Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH:8]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)N.[C:20]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=O)[CH3:21]>CO>[CH3:21][C:20]1[C:23]2([CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:16]([OH:19])(=[O:18])=[O:17])[CH:14]=2)[N:8]=1.[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(=O)C1CCOCC1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C12CCOCC2
Product: CC[NH+](CC)CC

Procedure:
9.8 ml of triethylamine was added to a solution of 6.59 of p-hydrazinobenzenesulfonic acid in 30 ml of methanol to obtain a homogeneous solution. Then, to the solution was added 4.49 g of 4-acetyltetrahydropyran and refluxed for 1 hour. The solvent was evaporated under reduced pressure, followed by adding 30 ml of acetic acid and refluxing for 30 hours. Acetic acid was evaporated under reduced pressure and 7.1 g of desired oily product was isolated by silica gel column chromatography.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](OCC)=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c(-c2ccccc2)nn1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1c(-c2ccccc2)c(-c2ccccc2)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
228 Grams of crude ethyl 1-benzyl-3,4-diphenylpyrazole-5-carboxylate (prepared as described below) dissolved in 3200 ml of anhydrous diethyl ether are added, at 0°C and under a nitrogen atmosphere, to 47 grams of lithium aluminium hydride suspended in 1600 ml of anhydrous diethyl ether. The solution is stirred overnight at ambient temperature and then cooled to 0° C, whereupon 55 ml of water, 20.2 ml of 10N soda and 83 ml of water are slowly and successively added under a nitrogen atmosphere, and the resulting precipitate is filtered. The filtrate is evaporated under reduced pressure and the residue is dissolved in 360 ml of di-isopropyl ether. 1 -Benzyl-3,4-diphenyl-5-hydroxymethylpyrazole melting at 138° C is thus obtained.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:53][C:54]1([F:58])[CH2:57][NH:56][CH2:55]1.CCN(C(C)C)C(C)C>C1COCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22]([N:56]4[CH2:57][C:54]([F:58])([F:53])[CH2:55]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:50])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 52, 80 mg, 0.106 mmol) in THF (5 mL) was added 3,3-difluoroazetidine hydrochloride (41.1 mg, 0.317 mmol) and DIEA (0.092 mL, 0.529 mmol). The reaction mixture was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with water and acetonitrile (10% to 100%), to give the title compound as a yellowish solid after lyophilization (72 mg, 88% yield). LCMS (M+H)+: 770.1. 1H NMR (CDCl3, 500 MHz): δ 8.35 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.79 (s, 2H), 5.82 (d, 9.0 Hz, 1H), 5.50 (m, 1H), 4.75 (m, 1H), 4.58-4.34 (m, 4H), 4.09 (m, 1H), 3.75 (s, 3H), 1.33 (s, 9H), 0.81 (d, 7.0 Hz, 3H). RTA IC50: 800 nM.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][C:20]=12.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][C:22]([N:8]3[C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11][O:10][C:9]3=[O:12])=[N:21][C:20]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2ccccc2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
