Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:45])[CH2:18][NH:19][C:20](=[O:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:43])[O:28][CH2:29][CH:30]2[C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:12][CH:11]=1)=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C(Cl)Cl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:45])[CH2:18][NH:19][C:20](=[O:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:43])[O:28][CH2:29][CH:30]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]3[C:42]2=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(NC(=O)CNC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of #B120 (1 g, 1.63 mmol, 1.0 eq) in dry DCM (20 mL) at 0° C. was added trifluoroacetic acid (6 mL, large excess). The mixture was stirred at room temperature for 2 hrs and concentrated in vacuo. The residue was suspended in water (30 mL) and lyophilized to afford #B121 (1.2 g, 100%) as a slight yellow solid. 1H NMR (400 Hz, DMSO-d6): δ10.08 (s, 1H), 8.15 (br, 4H), 7.90 (d, 2H), 7.69 (d, 2H), 7.63 (d, 2H), 7.41 (m, 8H), 4.30 (m, 3H), 3.98 (m, 3H), 3.87 (d, 2H), 2.97 (m, 2H), 2.17 (m, 2H), 1.51 (m, 2H), 1.40 (m, 2H), 1.26 (m, 2H): LCMS (Protocol I): m/z 537.1 (M+Na]+, retention time=1.10 minutes.
Reaction SMILES: [C:1]([CH:4]1[CH:9]=[CH:8][CH2:7][N:6]2[C:10](=[O:20])[N:11]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[C:12](=[O:13])[N:5]12)([OH:3])=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH:4]1[CH:9]=[CH:8][CH2:7][N:6]2[C:10](=[O:20])[N:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:12](=[O:13])[N:5]12)([OH:3])=[O:2]
Reactant: COC(=O)CCn1c(=O)n2n(c1=O)C(C(=O)O)C=CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCn1c(=O)n2n(c1=O)C(C(=O)O)C=CC2

Procedure:
Methyl 5-carboxy-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-2-propionate was dissolved in methanol and the solution was stirred at room temperature for 2 hours with 1-M sodium hydroxide solution (1.1 mol equivalents). The mixture was acidified with concentrated hydrochloric acid and then evaporated to dryness. The residue was extracted with acetonitrile and the extracts were evaporated to give 5-carboxy-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-2-propionic acid of melting point 172°-175° C. (from acetonitrile).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[S:24]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]12>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:32]([C:29]2[N:26]3[C:25]([S:24][CH:28]=[CH:27]3)=[N:31][CH:30]=2)=[O:33])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cnc2sccn12
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3sccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.73 min; [M+H]+=483.3.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>C(O)CCC.O1CCOCC1>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:19]([F:24])[CH:18]=1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Reactant: Nc1ccc(Br)cc1F
Solvent: C1COCCO1
Solvent: CCCCO
Product: Fc1cc(Br)ccc1Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 90 °C
Yield: 58.1 %

