Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32]([O:34]CC(Br)CBr)=O.[CH3:40][NH2:41].C1COCC1>>[CH3:40][N:41]1[C:32](=[O:34])[C:4]2[CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:30])=[O:29])[NH:6][C:7](=[O:19])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=3)[C:3]=2[CH2:2]1
Reactant: CN
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(CBr)=C1C(=O)OCC(Br)CBr
Solvent: C1CCOC1
Product: CN1CC2=C(C1=O)C(c1ccc(C#N)cc1S(C)(=O)=O)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Under an argon protective gas atmosphere, (rac)-2,3-dibromopropyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (758.2 mg, 1.0 mmol; Example 7A) was mixed with a 1 M solution of methylamine in THF (20 ml, 20.0 mmol, 20 eq.), and the mixture was stirred at RT for 30 min. The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (328 mg, 67% of theory).
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13]CC2C=CC=CC=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:21])[CH:2]=[CH2:3].C([O-])=O.[NH4+]>CCO.[OH-].[Pd+2].[OH-]>[CH3:21][N:8]1[C:9]2[C:5](=[C:4]([CH2:1][CH2:2][CH3:3])[C:12]([OH:13])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: C=CCc1c(OCc2ccccc2)ccc2c1ccn2C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCc1c(O)ccc2c1ccn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
4-Allyl-5-(benzyloxy)-1-methyl-1H-indole (250.0 mg, 0.90 mmol) (Example 59) was dissolved in EtOH (15 mL), then 20% palladium (II) hydroxide on carbon (30 mg) was added, followed by ammonium formate (455 mg, 7.21 mmol). After stirring for 1 h at rt, the mixture was heated to 40° C. for 2.5 h. After cooling to rt, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 150 mg (88%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 1.02 (t, 3H), 1.73 (m, 2H), 2.85 (t, 2H), 3.76 (s, 3H), 4.33 (br, 1H), 6.40 (s, 1H), 6.78 (d, 1H), 7.02 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH3:10]O>>[CH3:10][O:8][C:7]([C@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1)=[O:9]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CO
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 0 °C

Procedure:
Cis-4-Hydroxy-D-proline (15 g, 115 mmol) was suspended in 150 mL anhydrous methanol under an argon atmosphere, then cooled to 0° C. before bubbling in HCl gas for 15 minutes. The solution gradually became homogenous. The argon and HCl gas lines were removed and the solution was refluxed for 4 h. The solution was cooled and then concentrated under reduced pressure. The crude material was redissolved in 100 mL methanol and diethyl ether was added until a precipitate formed. The precipitate was filtered off, washed with diethyl ether, and dried in vacuo overnight to reveal 1 (20 g, 95%) as a white solid. MS: APCI (AP+): 146 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.[CH2:23]([N:25]([CH2:28]C)[CH2:26]C)C>C1COCC1.ClCCl>[CH3:23][N:25]([CH:28]=[N:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[CH3:26]
Reactant: CCN(CC)CC
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C=Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 5-amino-3-(4-quinolylmethylen)-2-oxindole (287 mg, 1 mmol) and triethylamine (121 mg, 1.2 mmol) in THF (20 ml) was added portionwise at, 0° C. chlorodimethyl-formimminium chloride (154 mg, 1.2 mmol) and the stirring was continued at room temperature for 1 h. Then the reaction mixture was diluted with dichloromethane, the organic layer washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel (eluant ethyl acetate/methanol 1:1) to give pure title compound in 60% yield (205 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[Br-].[CH:19]1([CH3:22])[CH2:21][CH2:20]1.O>CN(C=O)C>[CH:19]1([CH2:22][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC1CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
4-Amino-3-nitrophenol (26.00 g, 165.5 mMol) was dissolved in 200 mL of anhydrous DMF under an atmosphere of dry N2. The reaction mixture was then cooled to 0° C. and to this mixture was added Cs2CO3 (64.7 g, 199 mMol), and cyclopropyl methane bromide (17.7 mL, 182 mMol). After stirring for 15 minutes, the reaction mixture was then warmed up to ambient temperature and then stirred overnight. The reaction mixture is then poured into 800 mL of water. The precipitate was collected via suction filtration and partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was saved and washed again aqueous 0.1 N NaOH, then with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 31.52 g of 4-cyclopropylmethoxy-2-nitro-phenylamine 133A as an orange solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[CH3:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[O:10][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1
