Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].[F-].[K+].O>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[N:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example G.1) (0.265 g, 0.41 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.115 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium (0.028 g, 0.024 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (5 mL), water (20 mL) was added and the water layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.081) as a light brown solid. Mp 281° C.
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.C[C:40]([CH3:42])=[O:41].C(=O)([O-])[O-].[K+].[K+].[C:49](OC(=O)C)(=[O:51])[CH3:50]>CCOCC.ClCCl.O>[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[C:49]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:33]=[CH:34][C:35]([O:38][C:40](=[O:41])[CH3:42])=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:51])[CH3:50]
Reactant: CC(C)=O
Reactant: Oc1ccc([S+](c2ccccc2)c2ccc(O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CC(=O)Oc1ccc([S+](c2ccccc2)c2ccc(OC(C)=O)cc2)cc1

Procedure:
Bis[4-hydroxylphenyl]phenysulfonium perfluorobutanesulfonate (10 g) and acetone were placed into a reaction vessel equipped with an agitator, a thermometer, a reflux condenser, and a tube for introducing nitrogen gas into the vessel. Under a nitrogen blanket, 4.6 g of potassium carbonate was added to the reaction vessel and the mixture was stirred for an hour. Acetic anhydride 3.43 gram was added and stirred overnight at room temperature. Dichloromethane (150 ml) and water were added to the reaction vessel and the mixture was stirred for 2 hours. The mixture was then placed into a separatory funnel and the organic (dichloromethane) layer was retained. The dichloromethane layer was washed several times with water, dried over anhydrous sodium sulfate, filtered, and the remaining volatile materials were evaporated to leave an oil. Ether was added to the oil and the mixture was stirred vigorously. A very sticky solid was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[O:9].[O:10]=[CH:11][C:12](=[CH2:14])[CH3:13].[CH3:15][OH:16]>>[CH3:8][O:9][CH2:13][C:12]([CH2:11][OH:10])([CH3:14])[CH:15]=[O:16]
Reactant: C=O
Reactant: C=C(C)C=O
Reactant: CO
Solvent: CCN(CC)CC
Product: COCC(C)(C=O)CO
Reaction time: 8 h
Yield: 78 %

Procedure:
22 g of triethylamine are added to a mixture of 590 g of methanol, 330 g of 30% strength formaldehyde solution and 210 g of methacrolein in the course of 10 minutes, and the solution is kept at the boiling point for 8 hours. The low-boiling components are separated off, after which 312 g (=78% yield, based on methacrolein) of the title compound of boiling point 120°-125° C./24 mbar are isolated by distillation under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH:8]2[CH2:14][N:13]([C:15](=[O:24])[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3I)[CH:12]([CH3:25])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:28].C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][N:38]=1)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH:8]2[CH2:14][N:13]([C:15](=[O:24])[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[CH:12]([CH3:25])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:28]
Reactant: Cc1ccc(I)c(C(=O)N2CC(COc3ccc(F)c(C)c3)CCCC2C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nccs2)c(C(=O)N2CC(COc3ccc(F)c(C)c3)CCCC2C)c1
Temperature: 100 °C

