Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:6]=[N:5][CH:4]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[CH3:18][N:9]([C:7]1[CH:8]=[N:3][CH:4]=[N:5][CH:6]=1)[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: CI
Reactant: N#Cc1cccc(Nc2cncnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cncnc1)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
NaH (148 mg, 6.17 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (14 mL) was added. The slurry was cooled to 0° C. and compound 15 (1.098 g, 5.596 mmol, 1.000 eq) was added as a solution in THF (14 mL). After stirring at 0° C. for 30 minutes methyl iodide (384 μL, 6.17 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 735 mg (62%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.57 (s, 2H), 7.58-7.56 (m, 1H), 7.51-7.44 (m, 2H), 7.44-7.38 (m, 1H), 3.35 (s, 3H); [M+1]+: 211.2.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[N:10]([CH3:18])[CH:9]=1)=[O:7])C.O.Cl>C(O)C>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[CH:9]=[C:8]2[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1cn(C)c2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c2cc(Br)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
1N Aqueous solution of sodium hydroxide (10 ml) was added at room temperature to a solution of 5-bromo-1-methyl-1H-indole-3-carboxylic acid ethyl ester (605 mg) in ethanol (10 ml) and stirred at 70° C. for three hours. After completion of the reaction, the reaction solution was cooled to room temperature, water and 1N hydrochloric acid aqueous solution were added and the precipitated solid was collected by filtration to give the titled compound (530 mg) as a white solid.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[S:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]2[N:8]([CH2:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:10][S:22]2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: ClCC[NH2+]CC1CCCC1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CCCC2)cc1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:34])=[NH:6].O>[Ni].CO>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:34])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc(-c3ccccc3)cc2)nc1N
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(N)c1cccc2c1CCC2=Nn1cc(-c2ccc(-c3ccccc3)cc2)nc1N

Procedure:
Analogously to Example 2, a mixture of 9.27 g (18.54 mmol) of 1-[4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(4-biphenylyl)-imidazole dihydrochloride, 800 ml of water, 820 ml of methanol and 7.3 g of Raney nickel is hydrogenated at 25°-51° C. and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered, the filtrate is acidified to pH 1 with concentrated hydrochloric acid, and concentration is carried out by evaporation in vacuo. Recrystallization of the residue twice from ethanol yields the title compound, m.p. 269°-270° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.32 (d, 1H); 8.03 (s, 1H); 7.62-7.83 (m, 8H); 7.35-7.53 (m, 3H); 3.36 (s, 4H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:48]1[CH2:49][CH2:50][CH:45]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:46][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N4CCCC4)CC3)ccc2[nH]1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-(1-pyrrolidinyl)-piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a brown solid (67%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[OH:20][CH2:21][C:22]1[N:23]=[N:24][N:25]([CH2:27][CH3:28])[CH:26]=1>>[CH2:27]([N:25]1[CH:26]=[C:22]([CH2:21][O:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[N:12][N:13]=[C:14]([C:15]4[CH:19]=[CH:18][O:17][N:16]=4)[N:4]3[N:3]=2)[N:23]=[N:24]1)[CH3:28]
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Reactant: CCn1cc(CO)nn1
Product: CCn1cc(COc2nn3c(-c4ccon4)nnc3c3ccccc23)nn1

Procedure:
The title-compound was prepared from 6-chloro-3-(3-isoxazolyl)-1,2,4-triazolo[3,4-a]phthalazine (prepared as described in Example 34, step b) and 4-hydroxymethyl-1-ethyl-1,2,3-triazole (prepared as described in Example 98 part a), following the procedure described in Example 98, but performing the reaction at −45° C. 1H NMR (360 MHz, CDCl3) δ 1.55 (3H, t, J=7.5 Hz, CH3), 4.40 (2H, q, J=7.4 Hz, CH2), 5.78 (2H, s, CH2), 7.31 (1H, d, J=1.7 Hz, Ar—H), 7.82 (1H, m, Ar—H), 7.95 (1H, m, Ar—H), 8.27 (1H, d, J=7.8 Hz, Ar—H), 8.64-8.66 (2H, m, 2 of Ar—H), 8.69 (1H, s, Ar—H); MS (ES30) m/e 363 [MH]+; Anal. Found. C, 56.24; H, 3.70; N, 30.65. C17H14N8O2 requires C, 56.35; H, 3.89; N, 30.92%.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[N:22]=[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]3=[N:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1(C)C=CC=CC=1>[N:19]1[N:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[N:22]=[C:21]2[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=12
Reactant: c1ccc(COc2ccc(OCCn3nc4ccccc4n3)cc2)cc1
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: Oc1ccc(OCCn2nc3c(n2)CCCC3)cc1
Yield: 67.8 %

