Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]([CH3:21])[C:19](=[O:22])[N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17](=[O:31])[C:16]=2[CH3:32])=[C:11]([CH3:33])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]([CH3:21])[C:19](=[O:22])[N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17](=[O:31])[C:16]=2[CH3:32])=[C:11]([CH3:33])[CH:10]=1
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C

Procedure:
A mixture of C4 (10 g, 21 mmol) and palladium hydroxide (2 g, dry) in methanol (300 mL) was stirred at room temperature for 24 hours under 40 psi of hydrogen. After filtration of the reaction mixture, the filtrate was concentrated to provide the product as a light yellow solid. Yield: 8.0 g, 21 mmol, 100%. 1H NMR (400 MHz, CDCl3) δ 6.92 (d, half of AB quartet, J=8.2 Hz, 1H), 6.81-6.87 (m, 2H), 5.52 (AB quartet, JAB=9.5 Hz, ΔνAB=2.7 Hz, 2H), 3.73-3.80 (m, 2H), 3.03 (s, 3H), 2.11 (s, 3H), 1.65 (s, 3H), 0.99-1.05 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][C:5]1([CH:11]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](O)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH2:23]([N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][C:3]2[CH:30]=[CH:31][CH:32]=[CH:33][C:2]=2[NH:1][C:12]1=[O:13])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccccc1OC1(C(C(=O)O)N(Cc2ccccc2)Cc2ccccc2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2OC2(CCCCC2)C1N(Cc1ccccc1)Cc1ccccc1
Yield: 63.4 %

Procedure:
A mixture of 2-(1-(2-Aminophenoxyl)cyclohexyl)-2-(dibenzylamino)acetic acid (0.6365 g, 1.43 mmol, Eq: 1.00), HOBT.H2O (307 mg, 2.00 mmol, Eq: 1.4) and EDCI (274 mg, 1.43 mmol, Eq: 1.00) in DMF (12 mL) were stirred at RT for 1 h and the mixture was diluted with EtOAc. The mixture was washed with sat. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 3-(dibenzylamino)-3H-spiro[benzo[b][1,4]oxazepine-2,1′-cyclohexan]-4 (5H)-one as an off-white solid (0.387 g, 64%). MS m/z 427.1 (MH+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].CN1CCC2C(=CC(NC3N=C(C4C(C5C=C(NC(=O)CC6SC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)=CC=2)C1>CCO.Cl>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([F:30])[CH:32]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)C(F)(F)F
Temperature: 80 °C