Procedure:
A mixture of 6-[(4-fluoro-3-methylphenoxy)methyl]-1-(2-iodo-5-methylbenzoyl)-2-methylazepane (3-1, 50 mg, 0.10 mmol, 1.0 equiv), tetrakis(triphenyl phosphine)palladium (35 mg, 0.030 mmol, 0.30 equiv) and 2-tributylstannylthiazole (94 mg, 0.25 mmol, 2.5 equiv) in toluene (1 mL) was heated at 100° C. for 1 hour. The reaction was cooled and filtered. The filtrate was concentrated and purified by reverse phase liquid chromatography (Sunfire C18 OBD 5 um, 20×150 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methyl-1-[5-methyl-2-(1,3-thiazol-2-yl)benzoyl]azepane (3-2). δ 7.96-6.14 (m, 8H), 4.77-0.88 (m, 21H). LRMS m/z (M+H) 496.2 found, 496.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4].C(O)(=O)C.O>O1CCCC1>[OH:12][CH2:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CCC(CO)CC1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To an ice-cold, stirred solution of acid from step 1 (700 mg, 3.8 mmol) in tetrahydrofuran (10 mL) was added borane-dimethyl sulfide complex (2 mL, 4.1 mmol). The reaction mixture was warmed to room temperature for 2 h and a 1:1 mixture of acetic acid/water (10 mL) was added. The resulting mixture was concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 hexanes/ethyl acetate) provided methyl 4-(hydroxymethyl)cyclohexanecarboxylate (560 mg): 1H NMR (500 MHz, CDCl3) δ 3.68 (s, 3H), 3.51–3.46 (m, 2H), 2.59–2.57 (m, 1H), 2.05–2.00 (m, 2H), 1.65–1.55 (m, 5H), 1.31–1.27 (m, 2H).
Reaction SMILES: [C:1]([C:3]1([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][C:6]([F:11])([CH2:9][OH:10])[CH2:5][CH2:4]1)#[N:2].[NH2:23][OH:24].[C:25]([C:32]([O:34][CH2:35][CH3:36])=[O:33])#[C:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[CH2:15]([O:14][C:13]([NH:12][C:3]1([C:1](=[NH:2])[NH:23][O:24][C:25](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:8][CH2:7][C:6]([F:11])([CH2:9][OH:10])[CH2:5][CH2:4]1)=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NO
Reactant: N#CC1(NC(=O)OCc2ccccc2)CCC(F)(CO)CC1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C=C(ONC(=N)C1(NC(=O)OCc2ccccc2)CCC(F)(CO)CC1)C(=O)OCC
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A flask was charged with benzyl 1-cyano-4-fluoro-4-(hydroxymethyl)cyclohexylcarbamate, Intermediate 33, (13.0 g, 42.4 mmol), EtOH (100 mL) and aqueous hydroxylamine (26.0 mL, 424 mmol). The reaction was stirred at 80° C. under nitrogen for 2 hours. The mixture was concentrated and the resulting residue diluted with CH2Cl2, washed with brine, dried (MgSO4) and the solvent evaporated to provide a colorless oil. The oil was dissolved in EtOH (100 mL) to which diethyl acetylenedicarboxylate (13.54 mL, 85 mmol) was added. The reaction was stirred under nitrogen for one hour. The solution was concentrated and the residue was dissolved in CH2Cl2 then purified by silica gel column chromatography eluting with hexane/ethyl acetate (0 to 100%). The appropriate fractions were combined and evaporated to give the title compound (13.01 g, 25.5 mmol, 60.2% yield)] as a light yellow syrup.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1>C(O)C>[F:9][C:10]1[N:15]=[C:14]([C:16]([NH2:17])=[O:2])[CH:13]=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:11]=1
Reactant: N#Cc1cc(C(F)(F)F)cc(F)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)cc(F)n1
Yield: 78.3 %

Procedure:
To 9 ml of ethanol were added 0.73 g of sodium bicarbonate and 0.61 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.7 g of 6-fluoro-4-trifluoromethylpyridine-2-carbonitrile was added at 0° C., and the mixture was stirred, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 6-fluoro-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:12])([C:13]2[CH:18]=[CH:17][C:16]([CH:28]=[O:29])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(Br)cc2)C1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 106.4 %

Procedure:
To a stirred solution of 3-(4-bromo-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (5 g, 15.14 mmol, 1 eq) in dry THF (60 mL) was added n-BuLi (16.6 mL, 18.17 mmol, 1.2 eq) at −78° C. under nitrogen atmosphere. Reaction mixture was stirred for 10 minutes at −78° C. under nitrogen atmosphere. At −78° C., DMF (1.748 mL, 22.71 mmol, 1.5 eq) was added in drop wise manner over a period of 10 minutes. Resulting reaction mixture was allowed to warm to −20° C. and stirred for 3 hours at −20° C. After complete consumption of starting material, reaction was quenched with 10% NH4Cl solution (10 mL) followed by water (100 mL) and extracted with ethyl acetate (3×40 mL). Combined organic phase was washed with brine solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as pale yellow thick oil (4.5 g, Crude). Crude compound was used as such for next reaction. LC-MS (m/z): 279.3 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14]([NH2:16])=[O:15]>O1CCOCC1>[C:13]([C:14]1[O:15][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[N:16]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(C)(C)C(N)=O
Solvent: C1COCCO1
Product: CC(C)(C)c1nc(-c2ccc(F)cc2)co1
Yield: 1254.2 %