Reactant: Cc1ccccc1CC(=O)O
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(Cc2ccccc2C)n1
Yield: 17.7 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-o-tolylacetic acid (0.568 g; 3.78 mmol); oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.165 g (18%) of ethyl 5-(2-methylbenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[CH:18]1([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:2][C:3]([NH:5][C@@H:6]4[CH2:11][O:10][C:9]5=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]5[CH2:7]4)=[O:4])[CH2:32][CH2:31]3)=[CH:36][CH:37]=2)[CH2:20][CH2:19]1
Reactant: c1cc(OC2CCNCC2)ccc1OCCOC1CC1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Oc2ccc(OCCOC3CC3)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 38.7 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(2-(cyclopropoxy)ethoxy)phenoxy)piperidine (277 mg, 1.0 mmol) as crude materials, 97 mg title compound was generated and yield was 39%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][C:6]=2[CH:17]=1.[H-].[Na+].I[CH3:21]>CN(C)C=O.O>[CH3:21][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][C:6]=2[CH:17]=1
Reactant: CCOC(=O)CC1=COc2ccc(O)cc2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1=COc2ccc(OC)cc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.8 g (12.75 mmol) of the ester obtained in Step B are dissolved in 30 ml of anhydrous N,N-dimethylformamide. 0.61 g (16 mmol) of sodium hydride is then added slowly to the reaction mixture previously cooled to 0° C. After 30 minutes of stirring under argon and at 0° C., 2.28 g (16 mmol) of iodomethane are added to the reaction medium. After 4 hours of stirring at ambient temperature, the solvent is evaporated in vacuo; the residue obtained is then taken up in water and then extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The title ester is obtained pure in the form of a white solid after passage over a silica column (eluant: ethyl acetate/petroleum ether: 30/70).
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([C:6]1[NH:7][C:8]2[C:13]([C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)(=[O:20])[CH3:19]
Reactant: COC(=O)c1ccc2c(CC(C)C)c[nH]c2c1
Reactant: CC(=O)Cl
Product: COC(=O)c1ccc2c(CC(C)C)c(C(C)=O)[nH]c2c1

Procedure:
Methyl 2-acetyl-3-isobutylindole-6-carboxylate (43 mg) was prepared from methyl 3-isobutylindole-6-carboxylate (99 mg) and acetyl chloride (0.073 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: C(N)(=O)C1C=CC=CC=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@@:17]([NH:36][C:37](=[O:48])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)([C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([F:35])[CH:26]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][C:12]=1[OH:49].Br[C:51]([CH3:57])([CH3:56])[C:52]([O:54][CH3:55])=[O:53].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@:17]([C:25]2[CH:30]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:28]=[C:27]([F:35])[CH:26]=2)([NH:36][C:37](=[O:48])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=2)[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][C:12]=1[O:49][C:51]([CH3:57])([CH3:56])[C:52]([O:54][CH3:55])=[O:53]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(O)c1)c1cccc(C(F)(F)F)c1
Agent: NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)c2cccc(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 180 °C
Yield: 29 %

Procedure:
