH:10])[C:19]([NH:15][CH3:14])=[O:20]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: CN1CP(=O)(OCCCl)N(C)C1=O
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)N(C)CP(=O)(O)O

Procedure:
This phosphonic acid is prepared in a similar manner using tris(2-chloroethyl) phosphite as the phosphorus ester reactant. The intermediate ester, 1,4-dimethyl-2-(2-chloroethoxy)-1,4,2-diazaphospholidin-5-one-2-oxide, 31P nmr -24.9 ppm, is hydrolyzed in the reaction mixture to give the acid: mp 171°-172° dec (acetic acid-water).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16].ClC(Cl)C>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[CH3:13]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cnc2ccccc2c1Cl
Temperature: 70 °C

Procedure:
A mixture of 3-amino-4-chloroquinoline (8.00 g, 1 eq), trimethylacetyl chloride (11 mL g, 2 eq), and anhydrous dichloroethane (150 mL) was heated at 70° C. After 6 hours more trimethylacetyl chloride (2 eq) was added and heating was continued for a total of 23 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with hexanes and then filtered to provide 7.16 g of N-(4-chloroquinolin-3-yl)trimethylacetamide as a solid. The filtrate was concentrated under reduced pressure to provide 5 g of crude N-(4-chloroquinolin-3-yl)trimethylacetamide.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([F:16])[CH:7]=1.[CH3:17]O>>[CH3:17][O:14][C:13](=[O:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][C:8]=1[F:16]
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Thionyl chloride (0.94 mL, 0.0129 mol) was added dropwise to a solution of (4-chloro-2-fluoro-phenyl)acetic acid (2.03 g, 0.0108 mol) in methanol (100 mL) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography (n-hexane/ethyl acetate=1/0 to 3/1) to give the title compound (2.11 g, 96%).
Reaction SMILES: [C:1]12([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=4)[C:18]=3[S:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]([C:23]4[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[C:18]=3[S:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCCSc1c(C(=O)NC23CC4CC(CC(C4)C2)C3)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC23CC4CC(CC(C4)C2)C3)cnn1-c1ccc(C(=O)O)cc1
Yield: 93.8 %

Procedure:
Methyl 4-[4-(1-adamantylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (143 mg, 0.32 mmol) (Intermediate#3) was dissolved in methanol and treated at ambient temperature with 2M aqueous sodium hydroxide solution. The mixture was stiffed at ambient for 18 h. Methanol was removed by evaporation under reduced pressure and the clear solution diluted with water (25 ml). 2M HCl was added to pH4 and the mixture extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the title compound as a white solid (132 mg, 94%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH:11](OCC)(OCC)OCC.[S:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22]1.C(OC(C)C)(C)C>>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[CH:11][NH:26][C:23]2[CH:24]=[CH:25][S:21][CH:22]=2)[C:4](=[O:9])[O:3]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccsc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CC(C)OC(C)C
Product: CC1(C)OC(=O)C(=CNc2ccsc2)C(=O)O1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Dimethyl-[1,3]dioxane-4,6-dione (5.0 g, 34.6 mmol) was combined with triethyl orthoformate (205 mL, 138 mmol) and stirred at 30° C. for 1 hour. Thiophen-3-ylamine (2.81 g, 28.3 mmol) was added in small portions at room temperature, at which time a white percipitate. The mixture was heated at 85° C. overnight. The reaction mixture was cooled to room temperature and isopropyl ether was added and the suspension was stirred for one hour. The precipitate was filtered off and washed with isopropyl ether and dried in vacuo. The intermediate was dissolved in methylene chloride and potassium carbonate was added and the suspension was stirred for 30 minutes. The solid was filtered off and the solution was concentrated to give 2,2-dimethyl-5-(thiophen-3-ylaminomethylene)-[1,3]dioxane-4,6-dione as the free base. In a single neck round bottom flask, dowtherm A (15 mL) was heated to 260° C. and 2,2-dimethyl-5-(thiophen-3-ylaminomethylene)-11,3]dioxane-4,6-dione was added in small portions. The mixture heated for 30 minutes and then was cooled to room temperature and isopropyl ether was added and the suspension was stirred for one hour. The precipitate was filtered off and washed with isopropyl ether and dried in vacuo to provide 3.43g (79%) of 4H-thieno[3,2-b]pyridin-7-one. 1H NMR (400 MHz, DMSO) d 7.93 (d, 1H), 7.79 (d, 1H), 7.21 (d, 1H), 5.99 (d, 1H); LC-MS: 152 (MH+); HPLC RT: 1.21.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([OH:3])=[O:2].[CH3:24]O.OS(O)(=O)=O>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[CH:14][C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)([O:3][CH3:24])=[O:2]
Reactant: CO
Reactant: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1c[nH]c2ncccc12
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Yield: 90 %