Procedure:
5.5 g of 1-benzyloxy-4-[2-(2H-benzotriazol-2-yl)ethoxy]benzene [prepared as described in Example 15(a)] were hydrogenated in a manner analogous to that described in Example 1(b) until no more hydrogen was taken up, whereby 2.8 g (69%) of 4-[2-(4,5,6,7-tetrahydro-2H-benzotriazol-2-yl)ethoxy]phenol having a melting point of 93° C. (from toluene) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[C:6](F)[C:7]=1[F:8].BrC1C=CC(F)=C(F)C=1.BrC1C=C(F)C(F)=C(F)C=1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1cc(-c2ccsc2)cc(F)c1F
Agent: Fc1cc(Br)cc(F)c1F
Agent: Fc1ccc(Br)cc1F
Product: Fc1ccc(-c2ccsc2)cc1F

Procedure:
The same procedures set forth above in Example (1)(a) for synthesizing 3(3,4,5-trifluorophenyl)thiophene were followed, with the exception that 1-bromo-3,4-difluorobenzene was substituted for 1-bromo-3,4,5-trifluorobenzene as the 1-bromo-substituted fluorobenzene.
Reaction SMILES: [NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9](OCC)=[O:10])(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[OH:10][CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][CH2:5][S:2]([NH2:1])(=[O:3])=[O:4]
Reactant: CCOC(=O)C(C)(C)CCCS(N)(=O)=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(CO)CCCS(N)(=O)=O
Yield: 58 %

Procedure:
A solution of 7.1 g of the ethyl 5-aminosulfonyl-2,2-dimethylvalerate obtained in Reference Example 26 in 20 ml of tetrahydrofuran was added dropwise to a suspension of 1.71 g of lithium aluminum hydride in 100 ml of tetrahydrofuran with ice-cooling and stirring. After completion of dropwise addition, the mixture was stirred at 0° C. for 40 minutes and after addition of aqueous tetrahydrofuran for decomposition of excess lithium aluminum hydride, the mixture was neutralized with 2N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was subjected to silica gel (100 g) column chromatography and elution was carried out with hexane-ethyl acetate (4:1) to provide 3.39 g of the title compound as oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([N:17]([CH3:24])[C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ncc(-c2ccccc2)nc1NC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ncc(-c2ccccc2)nc1N(C)C(=O)C(F)(F)F
Temperature: 65 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
Methyl 3-(methylamino)-5-phenylpyrazine-2-carboxylate. A solution of methyl 3-amino-5-phenylpyrazine-2-carboxylate (360 mg, 1570 μmol) in DCM (10 mL) was treated with DIPEA (547 μl, 3141 μmol) and trifluoroacetic anhydride (275 μl, 1963 μmol). The reaction stirred under nitrogen at 23° C. After 14 hours, the reaction was diluted with DCM (50 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, and concentrated in vacuo affording methyl 5-phenyl-3-(2,2,2-trifluoroacetamido)pyrazine-2-carboxylate as an orange solid, which was carried forward to the next reaction. A suspension of methyl 5-phenyl-3-(2,2,2-trifluoroacetamido)pyrazine-2-carboxylate (511 mg, 1571 μmol) and potassium carbonate (651 mg, 4713 μmol) in DMF (10 mL) was treated with iodomethane (196 μl, 3142 μmol). The reaction flask was capped with a septum and heated to 65° C. After 4 hours, the reaction was cooled to 23° C., diluted with EtOAc (75 mL) and washed with water (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 5-25% EtOAc/hexane), affording 221 mg (41%, 2 steps) of methyl 5-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)pyrazine-2-carboxylate as an yellow solid. A solution of methyl 5-phenyl-3-(2,2,2-trifluoro-N-methylacetamido)pyrazine-2-carboxylate (253 mg, 746 μmol) in MeOH (2 mL) and DCM (2 mL) was treated with sodium methoxide (0.5M solution in MeOH (2983 μl, 1491 μmol)). The reaction was stirred under nitrogen at 23° C. After 90 minutes, the reaction was diluted with brine (25 mL) and extracted with DCM (3×25 mL). The combined organic layers were dried (MgSO4) and concentrated, affording 179 mg (99%) of methyl 3-(methylamino)-5-phenylpyrazine-2-carboxylate as a yellow solid. Mass: Calculated: 243.261. Observed: 244.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.37 (1H, s), 8.07-8.17 (2H, m), 7.95 (1H, br. s.), 7.46-7.55 (3H, m), 4.00 (3H, s), 3.18 (3H, d, J=4.7 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([O:10][CH3:9])=[O:19])=[CH:17][CH:16]=1
Reactant: Cn1ccnc1C=O
Reactant: COC(=O)c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NCc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Methyl-2-imidazolecarboxaldehyde (5.0 mmol) and methyl-4-aminobenzoate (5.0 mmol) were mixed in MeOH (7 mL). Acetic acid (0.3 mL) was added and the mixture stirred for 30 minutes at room temperature. The reaction mixture was cooled, sodium cyanoborohydride (5.0 mmol) was added and the reaction allowed to stir at room temperature for a further 17 h. The reaction mixture was then concentrated under vacuum and partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H2O, brine, dried over MgSO4 and the solvent removed under vacuum. The residue was purified by flash chromatography (silica gel, 5% MeOH in DCM) to give methyl 4-{[(1-methylimidazol-2-yl)methyl]amino}benzoate: m/z=246 in MS ES+ as a pale yellow solid which was used directly in the subsequent step.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]([C@@H:9]2[O:21][C@H:20]([CH3:22])[C@@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[CH:7]=[N:6][C:5]=1[C:23]([O:25]C)=O)#[N:2].[NH3:27]>>[C:1]([CH2:3][C:4]1[N:8]([C@@H:9]2[O:21][C@H:20]([CH3:22])[C@@H:15]([OH:16])[C@H:10]2[OH:11])[CH:7]=[N:6][C:5]=1[C:23]([NH2:27])=[O:25])#[N:2]
Reactant: N
Reactant: COC(=O)c1ncn([C@@H]2O[C@H](C)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c1CC#N
Product: C[C@H]1O[C@@H](n2cnc(C(N)=O)c2CC#N)[C@H](O)[C@@H]1O