Procedure:
To a mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (see Example 1, Step C) (2.27 g, 5.4 mmol) in EtOH (60 mL) was added 3-fluoroaniline (0.62 mL, 6.48 mmol) and 5 drops of conc. HCl. The reaction was heated to 80° C. for 16 h, allowed to cool to rt and concentrated. The mixture was partitioned between DCM and saturated aq. NaHCO3. The separated aqueous layer was extracted twice with DCM and the combined organic layers were dried over MgSO4, filtered and concentrated to give, after trituration of the residue, the title compound as an off-white solid (2.15 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.78 (s, 1H), 8.83 (d, 1H, J=7.2), 8.43 (d, 1H, J=9.2), 8.30 (d, 1H, J=5.2), 7.97 (s, 1H), 7.79-7.72 (m, 2H), 7.52-7.40 (m, 4H), 7.22 (q, 1H, J=7.6), 7.12 (t, 1H, J=6.8), 6.69 (m, 1H), 6.56 (d, 1H, J=5.2).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:25]1[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:29][CH2:30]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 99.4 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (309 mg, 0.824 mmol, 1 eq.) in 10 mL of ethanol was added tert-butyl N-(piperidin-4-yl)carbamate (329 mg, 1.65 mmol, 2 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 442 mg (99%) of tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}carbamate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.40-1.53 (m, 11 H) 2.12 (d, J=11.40 Hz, 2 H) 3.32 (t, J=11.63 Hz, 2 H) 3.80 (br. s., 1 H) 4.41-4.68 (m, 1 H) 5.40 (br. s., 2 H) 7.16-7.24 (m, 2 H) 7.26-7.43 (m, 5 H) 7.51 (d, J=6.59 Hz, 1 H) 8.38 (s, 1 H), [M+H]+ 539.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:30])=[C:17]([C:27](=[O:29])[CH3:28])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]=4[C:25]=3[CH3:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+]>O.C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:30])=[C:17]([CH:27]([OH:29])[CH3:28])[C:18]4[O:22][C:21]([CH3:23])([CH3:24])[CH2:20][C:19]=4[C:25]=3[CH3:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c4c(c(C(C)=O)c3C)OC(C)(C)C4)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c4c(c(C(C)O)c3C)OC(C)(C)C4)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To the THF (1.5 ml)/methanol (1.5 ml) mixture solution of 1-{5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-yl}ethanone (120 mg, 0.294 mmol) synthesized in Example 80, sodium borohydride (133 mg, 3.52 mmol) was added and the mixture was stirred for 3 hours at room temperature. After diluting the reaction solution with water, THF and methanol in the reaction solution was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 99:1-80/20) and crystallized from ethyl acetate-hexane to obtain the title compound 60 mg (yield 50%). Melting point was 183 to 186° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[C:21]([B-](F)(F)F)([CH3:23])=[CH2:22].[K+]>C(O)CC>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:21]([CH3:23])=[CH2:22])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C=C(C)[B-](F)(F)F
Agent: [K+]
Solvent: CCCO
Product: C=C(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 38.3 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.41 g, 1.153 mmol) was combined with potassium isopropenyltrifluoroborate (0.189 g, 1.268 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.034 g, 0.046 mmol) and TEA (0.241 mL, 1.730 mmol) in n-propanol (10 mL) and heated in a microwave reactor at 120° C. for 90 min. Additional potassium isopropenyltrifluoroborate (0.086 g, 0.577 mmol) was added to the reaction mixture which was heated in a microwave reactor at 120° C. for an additional 30 min. The reaction mixture was filtered through celite and concentrated to dryness. The residue was dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified on 40 g silica gel eluted with 0 to 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethenyl)benzonitrile (0.140 g, 0.442 mmol, 38.3% yield) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (s, 1H), 7.46-7.54 (m, 2 H), 7.43 (s, 1H), 7.21 (s, 1H), 5.57 (s, 1H), 5.25 (s, 1H), 3.77 (s, 2H), 2.10 (s, 3H), 1.99 (br. s., 2H). LC-MS (ES+) m/z 317.19, 319.17 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[OH-:32].[Na+].O.OO>C1COCC1.C(O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([C@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([OH:14])[CH2:11][CH2:12][CH2:13][OH:32])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: C=CCC(O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(O)CCCO
Temperature: 25 °C

