Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP(CC(OCC)=O)(OCC)=O)C.[H-].[Na+].[F:17][C:18]1([F:46])[CH2:23][CH2:22][CH2:21][CH:20]([C@@H:24]2[CH2:29][C@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27][CH2:26][N:25]2C(OCC2C=CC=CC=2)=O)[CH2:19]1>C1COCC1>[F:46][C:18]1([F:17])[CH2:23][CH2:22][CH2:21][CH:20]([C@@H:24]2[CH2:29][C@H:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:27][CH2:26][NH:25]2)[CH2:19]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](c2ccccc2)C[C@H]1C1CCCC(F)(F)C1
Agent: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC1(F)CCCC([C@@H]2C[C@H](c3ccccc3)CCN2)C1
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (62.7 g, 0.28 mol) in THF (500 mL) at 0° C. was added NaH (6.77 g, 0.28 mol). After stirring for 1 h, a solution of compound 6 (48 g, 0.16 mol) in THF was added dropwise. The mixture was stirred at room temperature overnight, quenched with water, and extracted with EA. The combined extracts were dried over Na2SO4 and filtered. The filtrate was concentrated and purified on silica gel (PE:EA=30:1) to give 13 g of compound 7 in 30% yields.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10](C)[C:11]([OH:13])=[O:12])=C1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[CH3:26][N:27]([CH3:30])C=O>>[CH2:17]([N:27]1[C:26]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:3][CH2:10][C:11]([OH:13])=[O:12])=[CH:30]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C(=O)O)c1c[nH]c2ccccc12
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
8 ml of a solution of 1.00 g of indol-3-ylpropionic acid in dimethyl formamide were added gradually to 4 ml of a suspension of 460 mg (10.6 mmol) of sodium hydride (55% w/v dispersion in mineral oil) in dimethyl formamide at a temperature of -5° C., and the resulting mixture was stirred for 30 minutes at this temperature. After this time, 1.8 g (10.6 mmol) of benzyl bromide was added to the mixture which was then warmed to room temperature, stirred for 10 min, poured into ice-water, and acidified with a 1N aqueous solution of hydrogen chloride. The resulting aqueous layer was extracted with methylene chloride, and the extract was dried over anhydrous magnesium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was recrystallized from a 1:1 v/v mixture of ethyl acetate and hexane to yield 1.15 g (79%) of the title compound melting at 121°-122° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:8]=[CH:9][C:10]=1[Cl:11])=O.[C:25]1([NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31].CCN(C(C)C)C(C)C>>[Cl:11][C:10]1[CH:9]=[CH:8][C:7]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=2)=[CH:6][C:5]=1[C:3]1[CH:2]=[N:31][C:26]2[C:25]([N:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2
Reactant: Nc1ccccc1N
Reactant: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(=O)CBr)c2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(-c3cnc4ccccc4n3)c2)c1

Procedure:
Procedure D was performed using N-(3-(2-bromoacetyl)-4-chlorophenyl)-3,5-dimethoxybenzamide (0.029 g, 0.07 mmol), 1,2-phenylenediamine (0.021 g, 0.19 mmol) and DIPEA (0.042 ml, 0.24 mmol) to give N-(4-chloro-3-(quinoxalin-3-yl)phenyl)-3,5-dimethoxybenzamide as a light tan powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[F:41][C:42]([F:48])([F:47])[CH2:43][CH2:44][CH2:45]I>CN(C=O)C>[F:41][C:42]([F:48])([F:47])[CH2:43][CH2:44][CH2:45][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:5][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: FC(F)(F)CCCI