To a solution of (S)-4-phenyloxazolidin-2-one (0.737 g, 4.517 mmol) in DMF was added sodium hydride (0.189 g, 4.73 mmol) and the reaction stirred at ambient temperature for 45 minutes. 3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (1.00 g, 4.302 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction mixture was poured into water and the water layer extracted with ether. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using 2% EtOAc/DCM as the eluent to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-phenyloxazolidin-2-one (1.233 g, 3.433 mmol, 79.80% yield).
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[BrH:37].C(O)(=O)C>C(OCC)C>[BrH:37].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCCCCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodooctane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: BrC1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([C:26]3[CH:41]=[CH:40][C:29]([O:30][CH2:31][C@@H:32]([N:34]4[CH2:38][CH2:37][C@@H:36]([CH3:39])[CH2:35]4)[CH3:33])=[CH:28][CH:27]=3)[O:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([O:19]C2CCCCO2)=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[CH3:42][S:43]([O-:45])=[O:44].[Na+].N1CCC[CH:48]1C(O)=O.[OH-].[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu](I)I>[CH3:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][CH:9]([C:26]2[CH:41]=[CH:40][C:29]([O:30][CH2:31][C@@H:32]([N:34]3[CH2:38][CH2:37][C@@H:36]([CH3:39])[CH2:35]3)[CH3:33])=[CH:28][CH:27]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:42]([S:43]([CH3:48])(=[O:45])=[O:44])=[CH:3][CH:4]=1
Reactant: CC1=C(c2ccc(Br)cc2)C(c2ccc(OC[C@H](C)N3CC[C@@H](C)C3)cc2)Oc2ccc(OC3CCCCO3)cc21
Reactant: O=C(O)C1CCCN1
Reactant: CS(=O)[O-]
Agent: I[Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1=C(c2ccc(S(C)(=O)=O)cc2)C(c2ccc(OC[C@H](C)N3CC[C@@H](C)C3)cc2)Oc2ccc(O)cc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of (3R)-1-((2S)-1-(4-(3-(4-bromophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-2-yl)phenoxy)propan-2-yl)-3-methylpyrrolidine (32 mg, 0.052 mmol; intermediate from the synthesis of Example 54), sodium methanesulfinate (12 mg, 0.118 mmol), copper iodide (11 mg, 0.058 mmol), DL-proline (12 mg, 0.104 mmol), and sodium hydroxide (5 mg, 0.125 mmol) in DMSO (0.5 mL) was heated at 95° C. overnight. The reaction mixture was diluted with ethyl acetate (20 mL), washed (50 mL sat'd NaHCO3, 50 mL brine), and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was stirred in 80% AcOH/water (0.5 mL) overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase HPLC to give 4-methyl-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)-3-(4-(methylsulfonyl)phenyl)-2H-chromen-6-ol. 1H NMR (DMSO-d6; TFA salt): δ 11.60 (br, 1H), 7.93 (d, 2H), 7.62 (d, 2H), 7.34 (d, 2H), 6.92 (d, 1H), 6.83 (d, 2H), 6.64 (dd, 1H), 6.60 (br, 1H), 6.56 (d, 1H), 6.00 (s, 1H), 3.84 (m, 2H), 3.60 (m, 1H), 3.36 (m, 1H), 3.13 (s, 3H), 2.93 (m, 1H), 2.50 (m, 2H), 2.23 (m, 2H), 2.13 (s, 3H), 1.70 (m, 1H), 1.54 (m, 3H), 1.11 (m, 3H); LCMS: 534.9 (M+H)+.
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CN=C(C(N)=O)C=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[N:28]=1>>[CH3:33][C:29]1[N:30]=[C:31]([O:25][C:22]2[CH:23]=[CH:24][C:19]([NH2:18])=[CH:20][CH:21]=2)[CH:32]=[CH:27][N:28]=1
Reactant: Cc1nccc(Cl)n1
Reactant: Nc1ccc(O)cc1
Agent: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Product: Cc1nccc(Oc2ccc(N)cc2)n1

