Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C@H:3]([OH:30])[C@H:4]2[CH2:29][C@@:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[N:13](S(C5C=CC(C)=CC=5)(=O)=O)[N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2.Cl[C:32]1[C@H](O)[C@H]2C[C@@]3(C=1C1C=CC4C(=CN(S(C5C=CC(C)=CC=5)(=O)=O)N=4)C=1C3)CC2.S([O-])([O-])(=O)=O.[Ca+2].[OH-].[Na+]>CI.ClCCl.[Ag-]=O>[Cl:1][C:2]1[C@H:3]([O:30][CH3:32])[C@H:4]2[CH2:29][C@@:7]3([C:18]=1[C:17]1[CH:16]=[CH:15][C:14]4[NH:13][N:12]=[CH:11][C:10]=4[C:9]=1[CH2:8]3)[CH2:6][CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c4c(ccc32)C2=C(Cl)[C@H](O)[C@@H]3CC[C@@]2(C4)C3)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(ccc3n2)C2=C(Cl)[C@H](O)[C@@H]3CC[C@@]2(C4)C3)cc1
Agent: O=[Ag-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CI
Product: CO[C@H]1C(Cl)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (7R,8R,10aS)-6-chloro-3-[(4-methylphenyl)sulfonyl]-3,7,8,9,10,11-hexahydro-8,10a-methanoazuleno[2,1-e]indazol-7-ol and (7R,8R,10aS)-6-chloro-2-[(4-methylphenyl)sulfonyl]-2,7,8,9,10,11-hexahydro-8,10a-methanoazuleno[2,1-e]indazol-7-ol prepared as described in Step 2 (0.040 g, 0.091 mmol) was dissolved in methyl iodide (2 mL) and silver(I) oxide (0.080 g, 0.35 mmol) and calcium sulfate (0.080 g, 0.59 mmol) were added. The mixture was stirred at room temperature for two days. The reaction mixture was diluted with dichloromethane and filtered through a pad of silica gel, rinsing with EtOAc. The solvent was evaporated under reduced pressure and the residue was dissolved in ethanol (2 mL) and treated with 1N aqueous sodium hydroxide (0.30 mL, 0.30 mmol). After 2 hours, the reaction mixture was diluted with dichloromethane and dried over MgSO4. The solution was filtered through a pad of silica gel and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (elution with 1:1 EtOAc/hexanes) to yield (7R,8R,10aS)-6-chloro-7-methoxy-3,7,8,9,10,11-hexahydro-8,10a-methanoazuleno[2,1-e]indazole.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][S:9]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCSc2cc(Br)ccc21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c(c1)SCCC2
Yield: 100.4 %

Procedure:
A solution of 7-bromo-2,3-dihydro-4H-thiochromen-4-one (1 g) in trifluoroacetic acid (12 ml) was treated with triethylsilane (1.48 ml) and the mixture was stirred at reflux for 4 h. Water was added and the mixture extracted with ethyl acetate. The organic solution was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on a Biotage cartridge (40 g) eluting with petrol-diethyl ether (10:1) to give the title compound (946 mg). LCMS RT=3.71 min
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[CH2:11][CH:10]=[CH:9]2)([CH3:3])[CH3:2].[Br:13]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.C(OCC)C.O>[CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[CH2:11][C:10]([Br:13])=[CH:9]2)([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cccc2c1CC=C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cccc2c1CC(Br)=C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Using a 200 ml Erlenmeyer flask as the reactor, 7.00 g (44.20 millimoles) of 7-isopropylindene was dissolved in a mixed solvent of 0.91 g (106.08 millimoles) of distilled water and 60 ml of dimethyl sulfoxide. To this reaction solution there was added 9.44 g (53.03 millimoles) of N-bromosuccinimide while cooling on ice, and the mixture was then stirred for one hour at room temperature. After hydrolysis with distilled water while cooling on ice, extraction was performed several times with diethyl ether, and the extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtration of the magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained product was transferred to a 200 ml Erlenmeyer flask and dissolved in 70 ml of toluene. To this solution there was added 0.84 g (4.42 millimoles) of p-toluenesulfonic acid hydrate, and the mixture was heated to reflux for 4 hours. After reflux, hydrolysis was performed with distilled water while cooling on ice, and extraction was performed several times with diethyl ether. The extract was washed once with a saturated sodium bicarbonate aqueous solution, washed once with saturated saline, and then dried over anhydrous magnesium sulfate. After drying, the magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, and purification was performed with a silica gel column to obtain 10.2 g of 7-isopropyl-2-bromo-indene as a reddish brown oil (97% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.C[O:27][C:28]([C@H:30]1[CH2:34][C@H:33]([N:35]2[CH:39]=[C:38](I)[CH:37]=[N:36]2)[CH2:32][N:31]1C(OCC1C=CC=CC=1)=O)=[O:29].[F-].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:38]2[CH:37]=[N:36][N:35]([C@@H:33]3[CH2:32][NH:31][C@@H:30]([C:28]([OH:29])=[O:27])[CH2:34]3)[CH:39]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: COC(=O)[C@H]1C[C@H](n2cc(I)cn2)CN1C(=O)OCc1ccccc1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn([C@@H]3CN[C@@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Temperature: 60 °C

Procedure:
A mixture of 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (151 mg, 0.428 mmol), (2R,4S)-4-(4-iodopyrazol-1-yl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (177 mg, 0.389 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), potass fluoride (67.8 mg, 1.17 mmol), and 4:1 dioxane:water (4 mL) was heated in the microwave reactor at 85° C. for 30 min. The solution was dry-loaded onto silica gel for column chromatography, eluting with 2→5% MeOH/DCM. The fractions containing the product were concentrated in vacuo and dissolved in conc. HCl. The material was heated to 60° C. for 3 h in a sealed tube. The solvent was removed on the corrosive pump to afford the title compound as an orange solid. 1H NMR (400 MHz, CD3OD): δ=2.55-2.67 (m, 1H), 2.74 (br. s., 1H), 3.76-3.87 (m, 2H), 4.45 (t, J=8.6 Hz, 1H), 5.25 (dd, J=6.1, 3.0 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.49-7.55 (m, 1H), 7.88 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[CH3:55][N:56]1[CH2:61][CH2:60][N:59]([C:62]2[CH:63]=[C:64]([OH:68])[CH:65]=[CH:66][CH:67]=2)[CH2:58][CH2:57]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:68][C:64]3[CH:65]=[CH:66][CH:67]=[C:62]([N:59]4[CH2:58][CH2:57][N:56]([CH3:55])[CH2:61][CH2:60]4)[CH:63]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: CN1CCN(c2cccc(O)c2)CC1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2)CC1

Procedure:
The title compound 87 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 87A: 1H NMR (DMSO-d6): δ 12.85 (s, 1H), 9.65 (s, 1H), 8.03 (d, J=7.67 Hz, 1H), 7.79 (d, J=7.98 Hz, 2H), 7.67 (d, J=7.67 Hz, 1H), 7.34-7.50 (m, 4H), 7.12 (t, J=8.13 Hz, 1H), 6.54 (dd, J=8.13, 2.3 Hz, 1H), 6.50 (t, J=2.15 Hz, 1H), 6.42 (dd, J=8.29, 2.15 Hz, 1H), 4.83 (s, 2H), 3.96 (t, J=6.29 Hz, 2H), 3.73 (t, J=5.83 Hz, 2H), 3.10-3.18 (m, 5H), 3.03 (t, J=5.98 Hz, 2H), 2.90-2.98 (m, 2H), 2.85 (s, 3H), 1.95-2.02 (m, 2H). ESI (+)/MS: 669 M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:8])([F:7])[CH2:4][O:5][NH2:6].[C:9]([CH:12]1[CH2:15][N:14]([C:16](=[O:30])/[CH:17]=[CH:18]/[C:19]2[CH:20]=[C:21]3[C:26](=[N:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]3)[CH2:13]1)(=O)[CH3:10]>CO>[O:30]=[C:16]([N:14]1[CH2:15][CH:12](/[C:9](=[N:6]\[O:5][CH2:4][C:3]([F:8])([F:7])[F:2])/[CH3:10])[CH2:13]1)/[CH:17]=[CH:18]/[C:19]1[CH:20]=[C:21]2[C:26](=[N:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2