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CCCC(F)(F)F)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a cooled (−15° C.) solution of methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.100 g; 0.295 mmol) in dry DMF (1.5 mL) was wadded a 1N solution of LHMDS in THF (0.324 mL; 0.324 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of 1,1,1-trifluoro-4-iodo-butane (0.076 mL; 0.589 mmol). After stirring for 2 h at (−15° C.) the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.102 g (66%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH2:13]([O:20][C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[C:30]([O:32][CH3:33])=[O:31])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ICC>C1COCC1>[CH2:13]([O:20][C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@:25]1([CH2:1][CH3:2])[C:30]([O:32][CH3:33])=[O:31])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)[C@H]1CCCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CC[C@@]1(C(=O)OC)CCCC[C@@H]1NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a cold (−78° C.) solution of N-isopropylpropan-2-amine (0.77 mL, 5.49 mmol) in THF (7 mL) was added, dropwise, n-butyllithium (3.43 mL of 1.6 M solution, 5.49 mmol). The mixture was stirred at −78° C. for 10 minutes. Then a solution of methyl (1S,2S)-2-benzyloxycarbonylaminocyclohexanecarboxylate, 38a, (0.40 g, 1.37 mmol) in THF (2.5 mL) was added over a period of 3 minutes. After 15 minutes, the mixture was warmed slightly (−40° C.) for 15 minutes and recooled to −78° C. for a further 10 minutes. Then, iodoethane (0.86 g, 0.44 mL, 5.49 mmol) was added, dropwise over 3-5 minutes. The reaction mixture was maintained at −78° C. for 2 hours and allowed to warm to room temperature overnight. The reaction was quenched with 5 mL aqueous saturated NH4Cl solution, extracted with EtOAc (3×), washed successively with 1N HCl and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-20% EA/Hex slow gradient elution) provided 275 mg (63% yield) of the desired product (38b). NMR indicated a diastereomeric ratio greater than 10 to 1 (cis vs trans).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[CH2:9][C:10]1[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:12][C:13]([NH2:17])=[N:14][C:15]=1[CH3:16]>CS(C)=O.CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:17][C:13]1[N:14]=[C:15]([CH3:16])[C:10]([CH2:9][C:8]2[CH:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:26]=[CH:25][CH:24]=2)=[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:12]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CCl)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Potassium cyanide (0.61 g) was added to a stirred solution of the product from step (v) (0.62 g) in DMSO (5 mL) and DMF (5 mL) and the mixture stirred at rt for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, dried and evaporated under reduced pressure to give the subtitle compound as a yellow oil 0.59 g that was used without further purification.
Reaction SMILES: FC(F)(F)[C:3]([O:5][C:6](=[O:11])[C:7](F)(F)F)=[O:4].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH3:20])[CH:15]=[CH:16][CH:17]=[C:7]([C:6]([OH:5])=[O:11])[CH:19]=1.[C:14]1([CH3:20])[C:19]([C:3]([OH:5])=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccccc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccc(C(=O)O)c1
Product: Cc1ccccc1C(=O)O
Temperature: 200 °C
Reaction time: 2 h

Procedure:
A mixture of toluene (5 mL), trifluoroacetic anhydride (1 mL), and the catalyst solution as prepared above (0.3 mL) was pressurized, at room temperature, with air (1000 psig) and CO (120 psig). The resulting mixture was stirred at 200° C. for 2 hours. After the mixture was cooled down to room temperature, the solvents were evaporated. The residue was redissolved in ether and analyzed by GC-MS with chlorobenzene as an internal standard. A mixture of p-toluic acid and m-toluic acid (70:30) was produced with TON=20, along with trace amounts of o-toluic acid.