Procedure:
In a 250-mL round-bottom flask, 2-chloro-6-trifluoromethoxy-1,3-benzothiazole (5.36 g, 21.14 mmol) and 4-bromo-2-fluoroaniline (4.82 g, 25.36 mmol) were combined in 100 mL n-butanol containing 1% 4.0 M HCl in dioxane, and heated at 90° C. overnight. The mixture was cooled to rt and the solvent was removed under reduced pressure. Ethyl acetate (50 mL) was added, and the mixture was ultrasonicated by suspending the flask in an ultrasonication bath for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Acetonitrile (50 mL) was added to the mixture, which was then ultrasonicated for 30 minutes and then filtered to provide the product as a white solid (5 g, 58%). LC-MS m/z 409.1 (MH+), ret. time 4.02 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][CH3:11])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Br:17][C:18]1[CH:19]=[C:20]([C:25](Cl)=[O:26])[C:21]([Cl:24])=[N:22][CH:23]=1.O>CC#N>[Cl:24][C:21]1[C:20]([C:25]([NH:1][C:2]2[C:3]([NH:9][CH2:10][CH3:11])=[N:4][C:5]([F:8])=[CH:6][CH:7]=2)=[O:26])=[CH:19][C:18]([Br:17])=[CH:23][N:22]=1
Reactant: CCNc1nc(F)ccc1N
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCNc1nc(F)ccc1NC(=O)c1cc(Br)cnc1Cl
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
To a cooled solution (4° C.) of 3-amino-2-(ethylamino)-6-fluoropyridine (31.0 g, 200 mmol) in MeCN (160 mL) was added solid NaHCO3 (50.4 g, 600 mmol). After 15 min, a solution of 5-bromo-2-chloro-3-pyridinecarbonyl chloride (1 equiv., 200 mmol) in MeCN (155 mL) was added. After 60 min at room temperature, the reaction mixture was poured into water (1.2 L) and stirred for 30 min. The resulting solid was filtered, dried under reduced pressure at 50° C. overnight. The title compound (73.7 g, 99% yield) was obtained as a black solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:40]([O:39][C:37](=[O:38])[CH2:36][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.800 g, 1.76 mmol), tert-butyl 2-bromoacetate (130 μL, 0.88 mmol) and K2CO3 (0.972 g, 7.04 mmol) in DMF (35 mL) was heated at 80° C. for 2 h. Upon which additional tert-butyl 2-bromoacetate (130 μL, 0.88 mmol) was added, heating at 80° C. was continued for a further 1.5 h. The mixture was allowed to cool to RT and concentrated in vacuo. Diluted with CH2Cl2 and extracted with water (3×). Dried under Na2SO4 and concentrated in vacuo to give tert-Butyl 5-(2-(3-(2-tert-butoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.950 g, 1.68 mmol, 95%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:21]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:30])C(=O)C1>C(#N)C.O>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[C:21]=1[I:30])[CH3:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(NC(=O)OCc1ccccc1)c1cn2cccnc2n1
Solvent: CC#N
Solvent: O
Product: CC(NC(=O)OCc1ccccc1)c1nc2ncccn2c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-imidazo[1,2-a]pyrimidin-2-yl-ethyl)-carbamic acid benzyl ester (5.3 g, 17.90 mmol) in acetonitrile (30 mL) was added n-iodosuccinimide (4.0 g, 17.90 mmol) and stirred at rt overnight. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to provide [1-(3-iodo-imidazo[1,2-a]pyrimidin-2-yl)-ethyl]-carbamic acid benzyl ester: LC-MS (ESI) m/z 422.8 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4](S)[N:3]=1.[OH-:18].[Na+].OO.Cl>CO>[OH:18][C:4]1[N:3]=[C:2]([OH:1])[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[N:5]=1
Reactant: [OH-]
Reactant: Oc1nc(S)nc2c(-c3ccccc3)cnn12
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Product: Oc1nc(O)n2ncc(-c3ccccc3)c2n1

Procedure:
To a mixture of 4-hydroxy-2-mercapto-8-phenylpyrazolo[1,5-a]-1,3,5-triazine (130 mg), 0.25N sodium hydroxide solution (4 ml) and methanol (3 ml) is with stirring added 30% hydrogen peroxide (1 ml) under ice cooling. The mixture is reacted for one hour, and the reaction mixture is adjusted to pH 1-2 with conc. hydrochloric acid. The resulting precipitate is separated by filtration, washed with water and methanol and dried to give the title compound (25.8 mg).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].I[CH3:15].O>CN(C)C=O>[CH3:5][C:2]([C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)([CH3:1])[CH2:3][O:4][CH3:15]
Reactant: CC(C)(CO)c1ccncc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)(C)c1ccncc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(1,1-dimethyl-2-hydroxyethyl)pyridine (15 g) in dry dimethylformamide (150 ml) was treated with sodium hydride (80% oil dispersion; 3.3 g) under nitrogen at 0° C. with stirring. After 15 minutes at 0° C., this mixture was cooled to -20° C., and a solution of iodomethane (7.4 ml) in dry dimethylformamide (50 ml) was added dropwise during 5 minutes. The mixture which changed from a white to an orange precipitate was allowed to slowly warm to ambient temperature, and stirred overnight under nitrogen. After pouring into excess water, the mixture was extracted with three portions of dichloromethane. The extract was washed with water twice, dried over anhydrous magnesium sulphate and evaporated in vacuo to give a dark oil after further evaporation of added toluene. This oil was chromatographed on silica gel (Merck; 0.04-0.063 mm) under medium pressure using a mixture of dichloromethane and ethyl acetate (2:1) as solvent to give 4-(1,1-dimethyl-2-methoxyethyl)pyridine (11.0 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:17]([C:15]1[C:2]([Cl:1])=[C:3]([Cl:16])[C:4]2[O:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]=2[CH:14]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Cl
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCC(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a stirred solution of ethyl 6,7-dichloro-2,3-dihydro-2-benzofurancarboxylate (13.4 g, 0.05 mole) and butyryl chloride (10 ml, 0.09 mole) in CH2Cl 2 (30 ml) cooled to 5° C. in an ice bath was added aluminum chloride (22.5 g, 0.17 mole) over a 10 minute period. The reaction mixture was stirred for 1 hour at 25° C. then for 20 minutes at reflux. The reaction mixture was poured into ice water, extracted into ether, washed with water and the ether evaporated in vacuo. The residue was treated with 10 N sodium hydroxide (100 ml) and the resultant sodium salt filtered and suspended in dilute hydrochloric acid which was extracted with ether (206 ml), washed with water, dried over magnesium sulfate, evaporated to 50 ml and treated with hexane to give 12.0 g of 5-butyryl-6,7-dichloro-2,3-dihydro-2-benzofurancarboxylic acid which melted at 124°-125° C.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:19][CH:18]=[CH:17][CH:16]=2.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:22]1([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:21]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[CH:1]1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cccnc12
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3cccnc3c21
Yield: 21.3 %