Procedure:
N-((1R)-1-Benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert-butylester (3.95 g, 11.60 mmol) was dissolvend in THF (90 mL) and added to a solution of 9-borabicyclo[3.3.1]nonane (46.64 mL of a 0.5M solution in THF, 23.32 mmol) in THF (90 mL). The solution was heated to reflux for 16 h. The mixture was cooled to room temp. Ethanol (22 mL) was added dropwise. 6N Sodium hydroxide solution in water (6.6 mL, 39,44 mmol) and subsequently hydrogen peroxide (35% solution in water) were added slowly. The reaction mixture was heated to reflux for 1 h and cooled to room temp. It was given onto 1N sodium hydroxide solution (200 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a 37% solution of sodium hydrogensulfite (150 mL). The solution was dried over magnesium sulfate. It was washed with a 37% solution of sodium hydrogensulfite (200 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with 37% solution of sodium hydrogensulfite (200 mL) and dried over magnesium sulfate. The crude product was chromatographed on silica (180 g) with ethyl acetate and subsequently on silica (100 g) with dichloromethane/methanol/25% aqueous ammonia 100:10:1 to give 586 mg of ((1R)-1-benzyl-2,5-dihydroxypentyl)methylcarbamic acid tert-butylester.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3]([NH:5][NH2:6])=[O:4].[Cl:9][CH2:10][C:11](Cl)=[O:12].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:9][CH2:10][C:11]([NH:6][NH:5][C:3](=[O:4])[C:2]([CH3:8])([CH3:7])[CH3:1])=[O:12]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)C(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NNC(=O)CCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
Under a nitrogen atmosphere, 2.86 g of 2,2-dimethylpropanohydrazide was dissolved in tetrahydrofuran, and 2.78 g of chloroacetyl chloride was then added at 0° C. The mixture was stirred at room temperature for 18 hours. After aqueous saturated sodium hydrogen carbonate was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2.58 g of N′-(chloroacetyl)-2,2-dimethylpropanohydrazide.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH:20]([CH3:29])[C:21]([O:23][CH2:24][CH2:25]N(C)C)=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1.[CH3:32][I:33]>ClCCl>[CH3:32][I:33].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH:20]([CH3:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1
Reactant: CC(Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1)C(=O)OCCN(C)C
Solvent: CI
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(dimethylamino)ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate in dichloromethane was added to a large excess of methyl iodide in dichloromethane. The mixture was stirred for 2 hrs at room temperature, then evaporated to give 2-dimethyl amino)ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate methyl iodide salt as yellow crystals mp 76° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:5]([CH2:16][C:17]2[CH:35]=[CH:34][C:20]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@@H:23]3[C:27]([O:29]C(C)(C)C)=[O:28])=[CH:19][C:18]=2[O:36][CH3:37])=[C:4]([CH3:38])[N:3]=1.FC(F)(F)C(O)=O.CO>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:5]([CH2:16][C:17]2[CH:35]=[CH:34][C:20]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@@H:23]3[C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[O:36][CH3:37])=[C:4]([CH3:38])[N:3]=1
Reactant: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN2CCC[C@@H]2C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of the product of step (ii) (70 mg) in chloroform (1.5 mL) was added trifluoroacetic acid (1.5 mL) and the mixture was stirred at RT. After 12 h, methanol (10 mL) was stirred at room temperature. After 12 h, the mixture was concentrated under reduced pressure. 10% aqueous potassium dicarbonate was added and the resulting mixture was extracted with chloroform/EtOH (3/1). The combined organic layer was dried and concentrated under reduced pressure to afford the sub-title compound (50 mg) as a white solid; 1H NMR (methanol-d4); 7.23 (1H, d), 7.02-6.97 (2H, m), 4.47 (1H, m), 4.34 (2H, s), 3.97 (3H, s), 3.85-3.80 (3H, m), 3.64 (1H, m), 3.45-3.41 (2H, m), 2.44 (1H, m), 2.28 (3H, s), 2.11 (2H, m), 1.96 (1H, m), 1.74-1.20 (7H, m), 0.87 (3H, t); LC-MS: m/z 472.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH2:19][Br:34])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(Br)ccc2c1CBr
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a stirred solution of (6-Bromo-3-methyl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone (4.0 g, 10.4 mmol) in carbon tetrachloride (40 mL) was added 2,2′-azobisisobutyronitrile (AIBN) (171 mg, 1.04 mmol) and N-bromosuccinimide (1.95 g, 10.9 mmol). The reaction mixture was heated at reflux for 6 h, and upon cooling to rt, the resulting precipitate was removed by filtration and the filtrate was concentrated. The crude residue was purified by column chromatography (10% ethyl acetate in hexanes) to afford the desired product (3.30 g, 65% yield) as a white solid. Rf=0.68 (10% EtOAc in hexanes). 1H-NMR (acetone): δ 7.98 (d, 1H), 7.91 (s, 1H), 7.74 (m, 2H), 7.64 (td, 2H), 5.16 (s, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(NCc2ccccc2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(NCc2ccccc2)nc1-c1ccc(C)cc1
Yield: 92.5 %

