Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][C@H:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.[CH3:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[S:53]([NH2:56])(=[O:55])=[O:54]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][C@H:25]([CH3:31])[CH2:26][C:27]([F:28])([F:30])[F:29])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([NH:56][S:53]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH3:46])(=[O:54])=[O:55])=[O:8]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Reaction time: 48 h
Yield: 87.8 %

Procedure:
A mixture of (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoic acid (14.28 g), 4-dimethylaminopyridine (4.39 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.34 g) and 2-methylbenzenesulfonamide (5.85 g) was dissolved in dry methylene chloride (270 mL) and the solution was stirred under an inert atmosphere for 48 h. The mixture was diluted with methylene chloride (300 mL) and washed three times with 1N hydrochloric acid. The combined hydrochloric washes were back washed with methylene chloride. The combined organic extracts were washed twice with water and evaporated. The residue was dissolved in a small volume of methanol and 1N sodium hydroxide and this solution was purified by flash chromatography over octadecylsilyl bonded silica gel ("Regis PREP-40-ODS" -irregularly shaped 32-74μ diameter particles, 72% silanol coverage, 21% carbon load) (450 g) eluting with 50:50 methanol:water, pH 7.1. The appropriate fractions (TLC, Rf =0.73, octadecylisilyl bonded silica gel, 200μ layer, 12% carbon load, 80:20 methanol:water, pH 6.1, 0.1% ammonium acetate buffer) were combined, the methanol evaporated, and the residual aqueous solution acidified to pH 1 with 1N hydrochloric acid. The resultant precipitate was filtered, washed (water), and dried under vacuum to give the title compound (16.7 g, 88%) as a white solid; mp 117°-120° C.; ee at least 99%.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CN=3)=NOC=2C)=NC=1>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: O=C(O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 80.9 %

Procedure:
As described for example 324, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (4.0 g, 12.2 mmol) was converted, instead of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (3.1 g, 81%) which was obtained as a white solid. MS: m/e=313.3 [M−H]−.
Reaction SMILES: [CH:1]1([C:4]2[N:8]3[C:9]4[CH:16]=[C:15]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:14]([C:23]5[CH:28]=[CH:27][C:26]([C:29]6([NH:33]C(=O)OC(C)(C)C)[CH2:32][CH2:31][CH2:30]6)=[CH:25][CH:24]=5)=[N:13][C:10]=4[O:11][CH2:12][C:7]3=[N:6][N:5]=2)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([C:4]2[N:8]3[C:9]4[CH:16]=[C:15]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:14]([C:23]5[CH:24]=[CH:25][C:26]([C:29]6([NH2:33])[CH2:30][CH2:31][CH2:32]6)=[CH:27][CH:28]=5)=[N:13][C:10]=4[O:11][CH2:12][C:7]3=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C3CC3)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C3CC3)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 459.2 %