Procedure:
A solution of 5-carboxy-3-[(7-azaindol-3-yl)methylene]-2-oxindole (3.053 g, 10 mmol), methanol (3.2 g, 0.1 mol) and H2SO4 95% (1 g) in benzene (100 ml) was heated in a Soxhlet apparatus for 10 h. To dry the distillate continuously, the cap of the Soxhlet contained anhydrous MgSO4. After cooling, water was added, the organic phase repeatedly washed with water and then evaporated under vacuum. Thus almost pure title compound was obtained in about 90% yield.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[N:12][OH:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 90.1 %

Procedure:
23.5 g (167 mmol) of 1-acetyl-4-piperidone (Aldrich Chemical Co., Milwaukee, Wis.) and 12.5 g (179 mol) of hydroxylamine hydrochloride were placed in a 250 mL flask with 200 mL of methanol. To the resulting mixture was added 19.0 g (180 mmol) of sodium carbonate, and the resulting mixture was allowed to stir at room temperature for 12-14 h. The reaction mixture was concentrated in vacuo to afford 23.5 g of 1-acetyl-4-hydroxyiminopiperidine as a white solid: 1H NMR (300 MHz, CDCl3) δ3.72 (dd, 2H, J=11.0, 6.0 Hz), 3.59 (ddd, 2H, J=13.8, 6.2, 6.2 Hz), 2.68 (ddd, 2H, J=10.6, 6.2, 6.2 Hz), 2.42 (ddd. 2H, J=12.2, 6.1, 6.1 Hz), 2.17 (d, 3H, J=3.9 Hz); 13C NMR (75 MHz, CDCl3) δ169.39, 169.29, 156.07, 155.78, 45.95, 44.31, 41.68, 39.65, 31.27, 30.46, 25.04, 24.42, 21.47, 21.44.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[ClH:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:30]2[S:29][C:28]([C:31]([NH:33][C@@H:34]3[CH:39]4[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]4)[CH2:35]3)=[O:32])=[CH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C1COCC1>CN(C=O)C>[ClH:12].[N:36]12[CH2:37][CH2:38][CH:39]([CH2:40][CH2:41]1)[C@@H:34]([NH:33][C:31]([C:28]1[S:29][C:30]3[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][NH:14][C:10]([NH:9][CH3:8])=[O:11])=[CH:23][CH:24]=[CH:25][C:26]=3[CH:27]=1)=[O:32])[CH2:35]2
Reactant: CN=C=O
Reactant: NCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)NCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Reaction time: 18 h

