Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C@@:6](CCC1C=CC=CC=1)([O:18][C:19](=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([O-:5])=[O:4]>C(O)(=O)C.[Zn]>[C:19]([O:18][C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][C:3]([OH:5])=[O:4])(=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCC[C@](CCc1ccccc1)(OC(=O)CCCCCCCCC)C(=O)C(=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Yield: 87 %

Procedure:
Ester 39 (10.15 g, 20.77 mmol) was dissolved in acetic acid (100 mL). Zinc (15.5 g, 237 mmol) was added, and the mixture heated to reflux for 4 h. The acetic acid was removed under vacuum and the residue azeotroped with toluene to dryness. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 60% ethyl acetate/hexanes over 50 min, 85 mL/min) to give the product 40 (7.2 g, 89%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 5.23-5.19 (m, 1H), 2.62-2.55 (m, 2H), 2.34-2.25 (m, 2H), 1.65-1.58 (m, 2H), 1.28-1.20 (m, 32H), 0.85 (m, 6H).
Reaction SMILES: [CH3:1][N:2]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)C(=O)C.Cl>CO>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([NH:2][CH3:1])[CH2:11][CH2:10]2)=[CH:22][CH:21]=1
Reactant: CC(=O)N(C)C1CCN(CCCCOc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Product: CNC1CCN(CCCCOc2ccc(F)cc2)CC1

Procedure:
0.05 mole of the compound obtained in stage D is refluxed for 12 hours in the presence of 570 cm3 of methanol and 340 cm3 of 5N hydrochloric acid. The methanol is evaporated and the mixture is poured into ice and then basified with sodium hydroxide. It is extracted with ether.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:17])=[N:4][C:5]([NH:15][NH2:16])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.BrC1C2N([C:33](=[O:36])NN=2)C(C)=CC=1C1C=CC(Cl)=CC=1>>[Br:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:6][C:5]2[N:4]([C:33](=[O:36])[NH:16][N:15]=2)[C:3]=1[CH3:17]
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Reactant: Cc1nc(NN)cc(-c2ccc(Cl)cc2)c1Br
Product: Cc1c(Br)c(-c2ccc(Cl)cc2)cc2n[nH]c(=O)n12
Yield: 96 %

Procedure:
The title compound (125 mg, 96% yield) as a pale yellow solid was prepared from 3-bromo-4-(4-chlorophenyl)-6-hydrazinyl-2-methylpyridine (120 mg, 0.384 mmol) by procedures analogous to those used for the preparation of 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. HPLC/MS: retention time=3.65 min, [M+H]+=338.2.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:12])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CO
Reactant: O=[N+]([O-])c1c(O)cccc1F
Product: COc1cccc(F)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 76, Step 5, using 3-fluoro-2-nitrophenol [Combi-Blocks, OR-7136] and methanol as the starting materials.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:24])([F:23])[C:8]([N:10]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]3[C:17]=2[C:12](=[CH:13][CH:14]=[CH:15]3)[CH2:11]1)=[O:9]>C(Cl)(Cl)Cl>[F:24][C:7]([F:6])([F:23])[C:8]([N:10]1[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:16]3[C:17]=2[C:18](=[CH:20][CH:21]=[CH:22]3)[CH2:19]1)=[O:9]
Reactant: O=C(N1Cc2cccc3cccc(c23)C1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=C(N1Cc2cccc3c(S(=O)(=O)Cl)ccc(c23)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chlorosulfonic acid (40 mmol) is added dropwise to a cold (0° C.) solution of 2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (8 mmol) in chloroform (800 mL). The resulting solution is stirred at 0° C. for 30 minutes. The cold bath is then removed and the solution is stirred at room temperature for 1 hour then cautiously poured into ice-water. The organic layer is separated, dried over magnesium sulfate and concentrated to afford the title compound. The crude product can be purified by recrystallization or chromatography.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:28])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:28][C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:29])[C@H:18]3[CH3:30])=[CH:15][C:14]=1[NH:13][C:10]1([CH3:12])[CH2:9][NH:8][CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CNC4)cc3N21
Yield: 101.2 %

