Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[O:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:21][CH2:20]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC(OCCN3CCOCC3)C2)cc1
Solvent: CCO
Product: C1CC(OCCN2CCOCC2)CN1

Procedure:
A solution of 30.8 g. (0.106 mole) of 1-benzyl-3-(2-morpholinoethoxy)pyrrolidine in 200 ml. of ethanol containing 10% palladium on charcoal was shaken at 60° C. in about three atmospheres of hydrogen until the theoretical amount of hydrogen was used. Concentration of the cooled filtered solution at reduced pressure gave a quantitative yield of oily product. The structure was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12](=[O:24])[NH:13][C:14]1[CH:15]=[N:16][C:17]([C:20](=[O:23])[CH2:21]Br)=[CH:18][CH:19]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[N:34]=2)[N:29]=[CH:28][C:27]=1[OH:38].ClCCl>CN(C)C=O.CO>[C:7]([O:11][C:12](=[O:24])[NH:13][C:14]1[CH:15]=[N:16][C:17]([C:20](=[O:23])[CH2:21][O:38][C:27]2[CH:28]=[N:29][C:30]3[C:35]([C:26]=2[NH2:25])=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[CH:18][CH:19]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)CBr)nc1
Reactant: COc1ccc2ncc(O)c(N)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(OCC(=O)c3ccc(NC(=O)OC(C)(C)C)cn3)c(N)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
Potassium carbonate (140 mg, 1.02 mmol, 1.5 eq) is added at room temperature to a stirred solution of [6-(2-bromo-acetyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (220 mg, 0.70 mmol, 1.0 eq) and 4-amino-6-methoxy-[1,5]naphthyridin-3-ol (130 mg, 0.69 mmol, 1.0 eq) in N,N-dimethylformamide (10 mL). After 30 minutes stirring at room temperature, solvent is removed and the residue is extracted with ethyl acetate (3×15 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 100:1, v/v) to afford {6-[2-(4-amino-6-methoxy-[1,5]naphthyridin-3-yloxy)-acetyl]-pyridin-3-yl}-carbamic acid tert-butyl ester as a red-brown solid (90 mg, 24% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH2:6][C@@H:7]2[C@H:10]([CH:11]=1)[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)CCC.O[C:21](C)(C(C)CC=C)CC(O)=O>>[CH3:1][C:5]1[CH2:6][C@H:7]2[C@@H:10]([C:11]=1[CH3:21])[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2
Reactant: CCCCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Reactant: C=CCC(C)C(C)(O)CC(=O)O
Product: CC1=C(C)[C@H]2C(=CC(=O)OC(C)(C)C)C[C@H]2C1

Procedure:
The compound of interest (4.2 g, 33%) was obtained as an oil substance (E/Z mixture) in the same way as in paragraph (10-c) using 3-hydroxy-3,4-dimethyl-6-heptenoic acid (10.1 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[Cl:31][C:32]1[CH:40]=[C:39]([C:41]#[C:42][CH2:43][O:44][CH3:45])[C:35]2[O:36][CH2:37][O:38][C:34]=2[C:33]=1[NH2:46].[Cl-].[NH4+]>CN(C)C=O>[Cl:31][C:32]1[CH:40]=[C:39]([C:41]#[C:42][CH2:43][O:44][CH3:45])[C:35]2[O:36][CH2:37][O:38][C:34]=2[C:33]=1[NH:46][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OC)c(OC)cc23)c2c1OCO2
Temperature: 25 °C
Yield: 39.4 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.5 ml) in tetrahydrofuran (1.0M, 1.5 mmol) was added dropwise to an ice-cold solution of 4-chloro-6,7-dimethoxyquinazoline (0.15 g, 0.7 mmol) and 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.176 g, 0.7 mmol) in dimethylformamide (4 ml). The mixture was allowed to warm to room temperature over 2 hours. A saturated solution of ammonium chloride was added and the mixture was partitioned between water and dichloromethane. The organic layer was separated, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. Flash chromatography on silica eluting with a mixture of 3-10% methanol in dichloromethane gave the product as a solid (0.118 g, 60%).
Reaction SMILES: C([BH3-])#N.[Na+].C(N[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14](COC3C=CC=C(C=O)C=3)=[CH:13][C:11]=2[N:12]=1)C.N1CCCCC1.C(O)(=O)C>CO>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[CH:8]1
Reactant: CCNc1nc2cc(COc3cccc(C=O)c3)ccc2o1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CO
Product: c1ccc2ocnc2c1
Yield: 108.8 %