Procedure:
51.0 μl (0.37 mmol) of triethylamine and 43.5 ld (0.73 mmol) of methyl isocyanate are added to a suspension of 85 mg (0.18 mmol) of 7-[2-(aminomethyl)phenyl]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride (Example 73) in 1 ml of a 5:1 mixture of THF and DMF. After 18 h at room temperature, the reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 65.5 mg (74% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:11][CH2:12][S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=[C:6]2[C:5](=[O:33])[N:4]([CH3:34])[C:3]1=[O:35].[Li+].CC([N-]C(C)C)C.[B:44](OC(C)C)([O:49]C(C)C)[O:45]C(C)C>C1COCC1>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:11][CH2:12][S:13][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]([B:44]([OH:49])[OH:45])=[C:6]2[C:5](=[O:33])[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1c(=O)c2cn(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(B(O)O)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1,3-Dimethyl-6-(2-(tritylthio)ethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 2)(3.6 g, 7.47 mmol) was dissolved in anhydrous THF (67.3 mL) at room temperature in an oven dried flask. The flask was evacuated and backfilled with nitrogen (×3) and cooled to −78° C. LDA (0.719 M, 16.63 mL, 11.96 mmol) was added over 10 mins followed by triisopropyl borate (2.76 mL, 11.96 mmol) and the reaction aged for 2 hr at −78° C. The reaction was quenched with saturated NH4Cl solution (60 mL) added via syringe under nitrogen and the mixture was warmed to room temperature and stirred overnight under nitrogen. The mixture was then diluted DCM (400 mL). The layers were separated and the aqueous extracted with DCM (2×100 mL). The combined organics were passed through a hydrophobic frit and the solvent was reduced to ˜20 mL under reduced pressure and EtOAc (100 mL) added to the resulting red oil. Reduction of solvent volume under reduced pressure to ˜25 mL afforded precipitation of a white solid. The solid was collected by reduced pressure filtration, washed with EtOAc (10 mL) and dried under vacuum 50° C. for 16 h to afford the title compound;
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:7](O)(C)[CH3:8].[N:11]1([C:17](=[S:19])[NH2:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:4][C:3]1[N:18]=[C:17]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[S:19][C:2]=1[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NC(=S)N1CCOCC1
Reactant: CC(C)O
Reactant: CCCC(=O)O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1C
Yield: 82 %

Procedure:
In a 100 mL round bottomed flask, to a solution of butanoic acid, 2-chloro-3-oxo-, ethyl ester (11.2 g, 68.4 mmol) in isopropyl alcohol (250 mL, 3300 mmol) was added morpholine-4-carbothioicacidamide (10.0 g, 68.4 mmol). The mixture was stirred at reflux for 1 hour, and then stirred at room temperature for 3 days. Volatiles were removed in vacuo, and the resulting residue was dissolved in ethyl acetate and diluted with saturated, aqueous sodium bicarbonate. The mixture was transferred to a separatory funnel, the layers were separated, and the organic layer dried with Na2SO4, filtered and concentrated in vacuo. The crude product was dissolved in DCM, adsorbed onto silica gel, and purified via column chromatography (120 g Isco column, gradient elution, 0-100% EtOAc/hexanes) to afford ethyl 4-methyl-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (14.51 g, yield for 2 steps, 82%). LC/MS: (FA) ES+ 257, 259; 1H NMR (400 MHz, CDCl3) δ 4.26 (dd, J=7.1, 7.1, 2H), 3.87-3.67 (m, 4H), 3.59-3.42 (m, 4H), 2.55 (s, 3H), 1.33 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Br:8][C:7]1[C:2]2[NH:1][CH:23]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[NH:16][S:13](=[O:15])(=[O:14])[C:3]=2[CH:4]=[C:5]([S:9](=[O:11])(=[O:12])[NH2:10])[CH:6]=1
Reactant: Nc1c(Br)cc(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: O=CC1CCCCC1
Product: NS(=O)(=O)c1cc(Br)c2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
2-Amino-3-bromo-5-sulfamoylbenzenesulfonamide was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 254-258° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([O:20]C)=[O:19].[OH-].[Na+]>O.C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3]1[C:8]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1c(CC(=O)O)cccc1C(=O)c1ccccc1

Procedure:
A mixture of 500 mg. (1.85 mmole) of methyl 2-dimethylamino-3-benzoylphenylacetate and 15 ml. of 3N sodium hydroxide was refluxed for 1.5 hr. under nitrogen. The cooled filtered reaction mixture was diluted with an equal volume of water and neutralized with glacial acetic acid. The precipitate which formed could not be recrystallized and was therefore dissolved in benzene and placed on a magnesium silicate column. The column was eluted with benzene-acetone to give 300 mg. of product which melted at 144°-146° C. after recrystallization from benzene-isooctane.