Procedure:
A solution of 3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (Example #148, Step G, 5 g, 10.4 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at ambient temperature for 3 h. The solvent was removed in vacuo to give (R)-7-bromo-4-methyl-6-(3-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.19 (s, 1H), 5.83 (s, 1H), 5.55 (s, 1H), 4.91 (q, J=6.4 Hz, 1H), 4.51 (s, 2H), 4.05 (m, 4H), 1.55 (s, 3H), 1.25 (d, J=6.4 Hz, 3H). LC/MS (Table 1, Method 6) Rt=0.656 min.; MS m/z: 380 [M+H]+ and 382 [M+H+2]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C@@H:16]12[C:25](=[O:26])[O:24][C:22](=[O:23])[C@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21]2>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:25]([C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([OH:24])=[O:23])=[O:26])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(O)[C@@H]1CCCC[C@H]1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Using, as starting materials, 2.3 g of 3,5-bistrifluoromethyl aniline, and 1.5 g (0.01 mole) of trans-cyclohexane-1,2-dicarboxylic anhydride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[C:27]([OH:42])[CH:26]=1)(=O)C.C[O-].[Na+]>CO>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[C:27]([OH:42])[CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cc(O)cc3occ(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](Oc2cc(O)cc3occ(CCc4ccccc4)c23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6-hydroxy-3-(2-phenylethyl)benzofuran (45 mg) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 0.015 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under deduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (28 mg).
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:30]C)=[CH:27][C:28]=5[CH3:29])[CH:20]=[C:19]([CH3:32])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl>O1CCOCC1>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH3:32])[CH:20]=[C:21]([C:23]5[C:28]([CH3:29])=[CH:27][C:26](=[O:30])[NH:25][CH:24]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1cc(C)c(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2c[nH]c(=O)cc2C)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 19.2 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,4′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (38 mg, 0.083 mmol) in 1,4-dioxane (1.5 mL) was added aqueous 4 M HCl (225 μL, 0.899 mmol) drop-wise. The reaction was stirred at 90° C. for 1.5 hours. The reaction was allowed to cool down to room temperature and then quenched with Et3N. The solvent was evaporated under reduced pressure. The crude compound was dissolved in ethyl acetate and washed with water (2×) and brine (1×). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethans) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a white solid (7 mg, 19%). ESI-MS m/z calc. 439.41. found 440.5 (M+1)+. Retention time 1.60 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:47]([CH3:48])[N:46]=[CH:45][CH:44]=2)=[CH:38][C:37]=1[CH3:49]>>[CH3:42][C:41]1[CH:40]=[C:39]([C:43]2[N:47]([CH3:48])[N:46]=[CH:45][CH:44]=2)[CH:38]=[C:37]([CH3:49])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(-c2ccnn2C)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccnn6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 5-(4-bromo-3,5-dimethylphenyl)-1-methyl-1H-pyrazole following a procedure analogous to that described in Step 2 of Intermediate 17. Mass spectrum (ESI+): m/z=527 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]1([C@@H:17]2[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][C:20](=[O:30])[O:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]I.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1.CCOC(C)=O>[C:26]([O:25][C:23]([N:22]1[C@@H:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:18]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:19][C:20](=[O:30])[C@@H:21]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][Cl:37])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reactant: ClCCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](CCCCCCl)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.0M solution of sodium bis(trimethylsilyl)amide in THF (55.0 mL, 55.2 mmol) is added at −78° C. to a solution of (5S,6R)-5,6-diphenyl-4-tert-butoxycarbonyl-morpholin-2-one (13.0 g, 36.8 mmol), 1-chloro-5-iodo-pentane (25.0 g, 108.0 mmol) and HMPA (55.0 mL) in THF (200.0 mL). The reaction mixture is stirred at −78° C. for 2 hours and at room temperature for 1 hour. The reaction mixture is diluted with EtOAc, washed with water and brine. After drying the organic phase over anhydrous Na2SO4, the solvent is removed under reduced pressure to afford the crude product that is purified by silica gel column chromatography to afford the title compound; m/z 358 [M-Boc+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12](I)[CH:13]=[C:8]2[N:7]=1)[CH3:2].[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH2:1]([O:3][C:4](=[O:35])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:19]([O:33][CH3:34])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([C:40]3[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=3)[CH:13]=[C:8]2[N:7]=1)[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1nc2cc(-c3cnn(C)c3)cnc2n1Cc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (11.80 g, 20.05 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.00 g, 24.03 mmol) in N,N-dimethylformamide (100 mL) and 2M aqueous sodium carbonate solution (10 mL) was added (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.87 g, 1.19 mmol). The resulting mixture was heated to 80° C. under a nitrogen atmosphere. After 4 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was diluted with water (150 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with water (300 mL) and brine (2×300 mL), dried over sodium sulfate, filtered, and concentrated. Chromatographic purification (silica gel, 5% methanol in dichloromethane elute) afforded 2.50 g (23%) of ethyl(3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a gray solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(I)cc2c(N2CCOCC2)c1S(C)(=O)=O
Yield: 80.6 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (1 g, 2.62 mmol), morpholine (274 mg, 3.1 mmol) and N,N-diisopropyl ethyl amine (406 mg, 3.1 mmol) were heated at 100° C. in dry N,N-dimethylformamide (10 mL) for 30 min. The reaction mixture was evaporated to dryness, and the residue extracted with dichloromethane, 10% Na2CO3 and sat. NaCl. The crude product was purified by chromatography on silica gel in dichloromethane/ethyl acetate 5:1. One obtained 913 mg (80%) of a yellow foam. MS: m/z=433 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14].C(O)(C(F)(F)F)=O>C(OC(C)=O)(C)C>[Cl:9][C:5]1[CH:6]=[C:7]([NH:8][CH:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cc(Cl)cnc1N
Reactant: CCC(=O)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: CCC(CC)Nc1cc(Cl)cnc1N
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 2,3-diamino-5-chloropyridine (7.0 g, 48.6 mmol, 1.0 equiv) and 3-pentanone (6.16 mL, 58.3 mmol, 1.2 equiv) in iPrOAc (100 mL) was added TFA (7.2 mL, 97.2 mmol, 2.0 equiv) by syringe. After stirring for 10 min, NaHB(OAc)3 (20 g, 97.2 mmol, 2.0 equiv) was added as a solid in several portions over ˜5 min. The reaction was allowed to stir overnight. The reaction mixture was then washed with satd. aq. NaHCO3 and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (10%-40% EtOAc/Hexanes) provided 5-chloro-N3-(pentan-3-yl)pyridine-2,3-diamine as a beige solid (2.6 g, 25%). m/z=214.1 [M+H]+
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35]CC)=[O:34])[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[S:26][CH2:25]1)[C:18]([O:20]CC)=[O:19])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C.[OH-].[Na+].O>[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([OH:35])=[O:34])[C:28]2[CH:38]=[CH:39][CH:40]=[CH:41][C:27]=2[S:26][CH2:25]1)[C:18]([OH:20])=[O:19])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(CCCCNC(=O)OCc2ccccc2)C(=O)OCC)CSc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)CSc2ccccc21
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Ethyl 3(R)-(5-benzyloxycarbonylamino-1-ethoxycarbonylpentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate hydrochloride (55 mg) obtained in Example 52-(1) is dissolved in a mixture of ethanol (3 ml) and 1N aqueous sodium hydroxide (2 ml). The solution is allowed to stand for 1 hour at room temperature, diluted with water (50 ml) and extracted with ethyl ether (20 ml). The aqueous layer is acidified to pH 4 with 1N hydrochloric acid, saturated with ammonium chloride and extracted ten times with ethyl acetate (20 ml each). The extract is washed with a small amount of water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to yield 3(R)-(5-benzyloxycarbonylamino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (40 mg) as colorless powder.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C(O)CCC>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]2)[CH:13]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccnc2)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2cccnc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(pyridin-3-yloxy)-cyclohexanecarboxylic acid methyl ester (0.141 g, 0.599 mmol) and hydrazine hydrate (0.029 ml, 0.59 mmol) in n-butanol (0.5 ml) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.061 g, 43%) as white solid, which was used in the next step without further purification. MS m/e: 236 (M+H+)
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[C@H:13]([C:25]([OH:27])=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:35]([O:34][C:33]([NH:32][CH2:31][CH2:30][O:29][NH:28][C:25]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][N:14]1[C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])=[O:17])=[O:27])=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: C[Si](C)(C)CCOC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)OCC[Si](C)(C)C
Yield: 53.6 %

