Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH2:31][C:32]([OH:34])=O)=[CH:22]1.[CH3:35][NH2:36]>C(#N)C.N1C=CC=CC=1>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][CH2:31][C:32]([NH:36][CH3:35])=[O:34])=[CH:22]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CN
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CNC(=O)CCc1c[nH]c2ccccc12
Reaction time: 0.5 h

Procedure:
A mixture of 57 g trifluoroacetic acid and 105 g trifluoroacetic anhydride in 400 ml anhydrous acetonitrile are added dropwise to a stirred suspension of 95.1 g 3-(3-indolyl)propionic acid in 500 ml anhydrous acetonitrile and maintained with stirring at -15° for 30 minutes. Under good cooling 500 ml anhydrous pyridine are added between -20° and -15° and quickly 238 ml of a 4.2 N solution of anhydrous methylamine in acetonitrile. The mixture is warmed with stirring at 0° for 15 minutes and maintained to 0° for 3 hours. 3-(3-indolyl)-N-methyl-propionamide (M.pt 97°-98° after crystallization from methylene chloride/ethyl acetate) is obtained after working up.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8](OC)=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17].O1CCOCC1>O>[CH3:23][C:22]1[C:13]2[NH:12][C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[C:8](=[O:9])[C:14]=2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1
Reactant: COC(=O)C1CCCCC1=O
Reactant: COC(=O)c1ccc(C)c(N)c1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c2[nH]c3c(c(=O)c12)CCCC3
Temperature: 130 °C
Yield: 31.7 %

Procedure:
A mixture of methyl 2-oxocyclohexanecarboxylate (1.0 g, 6.4 mmol), methyl 3-amino-4-methylbenzoate (1.06 g, 6.4 mmol), polyphosphoric acid (4 mL) and dioxane (6 mL) was heated at 130° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and the resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (100 mL) and SOCl2 (10 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (3×80 mL). The organic layer was separated, concentrated to give the crude product. Then the mixture was purified by chromatography column on silica gel (eluted with CH2Cl2/MeOH) to afford crude product, and the final product (0.55 g) was obtained from recrystallization using MeOH as solvent. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 7.41 (d, 1H, J=7.8 Hz), 6.99 (d, 1H, J=7.8 Hz), 3.73 (s, 3H), 2.78-2.81 (m, 2H), 2.50 (s, 3H), 2.35-2.37 (m, 2H), and 1.64-1.73 (m, 4H). MS (ESI) m/e [M+1]+272.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(C1C=C(B(O)O)C=CC=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:6]1=[O:11]
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=Cc1cccc(B(O)O)c1
Solvent: COCCOC
Solvent: O
Product: O=C1Nc2ccccc2C12CCCCC2
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (1.00 g, 3.57 mmol) in dimethoxyethane (20 cm3) was added tetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) under nitrogen. After 15 min. 3-formylphenylboronic acid (1.00 g, 6.93 g) was added followed by potassium carbonate (2.90 g, 21 mmol) in water (10 cm3). After 20 h at reflux, the mixture was cooled poured into water and extracted with EtOAc (×3). The combined organic extract was washed with sat. brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane, gradient elution) to afford the title compound (0.66 g, 2.15 mmol, 60%) as a white solid, 1H NMR (CDCl3) δ 1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J=8 Hz), 7.48 (dd, 1Hz), J=8, 2 Hz), 7.61 (t, 1H, J=8 Hz), 7.66 (d, 1H, J=2 Hz), 7.81-7.88 (m, 2H), 8.06 (t, 1H, J=2 Hz), 8.30 (s, 1H, br); MS ((+)ESI) m/z 306 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Br:12]Br.Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: Fc1cccc2ccccc12
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c2ccccc12
Reaction time: 2 h