Procedure:
Sodium cyanoborohydride (0.17 g) was added portionwise to a solution of 2-ethylamino-5-(3-formylphenoxymethyl)benzoxazole (0.80 g), piperidine (0.23 g) and acetic acid (0.76 ml) in methanol (10 ml) at 0° C. with stirring. The mixture was stirred at the same temperature for 2 hours and for further 6 hours at ambient temperature. The solvent was evaporated in vacuo. The residue was mixed with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel by eluting with a mixture of chloroform-methanol (20:1, V/V). The pure base was converted to the hydrochloride in a usual manner. The salt was dissolved in ethanol and reprecipitated with diethyl ether to give 2-ethylamino-5-3-piperidinomethylphenoxymethyl)benzoxazole (0.35 g) dihydrochloride.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.C[Al](C)C.[Si:21]([O:38][C@H:39]1[CH2:43][CH2:42][O:41][C:40]1=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Si:21]([O:38][C@@H:39]([CH2:43][CH2:42][OH:41])[C:40]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](O[C@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H](CCO)C(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)(c1ccccc1)c1ccccc1
Yield: 99.8 %

Procedure:
Synthesized according to General Procedure 5. The reaction was set up with sulfathiazole (11.2 g, 44 mmol), CH2Cl2 (150 mL), trimethylaluminum (2.0 M in hexanes, 22 mL, 44 mmol), and (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (12.6 g, 37 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (10% MeOH in DCM) afforded the desired amide as a white solid (22 g, 84% yield). 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76 (dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m, 8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1, 6.7 Hz, 1H), 3.64-3.59(m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91 (m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=596.5; tR=1.93 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)[C:13]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.5 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid (594.8 mg, 1.725 mmol) in methylene chloride (8.6 mL) and N,N-dimethylformamide (2 drops) cooled to 0° C. was treated with oxalyl chloride (226 μL, 2.587 mmol). The reaction mixture was stirred at 0° C. for 15 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to afford a red oil. This red oil was dissolved in tetrahydrofuran (4.03 mL), cooled to 0° C., and then slowly treated with a solution of 2-aminopyrazine (246.1 mg, 2.587 mmol) and pyridine (209 μL, 2.587 mmol) in tetrahydrofuran (4.3 mL). The resulting reaction mixture was stirred at 0° C. for 15 min and then stirred at 25° C. for 2 h. The reaction mixture was quenched with a 1N aqueous citric acid solution (20 mL) and then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (2×100 mL) and a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (207.3 mg, 28%) as a pale yellow foam: mp 93–96° C. (foam to gel); (ES)+-HRMS m/e calcd for C19H20ClN3O4S (M+H)+ 422.0936 found 422.0938.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:5]([Cl:17])=[CH:4][C:3]=1[O:18][CH3:19].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1/[C:8](=[N:21]/[OH:22])/[C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:18][CH3:19])=[CH:4][C:5]=1[Cl:17]
Reactant: NO
Reactant: COc1cc(Cl)c(C(=O)c2ccccc2F)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(Cl)c(/C(=N\O)c2ccccc2F)cc1Cl