Procedure:
(2S,5R)-5-(Benzyloxyamino)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidine-2-carboxylic acid (601 mg, 1.52 mmol) described in Example 101 and tert-butyl 2-(aminooxy)ethylcarbamate (303 mg, 1.72 mmol) of Reference Example 9 were dissolved in N,N-dimethylformamide (5.8 mL), to which was added 1-hydroxybenzotriazole.monohydrate (264 mg), followed by ice cooling. To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), a temperature was elevated to room temperature, followed by reaction for 5 h. Water was added to the reaction mixture and extracted with ethyl acetate. After the organic layer was washed with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and saturated brine sequentially, the organic layer was dehydrated over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 450 mg of the title compound (yield 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH2:28]([C:31]1[N:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1)[CH:29]=[CH2:30].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH2:28]([C:31]1[N:32]=[CH:33][C:34]([NH:37][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:35][CH:36]=1)[CH:29]=[CH2:30]
Reactant: C=CCc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CCc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 800.0 mg, 2.418 mmol) in methylene chloride (12 mL) cooled to 0° C. under nitrogen was treated with oxalyl chloride (0.64 mL, 7.336 mmol), followed by N,N-dimethylformamide (2 drops). The reaction mixture was stirred at 0° C. for 20 min and then stirred at 25° C. for 1.25 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in methylene chloride (12 mL), cooled to 0° C. under nitrogen, and then treated with a solution of 5-allyl-pyrazin-2-ylamine (0.37 g, 2.737 mmol) and pyridine (0.59 mL, 7.295 mmol) in methylene chloride (12 mL) over 1 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then at 25° C. for 1 h. The reaction mixture was then diluted with ethyl acetate and washed with a 1N aqueous hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH, 40L, Silica, 1/1 hexanes/ethyl acetate) afforded N-(5-allyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentylpropionamide (965 mg, 89.1%) as a white foam: LRMS for C22H26ClN3O3S (M−H)+ at m/z=446
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In a 20 mL vial were combined 4-fluoronitrobenzene (1.1 mL, 10 mmol), imidazole (0.68 g, 10 mmol), and sodium carbonate (1.1 g, 11 mmol) in dimethylformamide (5 mL). The mixture is shaken at 100° C. for 24 hours and then allowed to cool to room temperature and then diluted with water. Concentrated hydrochloric acid is added to bring the pH to 1, and then the mixture is extracted thrice with chloroform (10 mL). The acidic aqueous phase is then treated with 2.5 M sodium hydroxide solution to give a pH of 10. A light yellow solid is collected and washed with water to give 1-(4-nitrophenyl)-1H-imidazole.