Procedure:
Tert-butyl (1-(4-(1-cyclopropyl-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (36 mg, 0.012 mmol) was dissolved in TFA (1 ml) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and the residue was dried to give the desired product as an off-white solid (24 mg, 82% yield). LCMS (Method D) RT=0.747 min, M+1=436. 1H-NMR (500 MHz, CD3OD) δ 8.48 (1H, s), 7.53-7.47 (2H, m), 7.45-7.41 (2H, d), 7.38-7.33 (3H, m), 7.32-7.26 (2H, m), 5.66 (2H, s), 2.82-2.72 (2H, m), 2.63-2.55 (2H, m), 2.44-2.36 (1H, m), 2.30-2.19 (1H, m), 2.01-1.92 (1H, m), 1.28-1.17 (4H, overlapped ddd).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[H-].[Na+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([O:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:10][O:11][C:12]3[CH:20]=[C:16]4[C:15](=[CH:14][C:13]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:21])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1cccc(OCc2ccccc2)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1N(Cc2cccc(OCc3ccccc3)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a stirred solution of 5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one (1.0 g, 3.6 mmol) in dry N,N-dimethylformamide (18 mL) was added sodium hydride (60% in mineral oil, 0.17 g, 4.3 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 1 h, cooled in an ice/water bath, and 1-(benzyloxy)-3-(bromomethyl)benzene (1.4 g, 5.0 mmol) in dry N,N-dimethylformamide (2 mL) was added dropwise. The mixture was stirred at ambient temperature for 16 h. Water (200 mL) and ethyl acetate (200 mL) were added to the mixture. The organic solution was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic solution was washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate 3:1) to afford 1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (1.4 g, 82%) as a colorless solid: mp 66-68° C.; 1H NMR (300 MHz, CDCl3) δ 7.43-7.14 (m, 8H), 7.06-6.99 (m, 1H), 6.97-6.87 (m, 3H), 6.81-6.75 (m, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 5.10-5.00 (m, 3H), 4.85-4.75 (m, 1H), 4.84 (ABq, 2H), 4.56-4.47 (m, 2H), 2.98-2.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.9, 161.8, 161.3, 159.2, 142.1, 137.4, 136.6, 132.7, 129.9, 128.7, 128.6, 128.0, 127.5, 123.8, 123.4, 120.2, 119.9 (2C), 118.8, 114.0, 113.9, 109.3, 93.2, 80.5, 72.3, 70.0, 57.7, 44.0, 29.0; MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:25]([O:32][C:33](ON1C(=O)CCC1=O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O1CCOCC1>CO.O>[C:33]([NH:14][C@H:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
The reaction sequence is shown in FIG. 5. Nε-(tert-butoxycarbonyl)-L-lysine (2 g, 8.12 mmol) was dissolved in methanol (40 ml) and water (40 ml), and the pH was adjusted to 8 with triethylamine. A solution of N-(benzyloxycarbonyl-oxy)succinimide in dioxane (2.4 g, 9.7 mmol in 20 ml) was added to the above mixture and the pH was maintained at 8-9 with triethylamine. The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine. Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine was treated with 0.2 M calcium carbonate (4 ml) and the aqueous layer was removed to obtain a white solid. The solid was resuspended in N,N-dimethylformamide(40 ml) and benzyl bromide (1.16 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was worked up with ethyl acetate and water, and the organic layer was dried over magnesium sulphate. The solvent was removed to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester which was purified by silica gel chromatography using 25% hexane in ethyl acetate as a solvent. To Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester (1 g, 2.2 mmol) in methylene chloride (10 ml) was added trifloroacetic acid at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for further 2.5 hr at room temperature. The solvent was removed and the crude product was obtained. Pure Nα-CBZ-L-lysine benzyl ester was obtained by silica gel chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:21])[C:5]2[O:20][C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:8]=3[C:6]=2[CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:21])[C:5]2[O:20][C:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=3[C:6]=2[CH:7]=1
Reactant: CCOC(=O)N1C=Cc2c(oc3c(Cl)cc(Br)cc23)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2CC1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a solution of the product of step C (50 mg, 0.13 mmol) and trifluoroacetic acid (0.75 mL) at 0° C. was added triethylsilane (64 μL, 0.40 mmol). The reaction was allowed to warm to ambient temperature over 14 h then quenched by addition of aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (2×20 mL) and the combined organic extracts dried over anhydrous Na2SO4, filtered, and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 to 1:1 hexanes/ethyl acetate) to give ethyl 9-bromo-7-chloro-4,5-dihydro-1H-benzofuro[2,3-d]azepine-3(2H)-carboxylate (48 mg, 96%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.45-7.38 (m, 1H), 7.35 (d, J=1.4 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.78-3.67 (m, 4H), 3.20-3.10 (m, 2H), 2.88-2.75 (m, 2H), 1.29 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[Si:15]([O:5][CH2:4][CH2:3][CH2:2][NH2:1])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])[CH3:16]
Reactant: NCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCN
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-aminopropan-1-ol (2 g, 20 mmol) in DCM (10 mL), imidazole (79 mmol, 3 equiv.) was added and stirred at room temperature for 10 min. Reaction mixture was cooled to 0° C., t-butyl dimethyl silyl chloride (30 mmol, 1.2 equiv.) was added in portions and stirred the reaction mixture overnight at room temperature. Diluted the reaction mixture using DCM, the DCM layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. ELSD method LC/MS: Retention time: 1.5 min; (ES-API), m/z 189.7 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:44]([N:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[CH2:56]O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:55][CH2:54][CH2:53][C@@H:52]1[CH2:56][N:15]1[C:14](=[O:17])[N:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]2=[N:16]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: OC[C@@H]1CCCN1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(C[C@H]2CCCN2Cc2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 10.8 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (S)-1-benzyl-2-pyrrolidinemethanol (27 mg, 0.14 mmol) in THF (1.0 mL) and by following the procedure described in Example 2. The title compound, (R)-2-((1-benzylpyrrolidin-2-yl)methyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (8 mg, 11%) was obtained as yellow powder. MS M+H=530; 1H NMR (CDCl3) δ 8.14 (1H, s), 7.22-7.38 (11H, m), 7.10 (2H, d, J=10.0 Hz), 4.61-4.63 (1H, m), 3.50-3.56 (2H, q, J=13.2 Hz), 3.01 (1H, d, J=10.0 Hz), 2.85 (1H, d, J=10.0 Hz), 2.37-2.42 (1H, t, J=10.7 Hz), 1.99-2.02 (2H, m), 1.82-1.95 (1H, m), 1.70-1.80 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][NH:20][C:21]4([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30](=O)[CH3:31]>>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][N:20]([CH2:30][CH3:31])[C:21]4([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC1
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(=O)O)CC1