A solution of (R)—N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide benzamide, prepared as described in Example 264, (226 mg, 0.4 mmol), methyl 2-bromo-2-methylpropanoate (0.10 mL) and K2CO3 (326 mg, 2.36 mmol) in DMF (1 mL) was heated at 180° C. under microwave condition for 1200 seconds. The reaction mixture was allowed to cool, diluted with EtOAc and the organic layer was washed with H2O (2×), saturated NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO flash chromatography (silica gel, hexanes/EtOAc) to give (R)-methyl 2-(2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)benzamido)ethyl)phenoxy)-2-methylpropanoate (Example 273, 76 mg, yield: 29%). LCMS: RT=2.26 min [M+H] 666.4 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][CH:8]=1.[CH3:22][N:23]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[N:28]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:22][N:23]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH:33][C:13]([C:10]3[CH:9]=[CH:8][C:7]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)=[O:15])=[CH:29][C:27]=2[N:28]=1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4ccc(-c5ccccc5)cc4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Add oxalyl chloride (0.20 mL, 2.30 mmol) and 3 drops of DMF to a stirring suspension of Biphenyl-4-carboxylic acid (0.240 g, 1.15 mmol) in CH2Cl2 (5.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant biphenyl-4-carbonyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.200 g, 0.768 mmol) and pyridine (0.06 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aqueous) (2×25 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel 130 flash column chromatography (5×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product (0.168 g, 50%). mass spectrum (m/e): 441.3 (M+1). 1H NMR (400 MHz, CD3OD): δ 8.01-7.97 (m, 2H), 7.74-7.70 (m, 3H), 7.67-7.64 (m, 2H), 7.48-7.42 (m, 2H), 7.39-7.31 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 4.12-4.02 (m, 1H), 3.06 (s, 3H), 2.97 (d, J=12.0 Hz, 2H), 2.30 (s, 3H), 2.17 (dt, J=12.4, 2.8 Hz, 2H), 1.91 (dq, J=12.0, 4.0 Hz, 2H), 1.76 (d, J=12.6 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:19]3[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=4)[CH:20]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]([CH2:39][C:40](O)=O)#[N:38].C(Cl)CCl.CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>CN(C=O)C.CC(O)=O.O.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[C:19]4[CH:20]=[C:21]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=5)[N:22]=[CH:23][C:24]=4[N:25]=[C:40]3[CH2:39][C:37]#[N:38])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCC(=O)O
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c(N)cn2)c1
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(CC#N)n3-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from Step 3 (2.54 g crude) and cyanoacetic acid (0.88 g, 10.4 mmol) were dissolved in DMF (10 mL) and Et3N (3.6 mL) was added. To the solution was added EDC (2.2 g, 11.4 mmol), and the mixture was allowed to stir at rt for 2 days. The reactin mixture was poured into water and extracted with ethyl acetate. The separated organic layer was dried over MgSO4, filtered, and concentrated to give a dark oil. The oil was dissolved in AcOH (5 mL) and the solution was heated at 100° C. for 4 hours then cooled and concentrated in-vacuo to give the title compound as a dark foam that was taken on without further purification. MS (ES+) m/e 540 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[N:15]=[N:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.O1CCCC1>[CH2:3]([O:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]([OH:20])=[O:19])[N:15]=[N:14][N:13]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cn1nnnc1COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cn1nnnc1COCc1ccccc1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A 2.5N sodium hydroxide solution (100 ml, 0.25 mol) was added dropwise over fifteen minutes to ethyl 5-(1-benzyloxymethyl)tetrazolyl acetate 2 (36.21 gm, 0.131 mol) in 800 ml ethanol and 200 ml tetrahydrofuran at room temperature, causing a white precipitate. After one hour, the mixture was concentrated in vacuo. On liter of water was added and the aqueous phase was washed with two 400 ml portions of dichloromethane. The aqueous phase was acidified with 150 ml 2.5N hydrochloric acid and extracted with three 500 ml portions of ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate. Concentration in vacuo and trituration of the white solid from diethyl ether yielded 27.24 gm (84%) 5-(1-benzyloxymethyl)tetrazolylacetic acid 3 as a white solid: mp 125°-126°; 1H NMR (CDCl3 :DMSO d6, 10:1) δ 7.40 (5H, m), 5.87 (2H, S), 4.55 (2H, S), 4.09 (2H, S) mass spectrum FD 249 (M+H).
