Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:13]=1)=[N:7][C:8]([CH3:12])=[CH:9][C:10]=2[CH3:11])[CH3:2].[H-].[Na+].[CH2:16]([O:18][C:19](=[O:33])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:31]Br)[CH:27]=2)[CH:22]=1)[CH3:17]>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:18][C:19](=[O:33])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:31][N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])[CH:27]=2)[CH:22]=1)[CH3:17]
Reactant: CCOC(=O)Cc1ccc2cc(CBr)ccc2c1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2cc(Cn3c(CC)nc4c(C)cc(C)nc43)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (7) (1.38 g, 6.5 mmol) in 4 ml DMF was added sodium hydride (250 mg, 6.5 mmol) and the reaction mixture was stirred 15 minutes at ambient temperature. The product of Step 2, above (51) (3.07 mmol), was dissolved in 3 ml DMF and added to the reaction mixture and stirred at ambient temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate solution and brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude material was then chromatographed on silica gel using 50% EtOAc in hexanes as the eluant to yield the title compound (52) (95 mg).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([O:10][C:9]([F:8])([F:18])[F:19])=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Br)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 4.02 g (23.4 mmol) of 2-bromopropionyl chloride in 10 ml of methylene chloride was added to an ice-cooled solution of 5.0 g (23.4 mmol) of 4-(trifluoromethoxy)aniline hydrochloride, 4.65 g (59 mmol) of pyridine and 30 ml of methylene chloride. The mixture was stirred at ambient temperature for a period of 2.5 hours and then washed with two portions of dilute aqueous HCl and two portions of saturated aqueous sodium bicarbonate, dried over MgSO4, treated with charcoal, filtered and the filtrates evaporated to dryness. The residue was recrystallized from methylcyclohexane to give 5.43 g 74 percent of theoretical) of the above-named product as colorless crystals, m.p. 111°-112° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:34]2[C:35]([CH:40]=O)=[N:36][CH:37]=[CH:38][CH:39]=2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:40][C:35]2[C:34]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)([CH3:33])[CH3:32])=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester and 3-[1-(4-Chloro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[{3-[1-(4-Chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave {3-[1-(4-Chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH:18](OC)[O:19]C)[CH:15]=[CH:14][C:13]=2[N+:23]([O-:25])=[O:24])=[N:8][C:7]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5])[CH3:2].Cl>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=2[N+:23]([O-:25])=[O:24])=[N:8][C:7]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1ccccc1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccccc1
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A mixture of 0.089 g (0.2 mmole) of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VI.1a), 2 mL of actonitrile and 0.5 mL of 1 M hydrochloric acid was stirred at 60 degrees for 30 minutes. The mixture was concentrated under reduced pressure. The residue was diluted with 5 mL of saturated sodium bicarbonate and extracted twice with 20 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.080 g of 2-(5-formyl-2-nitro-phenylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VI.1b) as an orange oil. The crude was carried to the next step reaction without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:5])C.[Li+].[OH-].C1COCC1>O>[Cl:27][C:17]1[C:18]([O:25][CH3:26])=[CH:19][C:20]([O:23][CH3:24])=[C:21]([F:22])[C:16]=1[C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2cccnc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1F
Yield: 96.8 %

Procedure:
A mixture of 5-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 176.2) (235 mg, 0.60 mmol), a 2 N aqueous solution of LiOH (3 mL) and THF (3 mL) was stirred for 20 h at rt, diluted with H2O and extracted with Et2O. The aqueous layer was acidified to pH 4 by addition of a 2 N aqueous solution of HCl. The resulting white precipitate was collected by vacuum filtration providing 210 mg of the title compound: ESI-MS: 362.1 [M+H]+; tR=4.24 min (System 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1.Cl.C(O)(C)C>O1CCOCC1>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(OC)cc2CC1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
Combined 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55 mg, 0.00022 mol), (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (86 mg, 0.00024 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (70 uL) and Isopropyl alcohol (2.2 mL, 0.029 mol;) in microwave vessel. Heat at 130° C. for 10 minutes. Heat for another 10 minutes. Cool to room temp. Solid precipitated out of solution. Filtered off solid. The filtrate was treated with MP-carbonate 250 mgs and stirred for 30 min. The mixture was concentrated and purified by ISCO chromatography (40 g SiO2 column, gradient 100% DCM to 10% MeOH/DCM. Isolated 5-Chloro-N*2*-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as an off-white solid (49 mgs, 39%) Melting point: 138-140° C. δ 8.30 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 6.65 (s, 1H), 6.57-6.52 (m, 2H), 3.94-3.88 (m, 10H), 3.36 (br s, 2H), 3.39 (d, J=1.7 Hz, 3H), 3.18-3.17 (m, 4H), 2.90-2.74 (m, 10H); LC/MS: 568.87 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCNC(=O)Nc1ccccc1)CCCC3