Procedure:
1-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid (prepared as described in Example 27) was reacted with acetaldehyde using an analogous method to that described for the equivalent step in Example 24 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO d6) 0.90 (t, 3H); 0.95-1.30 (m, 4H); 2.90 (m, 2H); 3.91 (s, 3H); 4.08 (s, 2H); 7.12 (s, 1H); 7.28 (dd, 1H); 7.40-7.60 (m, 2H); 8.20 (s, 1H); 8.40 (s, 1H); 9.65 (bs, 1H), 12.18 (bs, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:22]([CH3:25])([CH3:24])[OH:23])[CH:5]=[C:6]([O:20][CH3:21])[C:7]=1[O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[N:12]=[C:11]([CH3:19])[N:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][CH2:33][CH2:34][CH:35]([NH2:39])[CH2:36][CH2:37][CH3:38]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:22]([CH3:25])([CH3:24])[OH:23])[CH:5]=[C:6]([O:20][CH3:21])[C:7]=1[O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:39][CH:35]([CH2:36][CH2:37][CH3:38])[CH2:34][CH2:33][CH3:32])[N:12]=[C:11]([CH3:19])[N:10]=1
Reactant: CCCC(N)CCC
Reactant: COc1cc(C(C)(C)O)cc(Br)c1Oc1nc(C)nc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCC(CCC)Nc1nc(C)nc(Oc2c(Br)cc(C(C)(C)O)cc2OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-methoxy-α,α-dimethyl-4-[[6-chloro-2-methyl-5-nitro-4-pyrimidinyl]oxy]benzenemethanol (1.88 g) in anhydrous 1,4-dioxane (50 mL) with 0.50 g of potassium carbonate, 4-heptylamine (1.00 mL) was added and the solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was taken up in water and extracted with methylene chloride. The extracts were combined and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane to yield the title compound, mp 138° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Br:32][C:33]1[CH:34]=C2[C:40](=[CH:41][CH:42]=1)[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37]C2>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[Br:32][C:33]1[CH:34]=[C:6]2[C:40]([C:39]([CH3:43])([CH3:44])[CH2:38][CH2:37][C:5]2=[O:7])=[CH:41][CH:42]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: [Cr+6]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [O-2]
Solvent: c1ccccc1
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Reaction time: 1 h

Procedure:
To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100 ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic a 1 acid was added a solution of 10 g (41.8 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125 ml of benzene. The reaction mixture was stirred for 1 hour, quenched with ice cold water and extracted with Et2O (3×100 ml). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (silica, 10% EtOAc-hexane) to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][OH:16])[C:12]([OH:17])=[C:11]([CH3:18])[C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(C)[C:21](S(O)(=O)=O)=CC=C[CH:25]=1>COC(OC)(C)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH3:18])[C:12]2[O:17][C:20]([CH3:21])([CH3:25])[O:16][CH2:15][C:13]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)cc(CO)c(O)c1C
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: COC(C)(C)OC
Product: Cc1c(OCc2ccccc2)cc2c(c1C)OC(C)(C)OC2
Yield: 709 %