Procedure:
To a 50 mL round-bottomed flask equipped with condenser and N2 inlet were added 3.75 mL (5.0 g, 34.25 mmol) 1-fluoronaphthalene and 10 mL carbon tetrachloride, followed by dropwise addition of 1.7 mL (5.5 g., 34.375 mmol) bromine over 3 min. The reaction was heated to 50-60° C. as HBr was evolved for 2 hour, then cooled and concentrated. The residue was dissolved in methanol and kept overnight at 0° C. After filtration with cold methanol, the product, with melting point close to room temperature, was 4.62 g (60%) of a yellow oil. 1H-NMR (δ, CDCl3): 7.02 (t, J=8, 1H), 7.6-7.7 (m, 3H), 8.10 (d, J=8.5, 1H), 8.20 (d, J=8.5, 1H); GCMS (%): 224/226 (parent, Br79/Br81 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:5]([N:7]([CH3:16])[C@H:8]([C:13]([OH:15])=O)[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6].Cl.C[O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26]>>[CH3:20][C:18]1[CH:17]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:19]=1)[C:5]([N:7]([CH3:16])[C@H:8]([C:13]([NH:26][C@H:25]([C:24]([OH:37])=[O:23])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:15])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6]
Reactant: CC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)c1cc(C)cc(C)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)N(C)C(=O)c1cc(C)cc(C)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-(L)-isoleucine (prepared following the procedure described in example 78) with (L)-tryptophan methyl ester hydrochloride according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dimethylbenzoyl)-N-methyl-(L)-isoleucinyl-(L)-tryptophan; FAB-MS m/e 464 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15].[Li]CCCC.[B:22](OC)([O:25]C)[O:23]C.[NH4+].[Cl-].Cl>C1COCC1>[CH3:11][O:10][C:4]1[C:3]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:2]([B:22]([OH:25])[OH:23])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)c(OCC(C)C)c1OC
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(OCC(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere 1-bromo-2-isobutoxy-3,4-dimethoxy-benzene (6.7 g, 23.2 mmol) was dissolved in dry THF (50 mL). The solution was cooled to −70° C. while n-BuLi (2.0 M in pentane, 12.8 mL, 25.5 mmol) was added over 10 min. The solution was stirred for 20 min at −70° C. after which trimethyl borate (5.2 mL, 46.4 mmol) was added over 10 min. The solution was kept at −70° C. for 15 min after which it was heated to RT over 15 min and stirred at RT for 30 min. Saturated aq. NH4Cl (200 mL) was added and the solution was adjusted to pH 1 with 4N HCl (10 mL). The mixture was extracted with EtOAc (×3). The combined organic phases were dried (Na2SO4), filtered and concentrated to afford an oil. The crude product was purified by flash chromatography using heptane:EtOAc 4:1->3:1 as the eluent to afford a crystalline compound which was recrystallised from petroleum ether:Et2O (90:10) to afford the title compound as a crystalline compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][C@H:10]([N:22]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:23]([C:25]2[N:29]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:28]3[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=3[N:26]=2)=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:44]1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH2:44][C:32](=[O:34])[CH2:31][CH2:30][N:29]1[C:28]2[CH:35]=[CH:36][CH:37]=[CH:38][C:27]=2[N:26]=[C:25]1[C:23]([N:22]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@H:10]1[CH2:11][C@@H:12]([C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:24]
Reactant: On1nnc2ccccc21
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCC(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCC(N)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.7 %