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (919 mg, 2.76 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. The reaction mixture was then treated with phenyl isocyanate (300 μL, 2.76 mmol) and Et3N (0.77 mL, 5.51 mmol) and allowed to warm slowly to room temperature. After stirring overnight, the reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et2O (30 mL) and a few drops of MeOH. The solid was isolated by filtration and dried under vacuum to give 460 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-phenylurea as a white powder. m.p. 180-182° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[CH:5]2.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: Cc1cc2cc(Cl)ccc2nc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc2ccc(Cl)cc2cc1CBr
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To a solution of 6-chloro-2,3-dimethylquinoline (2.0 g, 10.5 mmol) in carbon tetrachloride (80 ml) benzoyl peroxide (100 mg) and N-bromosuccinimide (3.7 g, 21.0 mmol) were added. The reaction mixture was refluxed for 4 hours, and then cooled to room temperature. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate/petroleum ether as the eluent to give 0.90 g 3-bromomethyl-6-chloro-2-methylquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(=O)CC.[Cl-].[Na+].O.[I-].[Li+].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH2:10][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)c1cc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 98.2 %

Procedure:
A stirred mixture of 5-bromomethyl-2-nitro-benzoic acid methyl ester (50.5 g, 184 mmol), di-tert-butyl iminodicarboxylate (40.15 g, 185 mmol), cesium carbonate (123.1 g, 377.7 mmol), and lithium iodide (1.23 g, 9.21 mmol) in 2-butanone (556 mL) was heated to reflux in a 100° C. oil bath for 12 hours while stirred with a mechanical stirrer. The mixture was allowed to cool to room temperature. To the mixture, was added brine (300 mL), water (300 mL), and ethyl acetate (750 mL), and the mixture was stirred for 10 minutes. The suspension was filtered through a pad of Celite. The two layers were separated, and the organic layer was evaporated to a less volume. The aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (500 mL), dried over magnesium sulfate while de-colored at the same time by charcoal at room temp with stirring for 30 minutes. The black mixture was filtered through a pad of Celite. The filtrate was evaporated to give 5-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil (74.18 g, 98% yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[C:10]([OH:12])[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C)C=O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:12][C:10]2[CH:9]=[N:8][N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=3)[CH:11]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(-n2cc(O)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-n2cc(Oc3ccc([N+](=O)[O-])cc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
1-p-Tolyl-1H-pyrazol-4-ol (1.0 g, 5.75 mmol) in dimethylformamide was added to the cold slurry of sodium hydride (344 mg, 8.61 mmol). Reaction mixture was stirred for 0.5 hour followed by addition of 4-fluoro nitro benzene (810 mg, 5.74 mmol) in cold condition. Reaction mixture was stirred at 20-35° C. for 20 minutes. Water was then added to quench the reaction. The aqueous layer was extracted with diethylether and the combined organic layer was washed with brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum at 40° C. and the product was purified by column chromatography using mixture of petroleum ether and ethyl acetate.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.CON(C)[C:15](=[O:17])[CH3:16]>CCOCC>[CH3:6][C:7]1[N:8]=[C:9]([C:15](=[O:17])[CH3:16])[S:10][CH:11]=1
Reactant: Cc1cscn1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1nc(C)cs1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a stirred solution of n-BuLi (2M in pentane; 22.4 mL, 0.045 mol) in 70 mL of dry ether at −78° C. was added dropwise 4-methylthiazole (3.7 g, 0.037 mol) in 30 mL of ether over a period of 30 minutes. The mixture was stirred for 1 h, then N-methoxy-N-methylacetamide (4.37 mL, 0.041 mol) was added dropwise over 10 minutes. After 1 h of stirring at −78° C. the reaction mixture was washed with sat'd NaHCO3 and extracted with ether. The organic layer was dried with Na2SO4 and concentrated in vacuo to give 4.38 g (85%) of 2a as an oil that was used directly for the next step. 1H NMR (CDCl3) δ 7.2 (s, 1H), 2.75 (s, 3H), 2.5 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([O:20]C)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+].[ClH:28]>C(OCC)C.C(OCC)(=O)C>[ClH:28].[C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([OH:20])=[O:19])[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the methyl (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer of Step C (1.37 g, 4.61 mmol) and potassium trimethylsilanolate (0.68 g, 5.30 mmol) in diethyl ether (23 mL) was stirred at room temperature overnight. A saturated solution of hydrogen chloride in ethyl acetate was then added, the volatiles were evaporated and the residual solid used without further purification in the preparation of Examples detailed below.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc2c(c1)OCCO2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.36 g--see Preparation 1), 6-(2-bromoethyl)-1,4-benzodioxan (0.32 g), anhydrous potassium carbonate (0.75 g) and acetonitrile (20 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give a foam which was further purified by column chromatography on alumina eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.11 g.