Procedure:
Triethylorthoformate (2.8 mL, 16.6 mmol) was added to a solution of 1,1-dimethylethyl N-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (5.0 g, 15.1 mmol) in toluene (150 mL). The reaction was heated at reflux overnight with ethanol being collected in a Dean Stark trap. The reaction mixture was heated at reflux for an additional 6 hours and then p-toluenesulfonic acid (1.4 g, 7.5 mmol) was added and the reaction was refluxed overnight. A dark orange/brown oil had formed. The toluene supernatant was decanted off and concentrated under vacuum to provide 1.1 g of 1,1-dimethylethyl N-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The oil was identified as 4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine. This material was reacted with 1,1-dimethylethyl-dicarbonate to provide an additional 1 g of 1,1-dimethylethyl N-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The two lots were combined and carried on to the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[Br:19]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:19])=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CC(OC(C)=O)CC2
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c2c1CC(OC(C)=O)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A mixture of acetic acid 8-acetylamino-1,2,3,4-tetrahydronaphthalen-2-yl ester (2.2 g, 8.9 mmol) and bromine (1.7 g, 10.7 mmol) in 50 mL of acetic acid was stirred at room temperature for 18 h. The solvent was removed by rotoevaporation, and the residue was taken up in an diethyl ether/water mixture. The resulting solid was collected by filtration, and washed with diethyl ether. After drying the product (2.75 g) was obtained in 95% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[CH2:12]([N:19]1[C:23]([CH:24]=[O:25])=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]([CH:24]([OH:25])[CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: O=Cc1cncn1Cc1ccccc1
Product: OC(CCCc1ccc(F)cc1)c1cncn1Cc1ccccc1

Procedure:
1-benzyl-5-[4-(4-fluorophenyl)-1-hydroxybutyl]-1H-imidazole is prepared from 1-bromo-3-(4-fluorophenyl)propane and 1-benzyl-5-imidazole carbaldehyde by the same method described in example 7a).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)C(C)C

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with isobutyryl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H37N2O2Cl2 [(M+H)+] 565.2383, observed 565.2384.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][C:28]1([C:31]#[N:32])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:23](=[O:25])[NH:27][C:28]2([C:31]#[N:32])[CH2:30][CH2:29]2)[CH2:10]1)(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)O
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
The carboxylic acid 5A (195 mg, 0.5 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (65.2 mg, 550 μmol), HATU (380 mg, 1.00 mmol) and ethyldiisopropyl amine (262 μL, 1.5 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature over night. The reaction was concentrated under reduced pressure. The residue was diluted with 5% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with 1M aqueous hydrogen chloride solution and with saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure to yield (2S,4R)-tert-butyl 4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)-pyrrolidine-1-carboxylate 6H as a yellow oil (66%). MS ISP (m/e): 354.2 (100) [(M−BOC+H)]+, 398.1 (25) [(M-Isobutylene+H)]+, 454.1 (12) [(M+H)]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:21][C:9]=2[C:8]1=[O:28]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:7]([CH3:6])[C:8](=[O:28])[C:9]2[CH:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][C:10]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CN1C(=O)c2cnc(-c3ccccc3)nc2Nc2ccccc21
Solvent: Cc1ccccc1
Product: CN1C(=O)c2cnc(-c3ccccc3)nc2N(C(=O)CCl)c2ccccc21