Procedure:
Stir a mixture of 2-bromo-4′-fluoroacetophenone (100 g, 460 mmol) and 2,2-dimethylpropionamide (93.06 g, 20 mmol) in 1,4-dioxane (600 mL) at reflux for 2 days. Filter the reaction mixture and concentrate the filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 60:1 hexane:ethyl acetate to provide 55 g (55%) of the desired compound.
Reaction SMILES: N[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1Cl.BrCC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:17][C:14]([F:15])([F:16])[C:13]([N:9]1[CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:12]=2[CH2:11][CH2:10]1)=[O:18]
Reactant: Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: BrCc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Temperature: 50 °C

Procedure:
Using a method similar to the General Procedure 5-4, combine 6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.1 g, 0.35 mmol), 8-bromomethyl-quinoline (83.6 mg, 0.038 mmol), cesium carbonate (0.2 g, 0.68 mmol) and anhydrous acetonitrile (1 mL) in a sealed tube and heat at 50° C. for 12 h to obtain 7-chloro-6-[(quinolin-8-yl-methyl)-amino)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [Cl-].[NH4+:2].CC1C=CC(S([O:13][C@H:14]2[CH2:18]O[C@@H:16]3[C@@H:19](Br)[CH2:20][O:21][C@H:15]23)(=O)=O)=CC=1.N.CO>O.CC(O)C.[Zn]>[NH2:2][CH2:18][C@H:14]([C@@H:15]1[CH:16]=[CH:19][CH2:20][O:21]1)[OH:13]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A solution of ammonium chloride (600 mg, 11.2 mmol) in water (7.5 mL) was added to a solution of bromotosylate (47) (3.0 g, 8.26 mmol) in propan-2-ol (15 mL) under argon. Zinc dust (600 mg, 9.2 mmol) was then added in portions over 4 minutes and the mixture was stirred for 16 hours before filtering the suspension through celite in vacuo. The filter cake was washed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (60 mL) then the combined organic phase was washed with brine (60 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue was dissolved in ammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol), then divided into two equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:12][NH2:13]>CO>[CH3:2][C:1]1[C:4]2[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]=2[NH:13][N:12]=1
Reactant: NN
Reactant: CC(=O)C1C(=O)CCCC1=O
Solvent: CO
Product: Cc1n[nH]c2c1C(=O)CCC2
Temperature: 0 °C

Procedure:
To an ice-cold solution of 33.3 grams of 2-acetyl-1,3-cyclohexanedione in 400 ml of methanol was added dropwise a solution of 7.2 ml of hydrazine in 50 ml of methanol and the resulting reaction mixture was heated at reflux for 20 hours. The solvent was then removed under reduced pressure and the residue was triturated in ethyl ether to give 1,5,6,7-tetrahydro-3-methyl-4H-indazol-4-one as a yellow crystalline solid melting at about 154°-157° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:26]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)([C:14](=[O:25])[NH:15][C:16]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:26])([C:14](=[O:25])[NH:15][C:16]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)NC2(c3ccccn3)CC2)CC1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N)(C(=O)NC2(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of crude 4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester in DMF (0.5 mL) was added piperidine (0.2 mL). The mixture was stirred at room temperature. After 1 h, the solution was diluted with EtOAc (20 mL) and washed with water (4×20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified via flash chromatography on silica gel (10% MeOH in CH2Cl2 containing 0.1% NH4OH) to afford 74 mg of 4-amino-4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](N3CC4CN(C(OC(C)(C)C)=O)CC4C3)[N:15]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:14]=2[CH:38]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:40](F)(F)[C:41](O)=O>O>[CH:10]1([C:16]2[N:15]([CH2:33][CH:34]=[C:35]([CH3:36])[CH3:37])[C:14]3[CH:38]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[N:17]=2)[C:38]2=[CH:14][NH:15][CH2:40][CH:41]2[CH2:1][NH:9]1
Reactant: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc(NC(=O)c3ccccc3)cc21
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)=CCn1c(C2NCC3CNC=C32)nc2ccc(NC(=O)c3ccccc3)cc21
Yield: 95 %