Reaction SMILES: [Br-].[Li+].[CH3:3][Mg]Cl.[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH2:22][C:23](Cl)=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+]>C1COCC1.[Cu]Br.[Cu](Br)Br>[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH2:22][C:23](=[O:24])[CH3:3])[C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Reactant: C[Mg]Cl
Agent: Br[Cu]Br
Agent: [Cu]Br
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)=O)NC(=O)OCc1ccccc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Copper(I) bromide (60.9 g, 425 mmol, 1.2 equivalents (eq.)) was introduced into a 3 liter 4-neck flask (with dropping funnel, internal thermometer, argon inlet, rubber septa, in a cooling bath) and admixed with 250 ml of THF. A separate flask was initially charged at 10° C. with lithium bromide (75 g, 864 mmol, 2.4 eq.) and admixed with 470 ml of THF under argon. On completion of dissolution and recooling to RT, this solution was transferred to the suspension of the copper bromide. The resulting colorless to slightly greenish solution was cooled to −60° C., and methylmagnesium chloride (141 ml of a 3.0 M solution in THF, 423 mmol) was added within 15 min. A thick yellowish precipitate formed and the temperature rose to RT. After cooling again to −60° C., the solution from example 1 (prepared from 106 g of methyl (S)-2-benzyloxycarbonylamino-3-chlorocarbonylpropionate, 353 mmol, and 360 ml of THF) was added over about 30 min and the temperature was kept below −25° C. After the addition had ended, the mixture was stirred for another 1 h, and solid ammonium chloride (30 g) was added at −15° C. After a further 2 h, the mixture was filtered, the filtrate was diluted with 400 ml of heptane and 200 ml of saturated ammonium chloride solution were added. Once the mixture had been stirred at RT for 1 h, the organic phase was removed and washed repeatedly, and the aqueous phases were reextracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated on a rotary evaporator under reduced pressure and chromatographed on 1 kg of silica gel with 1:3 to 1:1 ethyl acetate/heptane. After the products had been combined and dried under reduced pressure, 83 g (84% yield) of a white solid were obtained. 1H NMR (300 MHz, CDCl3): 7.4 (m, 5H); 5.78 (m, 1H); 5.18 (s, 2H); 4.6 (s, 1H); 3.75 (“s”, 3H); 3.3-2.9 (2 dd, 2H); 2.2 (s, 3H)
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH:7]([NH:10][C:11](=[O:18])[C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4](=[O:23])[N:3]1[CH:24]([CH3:26])[CH3:25].[C:27]1([CH2:33][C:34](O)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][N:2]1[C:8](=[O:9])[CH:7]([NH:10][C:11](=[O:18])[C@@H:12]([NH:17][C:34](=[O:35])[CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:4](=[O:23])[N:3]1[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C[C@H](N)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Reactant: O=C(O)Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Yield: 70 %

Procedure:
In a manner similar to example 1, the title compound was prepared by the reaction of 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-amino-4-methyl-1-oxopentyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione with phenylacetic acid. The compound was purified on prep HPLC using the column YMC S5 ODS (20×100 mm) with a flow rate of 40 ml/min and gradient time of 10 min., using the solvent composition of solvent A as 10% MeOH—90% H2O—0.1% TFA, and solvent B as 90% MeOH—10% H2O—0.1% TFA. (70% yield). MS (ESI) 479.22 (M+H); Rf 1.42
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1
Reactant: Cc1ccc2nc(-c3ccccc3)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
N-Bromosuccinimide (25.9 gm) was added to a cold solution of 6-methyl-2-phenylbenzoxazole (30 gm) in carbon tetrachloride (250 ml). Benzoyl peroxide (500 mg) was added and the mixture was heated under reflux for 3 hr. in the presence of u.v. light. The solid residue was filtered off. The filtrate was evaporated down slightly, treated with carbon and allowed to cool. The crystals which were formed were recrystallised from benzene to yield 6-bromomethyl-2-phenylbenzoxazole, m.p. 162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12](=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+].C(O)C>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][C:12](=[CH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(=Cc1ccccc1)Sc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(SC(=Cc2ccccc2)C(=O)O)n1
Temperature: 50 °C

Procedure:
0.5 g (1.5 mmol) Methyl 2-(4,6-dimethoxy-2-pyrimidinylthio)-3-phenylacrylate and 95 mg (1.7 mmol) potassium hydroxide were added to a mixture of 5 ml water and 5 ml ethanol and the mixture heated at 50° C. for 8 hours. It was then diluted with about 100 ml water and extracted with ethyl acetate. The aqueous phase was acidified with 10% hydrochloric acid until it was pH 2 and extracted with ethyl acetate. After drying the ethyl acetate phase over magnesium sulphate, the solvent was evaporated under reduced pressure and the residue recrystallised from diisopropyl ether.