Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:37])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate (460 mg, 1.0 mol) (from Example 12b, Step 6 above) in CH2Cl2 was treated with a solution of 37% aq formaldehyde (1 ml) and NaBH(OAc)3 (436 mg, 2.0 mol) and stirred at room temperature overnight. The solution was diluted with CH2Cl2 (50 ml) and washed with 1 N NaOH, water, brine, concentrated in vacuo and the residue chromatographed (1:9:90 NH4OH:MeOH:CH2Cl2) to give 330 mg (70%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)-cyclohexanecarboxylate. MS found: (M+H)+=460.49
Reaction SMILES: C([O:8][C:9](=[O:35])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:34])[C@H:16]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[S:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:35])=[O:8])=[O:34])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)O)cc1

Procedure:
In 150 ml of methanol was dissolved 13.5 g of compound (49) and the compound was catalytically reduced for 5 hours in the presence of 10% palladium-carbon. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue thus formed was dissolved in ethyl acetate and extracted thrice each time with an aqueous sodium hydrogen carbonate solution. The extracts were combined with each other and washed once with ethyl acetate. After acidifying the aqueous layer with 1N hydrochloric acid, the desired compound was extracted with ethyl acetate. Thus, 2.0 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidyl-L-proline (50) was obtained as a foamy product. Also, from the organic layer formed after extracting the product with an aqueous sodium hydrogencarbonate solution, 9.1 g of the starting material (49) was recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>C(Cl)Cl.CCOC(C)=O>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 3-nitrobenzenesulfonyl chloride (1, 1.0 g, 4.51 mmol) in anhydrous CH2Cl2 (9.0 mL) was added N,N-dimethyl-ethylenediamine (2, 0.5 mL, 4.55 mmol) dropwise. The resulting solution was stirred at room temperature overnight before it was diluted with EtOAc (80 mL). The organic mixture was washed with saturated NaHCO3 (90 mL), brine (90 mL), and dried over MgSO4. The solids were filtered and the filtrate was concentrated on a rotavap to give 3 as a foam (0.8 g) which was used in the next step without further purification.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].Cl.N([O-])=O.[Na+].O(CC)C([S-])=[S:19].[K+]>O.[Ni](Cl)Cl>[Cl:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[SH:19]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: CCOC(=S)[S-]
Agent: Cl[Ni]Cl
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: O=C(O)c1ccc(Cl)c(S)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Amino-4-chlorobenzoic acid (34.3g) was added to 5N hydrochloric acid (120 ml) and cooled to 0° C. To the stirred suspension was added a solution of sodium nitrite (14.5g) in water (35 ml) over 30 min. with the temperature maintained at 0° to 5° C. The yellow diazonium solution, containing some suspended solid was added to a solution of potassium ethyl xanthate (37.5g) in water (60 ml), containing 0.2g nickel chloride, at 45°-50° C. Nitrogen evolution occurred and the yellow solid which precipitated at first decomposed to a red oil which then solidified. When the addition was complete, the mixture was heated to 70° C., cooled, and the red solid filtered off and washed with water. It was then boiled with a solution of potassium hydroxide (60 g) in water (300 ml) for 2 hr., cooled, filtered and acidified with excess hydrochloric acid. Thin-layer chromatography indicated the presence of 2 components in the precipitated creamy solid. Recrystallisation from acetic acid yielded a by-product, m.p. 240°-290° C., and dilution of the recrystallisation liquors gave a solid which was recrystallised from aqueous ethanol yielding mainly 4-chloro-3-mercapto-benzoic acid, m.p. 209°-211° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:36]=[CH:35][C:28]5[N:29]([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[CH:37][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:36]=[CH:35][C:28]5[N:29]([CH3:34])[C:30](=[O:33])[N:31]([CH3:32])[C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(c4)n(C)c(=O)n5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (7.0 mg, 0.011 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added 1N NaOH solution (0.5 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O4S: 627.2; found: 627.3. 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J=6.0 Hz, 1H), 8.47 (s, 1H), 7.98 (dd, J=5.6, 1.6 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.78 (s, 1H), 7.71-7.68 (m, 1H), 7.62-7.58 (m, 3H), 7.24 (d, J=8.4 Hz, 1H), 5.28 (s, 1H), 3.47 (s, 3H), 3.42 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.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.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9](/[CH:56]=[C:51]1\[S:52][C:53]([CH3:55])=[N:54][N:50]\1[CH2:46][CH2:47][CH2:48][CH3:49])=[O:11]
Reactant: O=C(O)CC1CC2CCC1C2
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)CC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3H) 0.98-1.18 (m, 4 H) 1.23-1.49 (m, 6 H) 1.62-1.73 (m, 2 H) 1.80-1.88 (m, 1 H) 1.89-1.95 (m, 1 H) 2.11-2.19 (m, 2 H) 2.23-2.31 (m, 1 H) 2.38-2.43 (m, 3 H) 4.02 (t, 2 H) 5.86-5.92 (m, 1 H); MS (ESI) m/z 307 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:11]Br)[CH2:8][O:7]C(C)(C)[O:5][CH2:4]1.C(=O)(O)[O-].[Na+].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[OH:7][CH2:8][C:3]1([CH2:4][OH:5])[CH2:2][N:25]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]1