Reactant: NOCC(F)(F)F
Reactant: CC(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Agent: Cl
Solvent: CO
Product: C/C(=N/OCC(F)(F)F)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
2,2,2-Trifluoroethoxyamine hydrochloride (37 mg, 0.24 mmol) was added to a solution of (E)-6-(3-(3-acetylazetidin-1-yl)-3-oxoprop-1-enyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (50 mg, 0.16 mmol) in methanol (4 mL). The reaction mixture was stirred at room temperature for 3 hours. After concentration to dryness the residue was diluted by addition of dichloromethane (50 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (1×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (95:5) as eluent to obtain the title product as a white solid (47 mg, 50%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][CH2:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[OH:29])=O)=[CH:17][CH:16]=1.O.CCCCCC>ClC1C=CC=CC=1Cl>[Cl:13][CH2:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]2[O:29][C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[N:21]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(O)c(NC(=O)c2ccc(CCl)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1ccc2oc(-c3ccc(CCl)cc3)nc2c1
Temperature: 175 °C

Procedure:
With stirring, 5 g (26.3 mmol) of p-toluenesulphonic acid monohydrate were added to 116 g (about 406 mmol) of 4-(chloromethyl)-N-(2-hydroxy-5-methylphenyl)benzamide in 700 ml of 1,2-dichlor-obenzene. The reaction solution was then heated to 175° C. (oil bath temperature) and stirred at this temperature on a water separator for 3 hours. The reaction solution was then cooled to room temperature, 200 ml of hexane were added and the mixture was stirred for about 1 hour. The precipitated solid was filtered off, washed with hexane and air-dried. This gave 56 g (217.29 mmol, 53% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>FC(F)(F)C(O)=O.C(O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOCc1nc2c(N)nc3c(c2n1CC1(O)CCCC1)CCCC3
Temperature: 60 °C
Reaction time: 120 h

Procedure:
A mixture of 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (prepared as described in Example 3, 0.50 g, 1.47 mmol) and platinum (IV) oxide (0.25 g) in trifluoroacetic acid (20 mL) was hydrogenated at 50 psi (3.5×105 Pa) for 5 d on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent and the filtrate was treated with saturated aqueous NaOH until the pH=14, then was extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to an oil that was purified by flash chromatography (silica gel, 10% methanol in dichloromethane). The appropriate fractions were combined and concentrated to yield a colorless oil. The oil was dissolved in ethanol and 2.7 M HCl in ethanol (1 mL) was added and the mixture was concentrated under reduced pressure. The resulting oil was dissolved in water and Na2CO3 was added until the pH=12. A gummy white solid formed and the mixture was heated at 60° C. for 20 min until a free flowing precipitate formed. The mixture was allowed to cool to rt and the precipitate was isolated by filtration and dried in a vacuum oven at 80° C. to provide 1-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol as a white solid, mp 171-173° C. 1H NMR (300 MHz, DMSO-d6) δ 5.78 (br s, 2H), 4.77 (br s, 2H), 4.66 (s, 1H), 4.45 (br s, 2H), 3.46 (q, J=7.0 Hz, 2H), 2.95 (m, 2H), 2.66 (m, 2H), 1.82-1.36 (m, 12H), 1.11 (t, J=7.0 Hz, 3H); MS (ESI) m/z 345 (M+H)+; Anal. Calcd for C19H28N4O20.2 H2O: C, 65.57; H, 8.22; N, 16.10. Found: C, 65.78; H, 8.27; N, 15.70.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[C:22]([F:25])[CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(F)ccc(F)c21