Procedure:
3-(2-{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl) carbamoyl}-1H-benzimidazol-1-yl)propanoic acid (215 mg) and 1H-1,2,3-benzotriazol-1-ol ammonium salt (84 mg) were dissolved in DMF (5 ml), WSC.HCl (142 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (199 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([O:26][CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)=[CH:23][CH:24]=5)[NH:19][CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.[H-].[Na+].Cl[C:37]([O:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:38]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([O:26][CH2:27][C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)=[CH:23][CH:24]=5)[N:19]([C:37]([O:39][C:40]5[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=5)=[O:38])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccn2c1CSC2c1cccnc1)c1cn(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a solution of 3-(pyridin-3-yl)-7-(6-phenylmethoxyindol-3-yl)carbonyl-1H,3H-pyrrolo[1,2-c]thiazole (200 mg, 0.443 mmol), prepared as in Example 4, in DMF (12 mL) was added NaH (60% oil dispersion, 19 mg, 0.465 mmol) and the reaction mixture was stirred for 7 min at ambient temperature. 4-nitrophenyl chloroformate (94 mg, 0.45 mmol) was added and the amber solution was stirred for two hours at ambient temperature. The reaction mixture was partitioned between H2O and ethyl acetate. The organic phase was dried over MgSO4, filtered,and concentrated. The title compound (98 mg), was purified by flash chromatography on silica gel (60 g, 1:1 ethyl acetate, hexanes).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]23[CH2:18][C:15]([C:19]([OH:21])=O)([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:9])[CH:5]=[N:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]23[CH2:18][C:15]([C:19]([NH:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)=[O:21])([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: Cc1cncc(C(=O)NC23CCCC(C(=O)O)(CC2)C3)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cncc(C(=O)NC23CCCC(C(=O)Nc4ccccn4)(CC2)C3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of 5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octane-1-carboxylic acid (intermediate 26, 100 mg, 0.35 mmol) and pyridin-2-amine (39 mg, 0.41 mmol) in DMF (5 mL) was added HATU (158 mg, 0.41 mmol) and DIPEA (0.5 mL). After stirring at room temperature for one hour, water (20 mL) was added, and the solution was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate: 2/1) to yield 35 mg (27%) of 6-methyl-N-{5-[(pyridin-2-ylamino)carbonyl]bicyclo[3.2.1]oct-1-yl}pyrazine-2-carboxamide as a white solid. Analytical data were listed in Table 3.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]2[N:14]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]5[N:33]=[C:34]([CH:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=5)=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:69](=[O:79])[CH:70]([NH:74][C:75]([O:77][CH3:78])=[O:76])[CH:71]([CH3:73])[CH3:72])[CH2:9]1)=O)(C)(C)C.C(OC(=O)NC1CCCN(CC2NC(C3C=CC(C4C=CC(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)=CC=4)=CC=3)=CN=2)C1=O)(C)(C)C>>[CH3:78][O:77][C:75]([NH:74][CH:70]([CH:71]([CH3:73])[CH3:72])[C:69]([N:10]1[CH:11]([C:13]2[N:14]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]5[N:33]=[C:34]([CH:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])[CH:36]=5)=[CH:30][CH:31]=4)=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][NH:8][CH2:9]1)=[O:79])=[O:76]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4cn(COCC[Si](C)(C)C)c(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)cn1COCC[Si](C)(C)C)C(C)C
Agent: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4cn(COCC[Si](C)(C)C)c(C5CNCN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)cn1COCC[Si](C)(C)C)C(C)C

Procedure:
3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazole was prepared using method 804 substituting 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester for {1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C53H77N9O8Si2 calculated 1023.5 observed [M+1]+1024.7; rt=2.81 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(=O)C(F)(F)F)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:12]=[CH:11][C:10]=2[CH2:34][C:35]([NH2:37])=[O:36])[CH:2]=1>CO.[OH-].[Na+].O>[N:22]1([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:34][C:35]([NH2:37])=[O:36])=[C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:14]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCN(C(=O)C(F)(F)F)CC3)cc2)cc1NCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccnc1
Reaction time: 0.33 h
Yield: 95 %