Reaction SMILES: CS(O)(=O)=O.O=[C:7]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)N=[C:10](CCC(OCC)=O)[CH2:9][CH2:8]1.[OH-:26].[Na+].[CH2:28]([OH:31])[CH2:29][CH3:30]>>[O:31]=[C:28]([O:31][CH2:28][CH2:29][CH3:30])[CH2:29][C:30]1[C:14]2[C:13](=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:12][C:7]=1[CH2:8][CH2:9][C:10]([O:31][CH2:28][CH2:29][CH3:30])=[O:26]
Reactant: CCOC(=O)CCC1=NN(c2ccccc2)C(=O)CC1
Reactant: CCCO
Reactant: [OH-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: CCCOC(=O)CCc1[nH]c2ccccc2c1CC(=O)OCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Methanesulfonic acid (1.15 equiv.) was added to a stirred solution of ethyl 3-(6-oxo-1-phenyl-1,4,5,6-tetrahydropyridazin-3-yl)propanoate from Step 1 in n-propanol (1.1 M). The mixture was stirred overnight at 80° C. The mixture was cooled to room temperature and neutralized with aqueous 1N NaOH (1 equiv.). Final mixture was concentrated under vacuum, diluted with toluene and concentrated again. The residue was purified by column chromatography on silica gel using automatized gradiant pump system CombiFlashRF (Teledyne ISCO) eluting with ethyl acetate/hexane (0:100 to 60:40) to give the title compound (79%) as a brown oil.
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])CC1.NC1C=[C:15]2[C:19](=[CH:20][C:21]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH2:18][CH2:17][CH2:16]2.Cl.CC(C)=O>O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([C:21]1[CH:20]=[C:19]2[C:18]([CH2:17][CH2:16][CH2:15]2)=[CH:6][C:5]=1[NH:4][CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[O:30]
Reactant: O=[N+]([O-])C=CN1CCOCC1
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1Cl)CCC2
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccccc1Cl)c1cc2c(cc1NC=C[N+](=O)[O-])CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1-Morpholino-2-nitroethene (3.93 g) was added to a mixture of 5-amino-6-(2-chlorobenzoyl)indan (4.50 g), 6N HCl (15 ml) and acetone (45 ml) and the whole mixture was stirred at room temperature for one hour. To this reaction mixture was added water to give crystals of 6-(2-chlorobenzoyl)-5-(2-nitroethenylamino)indan (5.40 g, 95.2%). Recrystallization from ethanol gave yellow needles, mp. 225°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][C:28]1([OH:31])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:26][CH2:27][C:28]4([OH:31])[CH2:30][CH2:29]4)[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[S:19][CH2:20][CH2:21][CH3:22])=[CH:4][CH:3]=1
Reactant: CCCSc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccc(Cl)cc1
Reactant: OC1(CCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2c(c(=O)n(CCC3(O)CC3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 65.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(propylthio)-1H-purine-2,6(3H,7H)-dione (124 mg, 0.34 mmol) in DMF (7 mL) was added 1-(2-bromoethyl)cyclopropanol (67.3 mg, 0.41 mmol, intermediate 46), followed by potassium carbonate (141 mg, 1.02 mmol). The reaction was stirred at 70° C. for 5 h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude yellow oil product (100 mg, 66.9% yield). LCMS MH+ 449.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14](OC(=O)C)(=[O:16])[CH3:15].CCCCCC>CO.[Pd]>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:14](=[O:16])[CH3:15])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(NC(C)=O)c(C)c1C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 2,3-dimethyl-4-nitroanisole (1.04 g, 5.74 mmol) in methanol (20 ml) was added 10%-Pd/C (100 mg) at room temperature, and the resulting solution was stirred under a hydrogen atmosphere. After 1 hour, the reaction solution was filtered by the use of Celite and the filtrate was concentrated under reduced pressure and then dried. The residue was dissolved in ethyl acetate (10 ml), followed by adding thereto acetic anhydride (0.867 ml, 9.18 mmol), and the resulting mixture was refluxed. After 2 hours, hexane (70 ml) was poured into the reaction solution and the crystals formed were filtered under reduced pressure and then dried to obtain N-(4-methoxy-2,3-dimethylphenyl)acetamide (1.02 g, 92%).