Product: CC1c2c(F)ccc(F)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5,8-Difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:28][C:29]([NH2:31])=[O:30].[N-:36]=[N+:37]=[N-:38].[Na+].CCCCCC>CN(C)C=O>[N:36]([CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[N:10]=[CH:9][C:8]([CH2:28][C:29]([NH2:31])=[O:30])=[C:7]([NH:6][CH2:5][C:4]3[CH:32]=[C:33]([F:35])[CH:34]=[C:2]([F:1])[CH:3]=3)[CH:12]=2)=[CH:19][CH:18]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCCc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: [N-]=[N+]=NCCCc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
268 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(3-methanesulfonyloxypropyl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 199) was dissolved in 1.5 mL of N,N-dimethylformamide, to which 71 mg of sodium azide was added and stirred at 80° C. for 30 minutes. After cooling, hexane was added to the reaction mixture, and the deposit was filtered. The filtered product was dissolved in chloroform, washed with water and saturated saline, and dried on anhydrous sodium sulfate. By evaporating the solvent, 229 mg (94%) of the title compound was obtained as a slight yellow crystalline powder.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@H:36]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[C:47]([NH:55][C:56](=[O:75])[C@@H:57]2[CH2:61][C@@H:60]([NH:62][C:63](=[O:74])[C@H:64]([OH:73])[CH2:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:59][NH:58]2)[CH:46]=1>ClCCl.C(N(CC)CC)C>[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[C:47]([NH:55][C:56](=[O:75])[C@@H:57]2[CH2:61][C@@H:60]([NH:62][C:63](=[O:74])[C@H:64]([OH:73])[CH2:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH2:59][N:58]2[C:32](=[O:34])[C@@H:31]2[CH2:35][C@@H:36]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:29])[CH:46]=1
Reactant: CN(C)CC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Triethylamine (33 μL), 1-hydroxybenzotriazole (30 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg) were added to a suspension of the crude N-tert-butoxycarbonyl-trans-4-(N,N-dimethylglycylamino)-L-proline (B) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 84 mg) in dichloromethane (5 mL) at 0° C. After stirring at 0° C. for 30 min and at room temperature for 14 hr, the solvent was removed in vacuo. The residue was diluted with saturated sodium hydrogen carbonate and extracted with chloroform-methanol (10:1,v/v). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (Whatman, PLK5F Silica Gel 150, chloroform:methanol=10:1, v/v) to afford the title compound (76 mg) as a colorless glassy solid: mass spectrum (EI+) m/e 715 (M+); (FAB+) m/e 716 (M+1).
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CN1CCN(c2ccccc2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(c2ccccc2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 28.7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-phenylpiperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 225, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-phenylpiperazin-1-yl)acetamido)propanamide (13.4 mg, 28.7%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.02 (s, 1H), 7.60 (d, 2H), 7.28-7.29 (m, 4H), 7.19-7.26 (m, 5H), 6.99-7.04 (m, 4H), 6.92 (d, 2H), 6.78 (t, 1H), 4.71 (m, 1H), 4.52 (s, 2H), 3.76 (m, 2H), 3.13 (m, 4H), 3.07 (s, 2H), 2.63 (m, 4H). MS (EI) for C34H35FN4O4. found 583.6 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15]Br)[CH:5]=1.CC([O-])=[O:20].[K+].CO.C[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][OH:20])[CH:5]=1
Reactant: COC(=O)c1cccc(-c2ncsc2CBr)c1
Reactant: CC(=O)[O-]
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cccc(-c2ncsc2CO)c1
Reaction time: 0.5 h

Procedure:
3-(5-Bromomethyl-thiazol-4-yl)-benzoic acid methyl ester was stirred in DMF (10 mL) together with KOAc (1.52 g) at 20° C. for 30 min. MeOH (20 mL) and NaOMe (0.84 g) were added and stirring was continued at 50° C. for 30 min. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt/hexane (1:2) as eluent to give 3-(5-hydroxymethyl-thiazol-4-yl)-benzoic acid methyl ester (1.43 g) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[CH:17]([O:20][CH3:21])[O:18][CH3:19])[NH:13][CH2:12][CH2:11][CH2:10]3)[CH2:3][CH2:2]1.[H][H]>C1COCC1.CO.[Pd]>[CH3:21][O:20][CH:17]([O:18][CH3:19])[C:16]1[N:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][NH:13]2)=[CH:8][C:7]=1[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: COC(OC)c1nc2c(cc1C1=CCOCC1)CCCN2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1C1CCOCC1)CCCN2
Temperature: 25 °C
Reaction time: 56 h

Procedure:
A suspension of 10% Pd on carbon (0.34 g) in a solution of 6-(3,6-dihydro-2H-pyran-4-yl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 313, 0.94 g, 3.24 mmol) in THF (60 ml) and MeOH (20 ml) was stirred under an atmosphere of hydrogen at room temperature for 56 h, at which point 1 equivalent of hydrogen had been consumed. The reaction mixture was flushed with argon, filtered and evaporated to give the title compound as a beige solid. (UPLC-MS 3) tR 0.54 min; ESI-MS 293.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])=[CH:5][C@H:6]1[CH2:10][NH:9][C:8](=[O:11])[CH2:7]1.[CH3:13][O:14][C:15](=[O:21])[C:16](C)(Br)[CH2:17][CH3:18]>O1CCCC1.O>[CH3:13][O:14][C:15](=[O:21])[CH:16]([N:9]1[CH2:10][C@H:6]([CH:5]=[C:4]([F:12])[F:3])[CH2:7][C:8]1=[O:11])[CH2:17][CH3:18]
Reactant: CCC(C)(Br)C(=O)OC
Reactant: O=C1C[C@@H](C=C(F)F)CN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(=O)OC)N1C[C@H](C=C(F)F)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A slurry of 60% sodium hydride suspension in mineral oil (0.80 g, 20.4 mmol) in tetrahydrofuran (28 mL) is cooled at 0° C. under a nitrogen atmosphere. A solution of substantially optically pure (S)-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one (IIIb) (2 g, 13.6 mmol) in tetrahydrofuran (8 mL) is added over a 30 minutes period. The reaction mixture is stirred 10 minutes at 0° C. then a solution of 2-bromo-butyric acid methyl ester (V) (3.20 g, 17.6 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred at 0° C. for 4.5 h then the reaction mixture is allowed to warm to room temperature and diluted with water (15 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (2×10 mL). The combined organic layers are dried over anhydrous magnesium sulfate and evaporated to afford 3 g (12.1 mmol, 89%) of compound (VIb), as a mixture respectively of epimer (VIba) and epimer (VIbb).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11](B(O)O)=[CH:12][C:3]1=2.Br[C:18]1[CH:22]=[C:21]([CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[O:20][CH:19]=1>>[CH2:28]([O:27][CH:23]([O:24][CH2:25][CH3:26])[C:21]1[O:20][CH:19]=[C:18]([C:11]2[CH:10]=[CH:9][C:4]3[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:16])([CH3:1])[C:3]=3[CH:12]=2)[CH:22]=1)[CH3:29]
Reactant: CCOC(OCC)c1cc(Br)co1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CCOC(OCC)c1cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)co1

Procedure:
Prepared according to procedure B from 4,4-dimethyl 2 oxo -1,4-dihydro 2H-benzo[d][1,3]oxazine-6-boronic acid and 3-bromo-5-diethoxymehyl furan. A brown gum: 1H NMR (DMSO-d6) δ10.2 (s, 1H), 8.12(s, 1H), 7.54-7.49 (m, 2H), 6.93-6.88(m, 2H), 5.56(s, 1H), 3.60-3.38(m, 4H), 1.67(s ,6H), 1.2-1.14 (m, 6H). .MS (ESI) m/z 344 [M−H]−. Anal. Calcd. For C19H23NO51/2 H2O: C, 64.39; H, 6.77; N, 3.95. Found C, 64.90; H, 6.79; N, 3.78.