Procedure:
66 mg of 4-[(pyridin-3-ylmethyl)amino}-6-({4-[4-(trifluoroacetyl)piperazin-1-yl]phenyl}amino}pyridine-3-carboxyamide (the compound of Example 354) was dissolved in 1 mL of methanol, to which 0.5 mL of 1 mol/L sodium hydroxide in water was added at room temperature, and stirred at the same temperature for 20 minutes. To the reaction mixture water was added, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:ammonia methanol=40:1 to 20:1) to obtain 51 mg (96%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[C@@H:10]([OH:14])[C@H:11]([OH:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([NH:8][CH2:9][C@@H:10]([OH:14])[C@H:11]([OH:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@H](O)C(=O)NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H](O)CNCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A flask was charged with 3.03 g (14.5 mmol) (2S,3R)-N-benzyl-2,3-dihydroxy-butyramide, 60 mL dry THF, and the mixture was cooled to 0° C. under a nitrogen atmosphere. To this solution, 1.65 g (43.5 mmol) lithium aluminum hydride powder was added in small portions. The mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature, and then heated at reflux overnight. The reaction mixture was then cooled to 0° C. and quenched by the slow addition of 1.65 mL water, 1.65 mL 15% aqueous sodium hydroxide solution, and 4.95 mL water, sequentially. The solids were filtered off, and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (1:1 dichloromethane/ methanol) to give 1.41 g (50%) of the title compound as a white solid. MS (APCI) (m+1)/z 196.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
To a solution of 4-chlorophenol (1.00 g, 7.78 mmol) in DMF (5 ml) at room temperature was added potassium carbonate (2.15 g, 15.56 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 15 min. Then, 4-chloro-3-nitropyridine (1.23 g, 7.78 mmol) was added and the resulting solution was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and evaporated. 4-(4-Chlorophenoxy)-3-nitropyridine (1.72 g, 88%) was obtained as a yellow solid, mp 93-94° C. (from EtOH), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C@@H:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(NC(C)C)(C)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[NH:36]([C:37]([NH:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C@@H:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C[C@H](c1ccccc1)n1cnc2cc(N)ccc21
Solvent: CO
Solvent: CC(C)NC(C)C
Product: COC(=O)C[C@H](c1ccccc1)n1cnc2cc(NC(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the crude mixture of methyl (3R)-3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and the corresponding 2-ethoxyethanol ester (186 mg, ca. 629 μmol) in methanol (5.5 mL) was added N,N-diisopropylamine (132 μL, 750 μmol) and phenyl isocyanate (82 μL, 750 μmol). The solution was stirred at room temperature for 12 hours, then evaporated in vacuo, and purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5) to afford the title compound, [LCMS (Method C, Mobile Phase I) RT=2.33 mins, MH+ 415].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])=[CH:3][C:2]=1[C:15]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:16].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>>[N+:1]1([O-:31])[C:2]([C:15]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:16])=[CH:3][C:4]([C:7]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)COC(=O)c1ccnc(C(=O)OCC(=O)OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COC(=O)COC(=O)c1cc[n+]([O-])c(C(=O)OCC(=O)OC)c1

Procedure:
From 1 g of di-(methoxycarbonylmethyl) pyridine-2,4-dicarboxylate and 1.1 g of MCPBA.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[C:21](O)(=[O:25])[C:22]#[C:23][CH3:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[C:21]([N:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])=[CH:12][CH:13]=2)[CH2:18]1)(=[O:25])[C:22]#[C:23][CH3:24]
Reactant: CC#CC(=O)O
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#CC(=O)N1CCc2ccc(C(=O)NOC3CCCCO3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 67 mg butynoic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated and the residue is purified by silica gel flash chromatography. 130 mg of a colorless foam are obtained after drying.
Reaction SMILES: CO.[C:3]([OH:13])(=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]>[Rh].C(O)(=O)C>[CH:6]1([CH:4]([OH:5])[C:3]([OH:13])=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)C(O)c1ccccc1
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C(O)C1CCCCC1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of 200 mL methanol were added 38.0 g mandelic acid, 2.5 mL acetic acid, and 7.5 g rhodium on carbon (5%, Engelhard 5864). The mixture was sealed in an autoclave, purged with nitrogen, and then filled with hydrogen gas. Hydrogenation was carried out at room temperature for 8 hours at 1400 psi hydrogen. The reaction mixture was then removed from the autoclave and filtered. The filtrate was concentrated and recrystallized from toluene. The colorless crystals were collected by filtration and dried under vacuum to give 31.8 g (80.5%) of racemic 2-cyclohexyl-2-hydroxyacetic acid. 1H NMR (DMSO-d6): δ (ppm) 3.71 (d, 1H), 1.66-1.55 (m, 6H), 1.16-1.09 (m, 5H). 13C NMR (DMSO-d6): δ (ppm) 175.27, 74.19, 41.15, 28.86, 26.74, 25.84, 25.76, 25.57. IR (KBr): ν (cm−1) 3440, 2933, 2856, 1718, 1450, 1280, 1255, 1230, 1103. Anal. Calcd. for C8H14O3: C, 60.74; H, 8.92. Found: C, 61.12; H, 9.28. mp 135-136° C.