Reaction SMILES: I.CS[C:4](=[N:19][CH3:20])[NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>C(O)C>[CH2:21]([NH:25][C:4]([NH:19][CH3:20])=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Agent: CC(=O)[O-]
Agent: I
Agent: [Pb+2]
Solvent: CCO
Solvent: O
Product: CCCCNC(=Nc1cc(C)ccc1N1CCOCC1)NC

Procedure:
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (12.2 g prepared as described in Example 227), n-butylamine (2.4 g) and ethanol (80 ml) was stored at ambient temperature for 4 months. Lead acetate trihydrate (9 g) was then added and the mixture heated under reflux for one hour to yield 1-(n-butyl)-2-(5-methyl-2-morpholinophenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 150° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: Nc1cccc(C(=O)O)c1
Product: COC(=O)c1cccc(N)c1
Product: Cl
Reaction time: 16 h
Yield: 98 %

Procedure:
To a suspension of 3-aminobenzoic acid (1.03 g mg, 7.52 mmol) in MeOH (80 mL) at 0° C. was added dropwise thionyl chloride (5 mL). The resulting solution was allowed to stir for 16 h before the solvent was removed by evaporation and the product precipitated with diethyl ether. The diethyl ether was removed by evaporation to yield the title compound (1.38 g, 7.38 mmol, 98%) as a white solid. Mp 176-178° C. 1H NMR (D2O, 300 MHz): δ 7.75 (dt, J=1.8, 3.3, 7.2 Hz, 1H, ArH); 7.71 (m, 1H, ArH); 7.42 (m, 1H, ArH); 7.37 (m, 1H, ArH); 3.66 (s, 3H, OCH3). Mass Spectrum (CI) m/z 152 (100%) [M+]. HRMS calcd for C8H10NO2 152.0712, found 152.0698.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]#[N:17])[C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(=O)(O)O.O>C(#N)C>[Br:18][C:12]1[C:13]([F:14])=[C:8]([C:5]2[C:4]([C:16]#[N:17])=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([F:15])=[CH:10][CH:11]=1
Reactant: N#Cc1cc(F)ccc1-c1c(F)cccc1F
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(F)ccc1-c1c(F)ccc(Br)c1F
Temperature: 70 °C
Reaction time: 7 h
Yield: 171.1 %

Procedure:
To a slurry of 4,2′,6′-trifluorobiphenyl-2-carbonitrile (5.0 g, 21.4 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (3.37 g, 11.8 mmol) in acetonitrile (45 ml) was added concentrated sulfuric acid (3.15 g, 32.2 mmol). The slurry was warmed to 70° C. and the resulting solution stirred for 7 h then aged at ambient temperature for 18 h. Water (45 ml) was added dropwise to the solution over 15 min. The layers were allowed to settle and the product rapidly crystallised. The slurry was left to stir for 0.5 h then the solid was collected by filtration, washed with 1:1 acetonitrile:water (10 ml) and left to air dry, which gave 3′-bromo-4,2′,6′-trifluorobiphenyl-2-carbonitrile (6.3 g, 94%) as a white solid: δH (360 MHz, CDCl3) 6.97–7.08 (1H, m), 7.38–7.54 (2H, m), 7.62–7.68 (1H, m).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)[CH3:7]>C(#N)C>[CH3:7][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][CH2:16][CH2:17][NH:18][C:3]([NH:2][CH3:1])=[O:4])=[CH:11][CH:10]=1)[CH3:5]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NCCSCc1ccc(CN(C)C)o1

Procedure:
Methylisocyanate (0.33 g) was added to a suspension of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine, phthalhydrazide complex (2 g) in acetonitrile (50 ml). After 2 hr the solution was filtered and the filtrate evaporated to give an oil which was purified by column chromatography (silica/methanol) to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylurea. Analysis Found: C, 52.38; H, 7.61; N, 15.25. C12H21N3O2S.1/4H2O requires: C, 52.24; H, 7.76; N, 15.32%.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[C:10](=[O:26])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12>C(O)(=O)C.[Cl-].[Na+].O.[Zn]>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[C:10](=[O:26])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:12]([OH:13])[C:3]=12
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc2c(c(Cl)c1=O)C(O)N(CCc1ccc3ccccc3n1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 139.2 %

Procedure:
Zinc (0.44 g, 6.8 mmol) was added to a solution of 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (1 g, 2.72 mmol, see Example c1)) in acetic acid (10 ml) and the reaction was stirred for 3 h under reflux. The reaction was cooled to r.t. and brine (20 ml) was added. The aqueous layer was extracted with THF (3×25 ml) and the combined organic phase was concentrated to dryness. The mixture was diluted with THF (30 ml)/MeOH (5 ml), filtered through a pad of silica gel and concentrated to give crude product (1.4 g 139% yield), which was used in the next steps without further purification.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:20]=[C:21]([S:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.[CH2:39](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:40]1[CH:45]=CC=C[CH:41]=1>>[CH2:6]([NH:8][C@H:9]([C:14]([NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([S:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:37])[F:38])[CH:20]=3)(=[O:26])=[O:27])[CH2:32]2)[CH2:35][CH2:34]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:40]([CH3:45])([CH3:41])[CH3:39]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-4-methyl-2-(neopentylamino)pentanoic acid from Step A of Example 244 for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.38 (s, 1H), 8.19-8.22 (m, 2H), 7.90-7.93 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 4.21-4.29 (m, 1H), 3.87 (dd, J=9.9, 2.6 Hz, 1H), 3.25 (dd, J=8.6, 5.6 Hz, 1H), 3.15-3.21 (m, 2H), 2.97 (dd, J=9.6, 7.0 Hz, 1H), 2.43-2.60 (m, 3H), 2.28-2.32 (m, 1H), 1.79-2.01 (m, 3H), 1.67-1.78 (m, 1H), 1.69 (ddd, J=13.6, 7.9, 5.7 Hz, 1H), 1.51-1.60 (m, 2H), 1.32 (ddt, J=9.3, 12.8, 6.4 Hz, 1H), 0.93 (d, J=6.6 Hz, 3H), 0.93 (s, 9H), 0.86 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 518 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[CH:8](OC)(OC)[O:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:8][O:9][CH:10]1[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)CO
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COC1OCC(CO)CO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.1 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (1.7 g, 16 mmol), trimethyl orthoformate (7 ml, 64.1 mmol), and p-toluenesulfonic acid monohydrate (275 mg, 1.6 mmol) was stirred at room temperature for 22 hours. To the reaction mixture, triethylamine (447 μl) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to obtain the title compound (1.4 g, 59.1% yield), which is a cis and trans (1:1) mixture, as a light yellow oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[N+](C)([O-])=O>[CH:6]([C:5]([C:14]1[CH:15]=[CH:16][C:11]([CH3:17])=[CH:12][CH:13]=1)=[O:9])([CH3:8])[CH3:7]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C(=O)C(C)C)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
At 10° C. a solution of 75 g AlCl3 in 100 ml nitromethane is added to a mixture of 49 g isobutyroyl chloride, 50 ml nitromethane and 100 ml toluene, after which the mixture is stirred during one hour. Then the reaction mixture is poured out into ice and extracted with ether. The ether solution is washed neutral, dried and evaporated. The residue is distilled under diminished pressure to obtain p-tolyl isopropyl ketone in a yield of 90%. 11 g of this ketone, dissolved in 50 ml methanol, is added to a solution of 10 g NaBH4 in 100 ml methanol/water 1:1. The reaction mixture is stirred during one hour, after that poured out into water and extracted with ether. The solution in ether is dried on MgSO4 and evaporated. Raw 2-methyl-1-(p-tolyl)propanol-1 is obtained in a yield of 97%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2ccc(Cl)nn2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1

Procedure:
A solution of 34.0 g of 3-(6-chloro-3-pyridazinyl)benzenamine, 18.8 ml of acetic anhydride, 28.7 ml of diisopropylethylamine and 750 ml of dichloromethane was stirred for 2.5 hrs. The solution was concentrated in vacuo to half of the original volume and 200 ml of hexane was added. The solution was filtered, affording 26.4 g of tan solid. The filtrate was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The residue and the solid collected previously were combined and recrystallized from dichloromethane-acetone-hexane to give 35 g of tan crystals, mp 203°-205° C.