Procedure:
This compound was prepared according to general method D from methyl 2-(2-(benzylamino)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.055 g; 0.136 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.049 g (92%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N+:12]([O-:23])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2ccncc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc[n+]([O-])cc2)cc1
Yield: 91.1 %

Procedure:
A solution of 4-(4-methoxyphenyl)pyridine (5.68 g) and metachloroperbenzoic acid (70%, 11.34 g) in chloroform is stirred for 2.5 hours at room temperature, concentrated under reduced pressure and purified by chromatography over silica gel (eluent dichloromethane/methanol from 100/0 to 90/10) to give 5.62 g of 4-(4-methoxyphenyl)pyridine 1-oxide used without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:9][CH:8]=1.CN(C)[CH:34]=[O:35]>O1CCCC1>[CH:34]([C:7]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:9][CH:8]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)n1COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C=O)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 33.1 %

Procedure:
n-Butyl lithium (2.5 M) in hexanes (1.6 mL, 4.00 mmol) was added dropwise to a stirring solution of (S)-tert-butyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (prepared by methods described in WO 2008/021928, WO 2008/021936 and WO 2008/021927)(1.70 g, 3.81 mmol) in tetrahydrofuran (20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 7 min, and then quenched with dimethylformamide (0.59 mL, 7.6 mmol) in one portion. The mixture was warmed to room temperature by removing the cooling bath, allowed to stir for 1 h, diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (0 to 100% ethyl acetate in hexanes) to afford (S)-tert-butyl 2-(5-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.26 mmol, 33% yield) as a yellow oil and a 2:3 mixture of regioisomers.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1COc1ccccc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
A mixture of methyl 2-(bromoethyl)-5-chlorobenzoate (100 mg, 0.38 mmol), 2-chlorophenol (43 μL, 0.42 mmol) and potassium carbonate (105 mg, 0.76 mmol) in N,N-dimethylforamide (2 mL) was stirred at room temperature for 3 h and at 50° C. for 4 hours. Water (5 mL) was added and the mixture was extracted with diethyl ether (15 mL×2). The combined organic extracts were washed with brine (15 mL) and dried (sodium sulfate). After removal of solvent, the residue was purified by pTLC eluting with hexane/ethyl acetate (9/1) to afford 103 mg (87%) of the title compound:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14][C:15](OC(C)(C)C)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:42]([NH:49][C@H:50](C(O)=O)[CH:51]([CH3:53])[CH3:52])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(Cl)CCl>[CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14][C:15](=[O:16])[C@H:50]([CH:51]([CH3:53])[CH3:52])[NH:49][C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
A 500 mL round bottom flask was charged with 46.52 g (99 mmol) N-tert-Butyloxycarbonyl-L-leucinyl-L-phenylalanine benzyl ester, 340 mL anhydrous m ethylene chloride (CH2Cl2), and 51 mL trifluoroacetic acid (TFA). The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours, and then concentrated in vacuo. The residue was azeotroped twice with toluene, and carried on. The same 500 mL round bottom flask containing the crude TFA salt was placed under a nitrogen atmosphere and charged with 21.5 g (99 mmol) Boc-L-valine, 13.4 g (99 mmol) HOBT, and 270 mL anhydrous THF The solution was cooled in an ice/acetone bath and 21.4 a (104 mmol) DCC was added in one portion. The mixture was stirred in the cold for 1 hour, and then warmed to room temperature and stirred overnight. The precipitated DCU was filtered off, and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed once with water, once with a 10% solution off citric acid, once with saturated NaHCO3, and once with brine. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The resultant solid was precipitated from ethanol with H2O to provide 41.96 g (75%) of the title compound.