Procedure:
A solution of 4-benzyloxy-6-hydroxymethyl-2,3-dimethyl-phenol (86 mg, 0.33 mmol) in dimethoxypropane (10 mL) in the presence of toluene sulfonic acid (7 mg) was stirred at RT for 15 h. It was added 30 mg of anion-exchange resin and stirring was continued for 20 more min. The resin was then filtered off and the solution was concentrated. The crude product was purified on silicagel column chromatography to afford 6-benzyloxy-2,2,7,8-tetramethyl-4H-benzo[1,3]dioxine as a white sticky solid (86 mg). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.51-7.35 (m, 5H), 6.45 (s, 1H), 5.02 (s, 2H), 4.85 (s, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.59 (s, 6H); 13C-NMR δ (ppm): 150.6, 143.3, 137.8, 128.5, 127.8, 126.3, 125.8, 115.9, 105.4, 99.1, 70.9, 61.1, 24.9, 12.2, 11.5.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].BrOBr.[C-:14]#[N:15].[Na+]>O>[C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8][C:14]#[N:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: C[C@H](CBr)COC(C)(C)C
Agent: BrOBr
Agent: [Na+]
Solvent: O
Product: C[C@H](CC#N)COC(C)(C)C
Yield: 66.2 %

Procedure:
A mixture of 23.1 g. (0.11 mole) of bromo ether (S)-(+)-3-tert. butoxy-2-methyl-1-bromopropane and 11.07 g. (0.225 mole) of sodium cyanide in 144 ml. of water was stirred and refluxed for 17 hours. After cooling, the reaction mixture was diluted with water and worked up by extraction with CH2Cl2 in the manner of Example 1. The crude product was chromatographed on 500 g. of silica gel. Elution with 9:1 parts by volume and 4:1 parts by volume hexane-ether followed by evaporative distillation gave (R)-(+)-4-tert. butoxy-3-methylbutyronitrile (11.3 g.; 64.5%) as a colorless liquid, b.p. 88°-90° C. (bath temperature) (11 mm Hg.); [α]25D + 7.41° (c 1.8, C6H6).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.[C:27]([O:31][C:32](=[O:44])[C@@H:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:44])[C@@H:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][I:20])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CI)C(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
To a suspension of PPh3-resin (5 g, 6.5 mmol) in methylene chloride (50 mL) at 0° C. is added iodine (1.65 g, 6.5 mmol) and imidazole (0.485 g, 7.12 mmol) then stirring is continued at 0° C. for 45 min. To this is added (S)-2-tert-butoxycarbonylamino-3-hydroxypropionic acid tert-butyl ester (0.81 g, 3.1 mmol) and the suspension is refluxed for 45 min. The suspension is filtered and the organic layer is washed with a saturated sodium bisulfite solution, water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21](=O)[CH3:22])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([CH:21]([NH2:30])[CH3:22])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(-c2nnn[nH]2)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-c1nnn[nH]1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanone (85 mg, 0.26 mmol), ammonium acetate (198 mg, 2.57 mmol) and sodium cyanoborohydride (32 mg, 0.51 mmol) in methanol (0.9 mL) and acetonitrile (0.9 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (45 mg, 53%). LCMS calculated for C6H13ClFN4 (M−NH2)+: m/z=315.1. found: 315.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:20]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=3)=[O:30])[C:19]([C:39]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=3[O:49][CH2:50][CH3:51])=[N:18]2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH:21]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[N:20]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)=[CH:33][CH:32]=3)=[O:30])[C:19]([C:39]3[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:42]=[CH:41][C:40]=3[O:49][CH2:50][CH3:51])=[N:18]2)=[CH:13][CH:12]=1
Reactant: OCCN1CCNCC1
Reactant: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CN2CCN(CCO)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(2-Hydroxyethyl)-piperazine (10 uL, 0.08 mmol) was added to a solution of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl)-methanone (20 mg, 0.03 mmol) and diisopropylethylamine (7 uL, 0.04 mmol) in anhydrous dimethylformamide (1.0 mL). The mixture was stirred overnight at 80° C. Evaporation of the solvent and chromatography of the residue over silica gel using 1-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-{(4-(2-hydroxyethyl)piperazine-1-yl)methyl}phenyl]methanone, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-{(4-(2-hydroxyethyl)piperazine-1-yl)methyl}phenyl]methanone hydrochloride as a off-white powder (21 mg, 98%). LR-MS (APCI): 726.1 [(M+H)+].