Procedure:
10 mg (0.02 mmol) of tert-butyl 5-[6-benzoylamino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate were dissolved in 200 μl of trifluoroacetic acid and 200 μl of water, and stirred at room temperature for 19 hours. The reaction mixture was diluted with water and freeze-dried. 10 mg (95%) of the desired product were obtained.
Reaction SMILES: [Na].Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>CC(C)=O>[CH2:12]([NH:16][C:17]([NH:10][C:3](=[NH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=O
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCNC(=O)NC(=N)c1ccccc1

Procedure:
Following a procedure similar to that described in Example 23 but using 7.7 g. sodium in 1100 ml. dry sodium, 52.4 g. benzamidine hydrochloride, and 33.1 g. butylisocyanate in 400 ml. dry acetone there was obtained, after recrystallization from ethyl acetate, 62.2 g. 1-butyl-3-(benzimidoyl)urea hydrochloride; m.p. 139°-141°C.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]#N)=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[OH2:15].CCO>>[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:1])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ccc(F)c2cc[nH]c12
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(F)c2cc[nH]c12
Temperature: 25 °C

Procedure:
Intermediate 1 was prepared according to procedures described in Wallace, O. B. et al. PCT int. appl. WO0204440, and as described in Steps A-D below. Step A A mixture of 4-fluoro-7-bromoindole (600 mg, 2.8 mmol) and CuCN (1.004 g, 11.2 mmol) in DMF (4 ml) was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was poured into a solution of ammonia in MeOH (30 ml, sat.) and the residue removed by filtration. The filtrate was added to a mixture of water (20 ml)/ammonia (20 ml, sat. aq.) and extracted with EtOAc/Ether (1/1) until TLC analysis showed no product in the aqueous phase. The combined organic extracts were washed with brine (2×200 ml) and water (200 ml), dried (MgSO4); evaporation in vacuo gave 4-fluoro-7-cyanoindole as a tan yellow solid (310 mg, 69%). Step B To a solution of KOH (13.04 g, 0.232 mol) in 14% H2O/EtOH (50 ml) was added 4-fluoro-7-cyanoindole (900 mg, 5.60 mmol). The resulting mixture was refluxed for 12 hours, slowly cooled to room temperature, and concentrated in vacuo to about 30 ml. The residue was acidified to pH 2 with HCl (˜5.5 N aq.). The precipitate was filtered, washed with excess of water, and dried under high vacuum to afford 4-fluoro-7-carboxyindole as a white solid (100% conversion). The material was used without further purification. Step C To a suspension of 4-fluoro-7-carboxyindole in a mixture of MeOH (18 ml)/PhH (62 ml) was added (trimethylsilyl)diazomethane (8.8 ml, 17.6 mmol, 2 M in hexane). The resulting mixture was stirred at room temperature for 30 min., quenched with excess acetic acid and evaporated in vacuo. The crude oily material was purified by flash chromatography using a gradient elution (Hexane to 10% EtOAc/Hexane) to afford 4-fluoro-7-carbomethoxy indole as a white solid (1.04 g, 83% two steps). Step D
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1([Se]Br)C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:11](=[O:19])[CH:10]=[CH:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: Br[Se]c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)N1C(=O)C=C[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
1.68 g (S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)pyrrolidin-2-one (1, R1=pivaloyl) is added to 10 ml toluene. The mixture is then cooled to −15° C. 5.5 ml Lithium bis(trimethylsilyl)amide (1 M in THF) is then added. After 1 h, a mixture of 1.3 g phenyl selenyl bromide in 10 ml toluene is added. After a further 30 min, 100 ml water is added. The phases are separated and the organic phase concentrated in vacuo. The residue is taken up in 25 ml ethyl acetate and then 5.1 ml hydrogen peroxide (37%) is added at room temperature. After 1 h, the phases are separated and the organic phase washed with a saturated sodium hydrogen carbonate solution and then dried (MgSO4). The mixture is concentrated in vacuo and purified by column chromatography, eluting with heptane/ethyl acetate 5:1 to afford (R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-1,5-dihydropyrrol-2-one. 1H NMR (CDCl3): 1.28 (9H), 2.70 (1H), 3.30 (1H), 4.97 (1H), 5.89 (1H), 7.06 (2H), 7.19 (2H), 7.31 (2H), 7.41 (4H).