Procedure:
1.6 ml (20 mmols) of chloroacetyl chloride are added dropwise at room temperature to a suspension of 3 g (10 mmols) of 6-methyl-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 30 ml of absolute toluene, and the mixture is then heated under reflux for 3 hours. After cooling, the precipitate which has been deposited is filtered off, and the filtrate is evaporated. The residue is stirred thoroughly with diethyl ether; yield: 3.3 g (86%) with m.p. 189° to 190° C. (from 2-butanone).
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]([NH:19][C:20](=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>C(O)(=O)C>[CH2:21]([C:20]1[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[CH:17][N:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNc1ccccc1
Reactant: O=CNC(=O)Cc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: c1ccc(Cc2ncnn2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
Phenylhydrazine hydrochloride (0.09 g, 0.6 mmol) in 5 mL glacial acetic acid was treated with triethylamine (0.06 g, 0.6 mmol), warmed to 70° C., treated with N-formylphenylacetamide (0.1 g, 0.6 mmol), and heated at 90° C. for 1 hour. The mixture was then allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organics were washed with saturated NaHCO3, 1M NaOH, water, and brine. The organics were then dried (MgSO4), and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40% hexanes/ethyl acetate) to provide the title compound. MS (ESI) m/e: 236 (M+H)+; 1H NMR (DMSO-d6) δ 4.2 (s, 2H), 7.05-7.1 (d, 2H), 7.17-7.3 (m, 3H), 7.45-7.6 (m, 5H), 8.1 (s, 1H); Anal. calcd. for C, 76.57; H, 5.57; N, 17.86. Found C, 76.32; H: 5.81; N, 17.63.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:24]([NH:28][CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([N:28]([CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: Clc1ccc(-c2cncc(Br)n2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 16.7 %

Procedure:
A mixture of 2-bromo-6-(4-chlorophenyl)pyrazine (0.27 g, 1 mmol), N,N-diisopropylethylamine (0.18 mL, 1 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.42 g, 1.5 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature and the residue dissolved in CH2Cl2 (50 mL), the organic extract was washed water (15 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Si, 40 g) eluting 1:9–1:1.5 EtOAc:cyclohexane afforded the title compound as a pale yellow oil 78 mg.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][NH:22][CH3:23])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CO.[Pd]>[Si:25]([O:24][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][CH3:23])([C:28]([CH3:30])([CH3:31])[CH3:29])([CH3:27])[CH3:26]
Reactant: CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CO
Product: CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 7 h

Procedure:
Intermediate 3 was dissolved in MeOH (25 mL) and Pd/C (10% w/w, 100 mg) was added. The resulting suspension was attached to a balloon filled with H2 and stirred for 7 hours. The reaction mixture was filtered through Celite diatomaceous earth and concentrated to give provide the title compound as a hard foam. ES/MS calcd. for C18H29N2O3Si+ 349.2. Found m/z=349.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.CO[Na]>O1CCCC1.CO>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:21])[CH:14]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]2=[O:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccnc1
Agent: CO[Na]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Nc2ccc(Br)cc2C(=O)C1c1cccnc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask was placed a solution of methyl 5-bromo-2-[2-(pyridin-3-yl)acetamido]benzoate (3 g, 7.73 mmol, 1.00 equivalent, purity 90%, Intermediate 51, step a) in tetrahydrofuran (30 mL). A 2.38 M solution of MeONa in MeOH (freshly prepared by dissolving 2.74 g of Na in 50 mL of anhydrous MeOH solution, 11.7 mL, 27.85 mmol, 4.00 equivalents) was then added. The resulting solution was stirred overnight at 20° C., and the precipitate was collected by filtration to give the title compound as a white solid.