Procedure:
A mixture of methyl 5-cyanomethyl-1-(5-deoxy-2,3-di-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxylate (2.20 g, 6.03 mmol) and liquid ammonia (30 ml) was placed in a steel bomb (40 ml) and heated at 100° for 7 hr. The ammonia was allowed to evaporate and the residue was subjected to a vacuum overnight to remove the last traces. The residue was absorbed on silica gel (5 g) and placed on a column of silica gel (60 g, packed in chloroform). Elution with chloroform-methanol (4:1) provided the pure product. Recrystallization from methanol provided colorless cubes (1.42 g, 88%); mp 173°-174° after drying at 100° for 3 hr; [α]D25 -47.8 C=1, H2O); uv λmaxpH 1 218 nm (ε 10,000), λmaxpH 7 233 nm (ε 10,200), λmaxpH 11 234 nm (ε 9,730); pmr (DMSO-d6): δ 1.35 (d,3,CH3), 5.66 (d,1,H1'), J = 5 Hz, 7.45 (d,2,NH2), 8.02 (s,1,C2H).
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:10][CH2:9][C:8]([CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][CH2:6]1)([CH3:4])[CH3:3].O.NN>CO>[NH2:12][CH2:11][C:8]1[CH2:9][CH2:10][C@H:5]([C:2]([OH:1])([CH3:3])[CH3:4])[CH2:6][CH:7]=1
Reactant: CC(C)(O)[C@@H]1CC=C(CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(O)[C@@H]1CC=C(CN)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A mixture of 0.62 g (2.1 mmol) (S)-2-[4-(1-hydroxy-1-methyl-ethyl)-cyclohex-1-enyl-methyl]-isoindole-1,3-dione and 20 ml MeOH was cooled to 0° C. Thereafter, 0.2 ml (6 mmol) hydrazine hydrate was added and the resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then concentrated in vacuo; triturated with CHCl3; filtered and then concentrated to a filtrate yielding 0.31 g (63%) solid product.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][CH3:19].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].[H-].[Na+]>CN(C=O)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH2:18][CH3:19])[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CBr
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 58.6 %

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-2-ethyl-4-hydroxy-1H-indole (911 mg, 2.8 mmol) was alkylated by treating with 0.26 mL (2.8 mmol) of methyl bromoacetate and 111 mg (2.8 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 655 mg (59% yield) of [[1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]butanoate (D57) (120 mg) in THF (5 mL) was added aqueous NaOH (2M, 2 mL). The reaction was stirred at 60° C. overnight. The mixture was acidified with aqueous HCl (2M) to pH 5-6, partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated and dried over anhydrous sodium sulphate. After removing the solvent, the crude product was purified by TLC separation to afford 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]butanoic acid (E35) (20 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 1.89 (2H, m), 2.29 (2H, t), 2.74 (2H, t), 3.63 (3H, s), 4.88 (1H, m), 7.17 (2H, m), 7.44 (2H, m), 7.77 (1H, d), 8.12 (1H, dd), 8.19 (1H, d), 11.98 (1H, br s). MS (ES): C24H24ClN3O4 requires 453; found 454.2 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33](C3CC(=O)N(O)C3=O)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.Cl>O1CCOCC1>[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([NH:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=3)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 40 °C
Yield: 99 %