Procedure:
A mixture of 2,5-dichloro-4-(2-fluorobenzoyl)anisole (3 g) and hydroxylamine hydrochloride (1.4 g) in pyridine (25 ml) is refluxed for several hours until no ketone remains. The pyridine is removed under high vacuum and the residue diluted with water, then extracted with chloroform. The chloroform solution is dried and the chloroform removed to give a solid which is recrystallized from ether to afford (z)-2'-fluoro-2,5-dichloro-4-methoxybenzophenone oxime, mp 188° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:35]=[CH:34][C:27]([CH2:28][CH2:29][CH2:30][PH:31](=[O:33])[OH:32])=[CH:26][C:25]=3[O:36][CH3:37])[N:14]=2)=[CH:4][CH:3]=1.[CH3:38][C:39]1([CH3:55])[C:43]([CH3:45])([CH3:44])[O:42][B:41]([C:46]2[CH:47]=[N:48][N:49]([CH2:51][CH2:52][CH2:53]O)[CH:50]=2)[O:40]1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:35]=[CH:34][C:27]([CH2:28][CH2:29][CH2:30][PH:31](=[O:32])[O:33][CH2:53][CH2:52][CH2:51][N:49]4[CH:50]=[C:46]([B:41]5[O:42][C:43]([CH3:45])([CH3:44])[C:39]([CH3:38])([CH3:55])[O:40]5)[CH:47]=[N:48]4)=[CH:26][C:25]=3[O:36][CH3:37])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Yield: 90.2 %

Procedure:
This material was prepared analogously to Example 44A using (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)ethylphosphinic acid (Compound 67B, 0.220 g, 0.365 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 0.0918 g, 0.364 mmol) to afford the title compound as an off-white foam (275 mg, 90%). MS (ESI): m/z 837.21/839.20 [M+H]+. UPLC: tR=1.14 min (UPLC-TOF: polar—2 min).
Reaction SMILES: C([O:3][C:4](=[O:37])[C@H:5]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:21]([NH2:28])=[N:22][C:23]([NH2:27])=[N:24][C:25]=3[CH3:26])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[NH2:27][C:23]1[N:22]=[C:21]([NH2:28])[C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][C@H:5]([C:4]([OH:37])=[O:3])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[CH:13][CH:12]=3)[CH2:19][CH2:18]2)=[C:25]([CH3:26])[N:24]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1)C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A mixture of 3.00 g (0.0058 mole) of N-[4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]-benzoyl]-L-glutamic acid diethyl ester and 12.5 ml of 1N aqueous sodium hydroxide solution in 150 ml of methanol was stirred at room temperature for four hours. The methanol was removed under vacuum at 23° C. and the residue was dissolved in 100 ml of ice water and then neutralized by the addition of 2.5 g (0.0129 moles) of citric acid. The solid precipitate was collected, washed with water, and then triturated several times with ethanol. The remaining solid was dried overnight in vacuo at 67° C. to give 0.75 g of the product as a white powder, mp 270° C. (dec.).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:18]2[NH:22][C:21]([CH3:23])=[C:20]([CH3:24])[CH:19]=2)=[O:17])=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.Br[CH2:44][CH:45]=[CH:46][CH3:47]>O1CCCC1>[CH2:44]([N:22]1[C:18]([C:16](=[O:17])[CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)=[CH:19][C:20]([CH3:24])=[C:21]1[CH3:23])[CH:45]=[CH:46][CH3:47]
Reactant: CC=CCBr
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2)[nH]c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=CCn1c(C(=O)CCc2ccc(F)cc2)cc(C)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
0.82 g (0.00731 mole) of potassium tert-butoxide was added to a solution of 1.39 g (0.00567 mole) of 5-[3-(4-fluorophenyl)propionyl]-2,3-dimethylpyrrole and 0.19 g (0.00074 mole) of 18-crown-6 in 40 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 20 minutes. 1.80 g (0.0115 mole) of 1-bromo-2-butene (a mixture of cis and trans isomers) were added to the mixture and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice-water and the aqueous mixture was extracted twice with 80 ml each of ethyl acetate. The extract was wahed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography through silica gel using a 1:10 mixture of ethyl acetate and hexane as an eluent to give 0.90 g of the title compound (cis/trans=22/78) as a pale yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:32])[CH:24]=1>ClCCl>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:28])=[C:25]([Cl:32])[CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reaction time: 22 h
Yield: 96.2 %