Reactant: NCc1ccccc1
Reactant: CC1(C)OCC(CBr)(CBr)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: OCC1(CO)CN(Cc2ccccc2)C1
Temperature: 135 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30.2 g of 5,5-bis(bromomethyl)-2,2-dimethyl-1,3-dioxane (0.1 mol), 24.0 g of sodium bicarbonate and 50 ml of dimethyl sulfoxide was heated to 135° C. A solution of 10.7 g of benzylamine in 50 ml of DMSO was then added dropwise with stirring over 1.5 hours. After addition was complete, the mixture was stirred for 2.5 hours at 135° C. After cooling, 100 ml of DMSO and 20 ml of water were added and the solution was extracted with pentane. The extract was washed with water and then shaken with 5% (w/w) sulfuric acid in order to extract the basic 3,3-bis(hydroxymethyl)-1-benzylazetidine acetone acetal.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:40]>C(OCC)(=O)C>[ClH:40].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:19]=2)[CH2:21][C:22]([C:33]([F:38])([F:39])[C:34]([F:36])([F:37])[F:35])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(C3=CCNCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[2-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-pyridin-4-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (350.0 mg, 4.2 mmol) prepared in Example 187 was added to a saturated solution of hydrochloric acid in ethyl acetate (10.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 300.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](O)=[O:9])=[O:4].O1CCCC1.CO>C(OCC)(=O)C>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(CO)cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
3-(Methoxycarbonyl)-5-nitrobenzoic acid (20.0 g, 88.9 mmol) was combined with tetrahydrofuran (150 mL) and cooled to 0° C. To this solution was added a 1 M borane tetrahydrofuran complex (178 mL, 178 mmol) cautiously over 15 min and the reaction mixture allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol and concentrated in vacuo to afford to afford a precipitate which was dissolved in ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 18.2 g (97%) which was used without further purification. 1H-NMR (CDCl3, 300 MHz) δ 8.70 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 4.84 (s, 2H), 3.95 (s, 3H). Mass spec.: 212.06 (MH)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[SH:26]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][S:26][C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Sc1cccs1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CSc2cccs2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and thiophene-2-thiol. m/e+ 351 for C20H19N2S2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.53 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.29 (dd, J=1.1, 5.1 Hz, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz, 1H), 6.95 (dd, J=1.1, 3.6 Hz, 1H), 6.87 (dd, J=3.6, 5.5 Hz, 1H), 4.40 (s, 2H), 2.37 (s, 3H), 2.33 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 145.528, 144.436, 137.718, 135.777, 132.167, 131.485, 131.098, 129.437, 128.391, 128.057, 127.944, 122.074, 121.711, 117.032, 114.621, 33.849, 21.527, 18.699 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([N:9]1[CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:12][CH2:11][N:10]1C(OCC1C=CC=CC=1)=O)=[O:8])=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][C:7]([N:9]1[CH:14]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:12][CH2:11][NH:10]1)=[O:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(=O)N1C(C(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(=O)N1NCCCC1C(=O)OC(C)(C)C
Yield: 96.6 %

Procedure:
A solution of 25.3g of 1-benzyl 3-tert.butyl 2-(2-ethoxycarbonylacetyl)hexahydropyridazine-1,3-dicarboxylate in 500 ml of methanol was hydrogenated over 2.3g of 10% palladium/carbon at room temperature and under atmospheric pressure. The catalyst was removed by filtration. Evaporation of the filtrate and recrystallization of the residue from hexane gave 16.9 g (97%) of tert.butyl 2-(2-ethoxycarbonylacetyl)hexahydropyridazine-3-carboxylate having a melting point of 86°-87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].Cl[C:13]([C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=O>>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:11][C:3]3[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=3[N:1]=2)=[CH:33][CH:32]=1)[CH3:31])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: CN(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Product: CN(Cc1ccc(-c2nc3cccc(C(=O)O)c3o2)cc1)C(=O)OCc1ccccc1

Procedure:
2-(4-(((Benzyloxycarbonyl)(methyl)amino)methyl)phenyl)benzo[d]oxazole-7-carboxylic acid is prepared from 3-aminosalicylic acid and benzyl 4-(chlorocarbonyl)benzyl(methyl)carbamate using identical conditions described in Example 3A. MS (ESI) m/e 417 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].S([O-])(O)=O.[Na+].[Br:16]([O-])(=O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.O.CCOCC>[Br:16][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(CO)c1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: COc1cc(CO)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of 5.00 g of 3-methoxybenzyl alcohol in MeCN-water (180 ml, 1:1) was added 8.60 g sodium hydrogen sulfite and 8.19 g of sodium bromate and the reaction mixture was stirred at room temperature for two hours. After the reaction, an aqueous solution of 10% sodium thiosulfate and Et2O were added, and liquid separation was performed. After the organic layer was sequentially washed with 5% K2CO3, water and saturated brine, and dried over MgSO4, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/4; v/v) to obtain 5.02 g of the title compound (colorless solid).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]3[NH:35][C:36]([C:38]([O:40]C)=[O:39])=[N:37][C:33]=3[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]3[NH:35][C:36]([C:38]([OH:40])=[O:39])=[N:37][C:33]=3[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3[nH]c(C(=O)O)nc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A solution of chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-1H-benzo[d]imidazole-2-carboxylate (84.4 mg, mmol) in THF (6 ml) was reacted with LITHIUM HYDROXIDE MONOHYDRATE (22.9 mg, 0.545 mmol) in water (3 ml) and stirred at rt overnight. The reaction mixture was treated with 1 N HCl (0.37 ml, pH 3-4) and extracted with ethyl acetate. The organic extract was washed with water and brine, dried with sodium sulfate, filtered and lyophilized to give chiral-5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-1H-benzo[d]imidazole-2-carboxylic acid (36 mg, 43.6%) a white solid, MS (ES+) m/z Calcd: [(M+H)+]: 626.15. found: 626.0.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:28])[C@@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[CH:2]([CH3:3])[CH3:1]
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)C(O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4S)-2-methyl-4-(trityl-amino)-hexan-3-ol (0.36 g, 1 eq, 0.97 mmol) in DCM (20 mL) under an argon atmosphere at room temperature, was added CF3COOH (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated from Et2O (10 mL) with hexane (90 mL) with stirring to give a yellow oil. The solvent was decanted from the oil, and the oil was washed with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil. Yield: 0.13 g (100%). (50% de 3R,4S: 50% de 3S,4S) 1H-NMR (d6-DMSO, 250 MHz): δ 0.85-1.01 (m, 9H, NH2CH (CH2CH3)CH(CH(CH3)2OH), 1.44-1.76 (m, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 2.94 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.17 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.40 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 7.54 (bs, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[C:12]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C>[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[C:12]1([C:17]([Cl:3])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1csc(C2(C(=O)O)CCCC2)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1csc(C2(C(=O)Cl)CCCC2)c1Cl
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
DMF (a catalytic amount) was added to a thionyl chloride (15 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarboxylic acid (1.59 g), followed by stirring at 75° C. for 30 minutes. The reaction solution was subjected to evaporation under reduced pressure to obtain 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbonyl chloride. A THF (20 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbonyl chloride was added dropwise to a THF (20 ml) solution of hydrazine monohydrate (12.6 ml) at 0° C., followed by stirring at 0° C. for 3 hours. After the reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated. The organic layer washed with brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure to obtain 1.65 g of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbohydrazide (pale yellow solid).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl.CO>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C(=O)OC(C)(C)C)CC4)cc2)n1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 34) (159 mg, 0.40 mmol) in dichloromethane (12 ml) was added trifluoroacetic acid (6 ml). The resulting mixture was stirred at room temperature for 30 minutes and then diluted with methanol. Reaction was purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and the solvent evaporated in vacuo to afford the title compound (D35). MS (ES+) m/e 296 [M+H]+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Br[C:11]([F:23])([CH:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.O>CN(C=O)C.CCOC(C)=O>[F:23][C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]2[CH:17]1[CH2:21][CH2:20][C:19]2=[O:22]
Reactant: CCOC(=O)C(F)(Br)C1CCC(=O)C1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(F)C2CCC(=O)C21
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Add 13.0 mL (75.0 mmol) of ethyldiisopropylamine to a solution of 2.0 g (7.5 mmol) of ethyl 2-bromo-2-fluoro-2-(3-oxocyclopentyl)acetate (Preparation 57) in DMF (8 mL), at 0° C., and stir the mixture overnight at room temperature. Add a solution of HCl 1N (20 mL), water (15 mL), and EtOAc (75 mL). Extract the organic layer, wash with saturated NaHCO3 (2×100 mL), water (2×100 mL), and brine (2×100 mL), dry over anhydrous MgSO4, filter and concentrate under reduced pressure. Purify the residue by column chromatography using EtOAc/hexane (1:4) as eluent to give the title compound (1.17 g, 84% yield) as a mixture trans:cis 5:1 of isomers as a colorless oil.