Procedure:
To 4-aminomethyl-benzoic acid (10.6 g, 70.1 mmol) in dioxane (130 mL) was added 9% aqueous Na2CO3 (150 mL) followed by 9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide (26 g, 77 mmol). The solution was heated to 40° C. for 12 h and then cooled to room temperature. The reaction was acidified with 1 M HCl (500 mL), and extracted with ether (300 mL) to obtain acid S23 as a fluffy white solid (25.9 g, 69.4 mmol, 99%). 1H NMR (500 MHz, d6-DMSO): δ 12.85 (broad s, 1H), 7.90 (m, 4H), 7.70 (m, 2H), 7.39 (m, 2H), 7.31 (m, 4H), 4.37 (d, 2H, J=6.8 Hz), 4.24 (d, 2H, J=5.8 Hz), 4.23 (t, 1H, J=6.8 Hz). APCI/MS: 372 (M+H+).
Reaction SMILES: N[C@@H](CC1C=CC=CC=1)[C@H](O)CN(CC1C=C(N(C)S(C)(=O)=O)C=C(C(C)C)C=1)C(=O)OC(C)(C)C.[C:37]([NH:40][C:41]1[CH:42]=[C:43]([CH:65]=[C:66]([C:68]([CH3:70])=[CH2:69])[CH:67]=1)[CH2:44][NH:45][CH2:46][C@@H:47]([OH:64])[C@@H:48]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:39])[CH3:38]>>[C:37]([NH:40][C:41]1[CH:42]=[C:43]([CH:65]=[C:66]([CH:68]([CH3:70])[CH3:69])[CH:67]=1)[CH2:44][NH:45][CH2:46][C@@H:47]([OH:64])[C@@H:48]([NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:39])[CH3:38]
Reactant: C=C(C)c1cc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc(NC(C)=O)c1
Agent: CC(C)c1cc(CN(C[C@@H](O)[C@@H](N)Cc2ccccc2)C(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)c1
Product: CC(=O)Nc1cc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(C)C)c1

Procedure:
tert-butyl (2S,3R)-4-(3-acetamido-5-isopropylbenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate was synthesized in a similar manner to Boc-protected tert-butyl (2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(3-isopropyl-5-(N-methylmethylsulfonamido)benzyl)carbamate by reducing tert-butyl (2S,3R)-4-(3-acetamido-5-(prop-1-en-2-yl)benzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][O:26]CC2C=CC=CC=2)=[C:23]([C:34]([NH:36][CH:37]2[CH2:39][CH2:38]2)=[O:35])[N:22]=[N:21]1)C1C=CC=CC=1>CO.C(O)(=O)C.[C].[Pd]>[CH:37]1([NH:36][C:34]([C:23]2[N:22]=[N:21][N:20]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[OH:8])[C:24]=2[CH2:25][OH:26])=[O:35])[CH2:39][CH2:38]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)c(O)c1
Yield: 101.6 %

Procedure:
1-{2-(Benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-[(benzyloxy)methyl]-N-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (1.50 g, 2.85 mmol) obtained in Example 316 was dissolved in methanol-acetic acid (9:1, 50 ml), and the mixture was stirred at room temperature for 68 hr in the presence of 10% palladium carbon (wet, purity 50%, 300 mg) under a hydrogen atmosphere. The reaction mixture was filtrated to remove the catalyst, the filtrate was concentrated, diluted with toluene (100 ml) and concentrated, and ethyl acetate was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (1.00 g, quant.). This powder (0.700 g) was crystallized from ethyl acetate, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (637 mg, 1.84 mmol, 64.7%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[C:18]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]4)[C:19]([Cl:21])=[CH:20][C:13]=3[N:12]=2)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:32])[CH:3]=1>[Ni].C1COCC1>[Cl:1][C:2]1[C:9]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[C:18]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([F:29])([F:31])[F:30])[CH2:24][CH2:23]4)[C:19]([Cl:21])=[CH:20][C:13]=3[N:12]=2)=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:32])[CH:3]=1
Reactant: Cn1c(Nc2cc(C#N)c(F)cc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: [Ni]
Solvent: C1CCOC1
Product: Cn1c(Nc2cc(CN)c(F)cc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The sub-title compound was prepared in analogy to Example 101, step (c) using 4-chloro-5-[5-chloro-1-methyl-6-(4-(trifluoromethyl)piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]-2-fluorobenzonitrile (264 mg; 0.54 mmol), Ra—Ni (3 mg), H2 (5 atm) and THF (30 mL).