Procedure:
To a mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (1,44 g) and triethylamine (0.95 g) in dichloromethane (40 ml), cooled in an ice bath, was added dropwise a solution of 4-bromo-2-chlorobenzoyl chloride (2.42 g) in dichloromethane (20 ml). The cooling bath was removed and after stirring for 22 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate, 0.5 N hydrochloric acid and water. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, then evaporated in vacuo to dryness to yield an off-white foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (2:1) resulted in a white foam (3.02 g), m.p. 77-80° C., MS m/z: 400 (M)+.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:15])OC(C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([O-:18])=[O:17].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)C>[N+:16]([C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[NH:8][C:9]2=[O:15])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cccnc2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (10.0 g), 4-nitroaniline (8.0 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.53 g), Pd2(dba)3 (2 g) and sodium tert-butoxide (12.5 g) in toluene (160 mL)-2-propanol (40.0 mL) was stirred at 100° C. under Ar overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4.0 g) as a light brown solid. A mixture of 3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (3.50 g), sodium hydride (0.400 g) and iodoethane (2.0 mL) in DMF (40 mL) was stirred at 20° C. under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 1-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) as a brown solid. A mixture of 1-ethyl-3-(4-nitrophenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) and 10% palladium-carbon (0.832 g) in EtOH (250 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3-(4-aminophenyl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.00 g) as a brown solid.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[N:3]=1.Cl.[OH2:24]>>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH2:14][S:13][C:4]2[N:3]=[C:2]([NH:10][C@H:11]([CH3:2])[CH2:6][OH:24])[C:11]3[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=3[N:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Reactant: O
Agent: Cl
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2F)nc2[nH]c(=O)cnc12

Procedure:
The titled compound was prepared by the method of Example 2, step (f) using the product from example 6, step (e) (75 mg). The reaction mixture was poured into water and acidified with conc. HCl. The suspended solid was removed by filtration, dried in air and recrystallized from acetonitrile to give a yellow solid (37 mg).
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:5][C:6](=[O:23])[C@@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O.[OH-].[Li+].C(O)(=O)C>C1COCC1.O>[CH2:12]([O:11][C:9]([NH:8][C@@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:28])=[O:2])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
N-(Benzyloxycarbonyl)-D-leucyl-L-leucine methyl ester (Example 29A, 1.12 g, 2.85 mmol) is provided at 0° C. in THF/water 2:1 (15 ml) and then lithium hydroxide monohydrate (140 mg, 5.71 mmol, 2 equivalents) is added. When the HPLC chromatogram (Method 2) shows complete conversion (about 1 h), the reaction mixture is adjusted to pH 3-4 with acetic acid, concentrated in vacuo under cold conditions and then freed of solvent by freeze-drying overnight. The crude product is purified by means of preparative HPLC (Method 13) whereby 958 mg (88.7% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:44]=[CH:43][C:23]([CH2:24][O:25][C:26]2[CH:27]=[C:28]([NH2:42])[CH:29]=[C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH:31]=2)=[CH:22][CH:21]=1)#[N:19]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15](=[O:17])[NH:42][C:28]2[CH:29]=[C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH:31]=[C:26]([O:25][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:44][CH:43]=3)[CH:27]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(COc2cc(N)cc(OCc3ccc(C#N)cc3)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cc(OCc3ccc(C#N)cc3)cc(OCc3ccc(C#N)cc3)c2)CC1
Yield: 64.6 %

Procedure:
Following the procedure of Example 107(e) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid 0.255 g (1.04 mmol) and [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-amine (0.37 g, 1.04 mmol) were used to afford 0.39 g of the required product. Percentage purity (LCMS): 94.8%, (M−1)=580.0-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CO)COc1ccc(Br)cc1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
To a mixture of 4-bromophenol (300 mg, 1.74 mmol) in DMF (10 mL) was added 3-bromo-2,2-dimethylpropan-1-ol (579 mg, 3.47 mmol) and potassium carbonate (720 mg, 5.22 mmol). The mixture was degassed with nitrogen three times and heated to 90° C. for 48 h. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash chromatography (EtOAc/petroleum ether=1:10 to 1:1) to give 3-(4-bromophenoxy)-2,2-dimethylpropan-1-ol (130 mg, 29%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), 6.79 (d, 2H), 3.73 (s, 2H), 3.54 (s, 2H), 1.02 (s, 6H).