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[Cl:21])(C)C)(C)(C)C.O.O.Cl[Sn]Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([Cl:21])[CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCCO)c(Cl)c1
Reaction time: 4 h
Yield: 3.4 %

Procedure:
A mixture of tert-butyl-(2-(2-chloro-4-nitrophenoxy)ethoxy)dimethylsilane (475 mg, 1.4 mmol) and SnCl2.2H2O (1.07 g, 5.7 mmol) in EtOH (40 mL) was heated to reflux and stirred for 4 hr. After allowing to cool, the mixture was poured into EtOAc (50 mL) and saturated NaHCO3 (50 mL), then filtered through celite. The filtrate was partitioned and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel and purified by column chromatography on silica gel using EtOAc/heptane (2:8 to 1:0) as eluent to give the product (9 mg, 3% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([O:6]C)=[O:5])[CH3:3].Cl.[CH3:9][C:10]([O:13][C:14]([NH:16][C@H:17]([C:20](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:21])[CH2:18][OH:19])=[O:15])([CH3:12])[CH3:11].ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)(Cl)Cl>[NH:16]([C:14]([O:13][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:15])[C@H:17]([C:18]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:19])[CH2:20][OH:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
25 g of H-Ala-OMe, HCl and 66 g. of Boc-Ser-ONb are dissolved in 500 ml DMF. The product is cooled in an ice bath and 25 ml of NEM, 24 g of N-hydroxy benzotriazole are added with magnetic stirring and the pH is maintained at 6.5 or 7 by addition of NEM. The product is stirred for 18 hrs. at ambient temperature. After TLC monitoring, the medium is evaporated to 90% (0.1 mm Hg--35° C.). The oil obtained is dissolved in 1.500 ml of chloroform, the product is washed with a solution of saturated sodium chloride (twice), 5% sulfate/potassium bisulfate solution (3 times), saturated sodium bicarbonate (5 times). The solution is dried over Na2SO4 and evaporated to dryness. An oil is obtained which is dried to constant weight (30°--0.1 mm Hg).
Reaction SMILES: CN(C1C=CC=CN=1)C.C[Si]([N:14]=[C:15]=[O:16])(C)C.C(Cl)Cl.[F:20][C:21]1[CH:47]=[CH:46][C:24]([O:25][C:26]2[C:40]([CH:41]3[CH2:45][CH2:44][CH2:43][NH:42]3)=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:23][CH:22]=1>O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[C:40]([CH:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:15]([NH2:14])=[O:16])=[CH:39][C:29]3[NH:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[N:32][C:28]=3[CH:27]=2)=[CH:46][CH:47]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: NC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 mg of dimethylaminopyridine and 0.059 ml of trimethylsilyl isocyanate were added in order to a methylene chloride (1 ml) solution of 31.2 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was stirred overnight at room temperature. Water was added to the reaction liquid, and extracted with ethyl acetate, and then washed with saturated saline. After dried and concentrated, the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] to obtain the entitled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=O)[CH3:9])=[CH:5][NH:4][N:3]=1.B(F)(F)F.CCOCC.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][NH:4][N:3]=1
Reactant: CC(=O)Nc1c[nH]nc1Cl
Agent: Cl
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCNc1c[nH]nc1Cl
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
A 250-mL, 3-neck round bottom flask was charged with N-(3-chloro-1H-pyrazol-4-yl)acetamide (4.75 g, 29.8 mmol) and tetrahydrofuran (50 mL). Borontrifluoride etherate (7.8 mL, 74.4 mmol) was added and the mixture was stirred for 15 minutes. Sodium borohydride (3.38 g, 89 mmol) was added (off-gassing) and the reaction was heated at 50° C. for 4 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate, sample was prepared by treatment of reaction mixture with hydrochloric acid, followed by sodium bicarbonate basification and ethyl acetate extraction] indicated that the reaction was complete. Water (40 mL) was added (off-gassing), followed by concentrated hydrochloric acid (6 mL, off-gassing). The mixture was heated at 50° C. for 5 hours and allowed to cool to 20° C. and stirred for 16 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran and basified with sodium bicarbonate. Ethyl acetate (50 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (25 mL) and the combined organic layers were concentrated to dryness to afford a colorless oil (2.80 g, 65%): 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.20 (d, J=1.6 Hz, 1H), 3.94 (s, 1H), 2.87 (q, J=7.1 Hz, 2H), 1.11 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, DMSO) δ 129.18, 127.11, 115.03, 41.06, 14.56; EIMS m/z 145 ([M]+).