Procedure:
This material is prepared by a method analogous to that described for preparation of 2C, starting from 4-amino-phenol and 4-chloro-2-methylpyrimidine.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:7]1=[O:21])=[O:4].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CC(O)=O.[Pd]>[C:24]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:23])([F:22])[F:1])[C:7]2=[O:21])=[CH:13][CH:14]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1[C@@H](NC(=O)C(F)(F)F)CCN1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CN2CC[C@H](NC(=O)C(F)(F)F)C2=O)cc1
Reaction time: 4.5 h

Procedure:
To a solution of 2,2,2-trifluoro-N-[1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-acetamide (0.75 g, 2.27 mmol) in AcOH (12 mL) is added acetic anhydride (1 mL) and a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is hydrogenated at room temperature on a Parr apparatus under 70 p.s.i. of H2. After 4.5 h, the reaction mixture is filtered through a pad of Celite, washed with CH2Cl2 and then MeOH. The crude product is concentrated in vacuo to yield 1.2 g of crude N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide as a residue (wet with HOAc). A solution of the crude N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide (1.2 g, wet with AcOH) in AcOH (12 mL) is cooled at 0° C. and acetic anhydride (1 mL) is added. The resulting mixture is treated with a catalytic amount of NaNO2, followed by the dropwise addition of fuming HNO3 (3.8 mL). The reaction mixture is stirred at 0° C. for 1.5 hours, then at room temperature for 1.5 hours. Upon re-cooling to 0° C., a mixture of ice/ice water is added slowly with stirring. The mixture is diluted further with water and extracted with EtOAc (3×50 mL). The combined organic layers are washed twice with water. The organic phase is dried over anhydrous MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to provide the title compound (0.65 g, 1.67 mmol) as a beige solid.
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClC(Cl)C>[CH:1]1[C:9]([NH:10][C:25](=[O:26])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CC(Cl)Cl
Product: O=C(Cc1ccccc1)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 6.6 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.10 g, 0.44 mmol), phenylacetyl chloride (0.058 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-yl-2-phenylacetamide (10 mg). MS (ESI) m/z 345; HPLC purity 100% at 210-370 nm, 10.6 min.; 100% at 252 nm, 10.6 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C23H24N2O+H+, 345.19614; found (ESI, [M+H]+), 345.1959.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH:24]([CH3:26])[CH3:25])/[C:16](=[N:18]/O)/[NH2:17]>N1C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([C:16]2[N:18]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[O:8][N:17]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Br
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C#N)cc3)n2)cc1Br
Temperature: 200 °C
Yield: 90.7 %

Procedure:
A 25 mL microwave vial equipped with a stirring bar was charged with 4-cyanobenzoyl chloride (0.4 g, 2.416 mmol), (Z)-3-bromo-N′-hydroxy-4-isopropoxybenzimidamide (0.5 g, 1.831 mmol) and pyridine (15 ml) to give an orange solution. The vessel was capped and the reaction heated at 200° C. for 20 min under microwave irradiation (Biotage Optimizer, 300 W). The solution was cooled, the reaction mixture was partitioned between aqueous HCl (10%, 150 mL) and DCM (40 mL) mixture, the DCM layer was drained, and the aqueous layer was extracted by DCM (2×20 mL). The combined DCM layers were washed by water (2×20 mL) and concentrated to afford white solid, which was purified via silica gel chromatography (40 g, 40% EtOAc:Heptane) to afford 4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (0.638 g, 1.660 mmol, 91% yield) as white solid. LC/MS (Method c) Rt=3.17 min.; MS m/z: 386.19 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO) ppm 8.40-8.32 (m, 2H), 8.23 (d, J=2.13 Hz, 1H), 8.14 (dd, J=8.14, 0.61 Hz, 2H), 8.05 (dd, J=8.65, 2.15 Hz, 1H), 7.36 (d, J=9.12 Hz, 1H), 4.89-4.77 (m, 1H), 1.35 (d, J=6.03 Hz, 6H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([F:15])=[CH:13][N:12]=[C:11]([C:16]([OH:18])=O)[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH:20]1([N:23]2[CH:27]=[N:26][N:25]=[C:24]2[C:28]2[S:29][CH:30]=[C:31]([NH2:33])[N:32]=2)[CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([F:15])=[CH:13][N:12]=[C:11]([C:16]([NH:33][C:31]4[N:32]=[C:28]([C:24]5[N:23]([CH:20]6[CH2:22][CH2:21]6)[CH:27]=[N:26][N:25]=5)[S:29][CH:30]=4)=[O:18])[CH:10]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Nc1csc(-c2nncn2C2CC2)n1
Reactant: O=C(O)c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1csc(-c2nncn2C2CC2)n1)c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Reaction time: 2 h

Procedure:
To a mixture of intermediate C.HCl (340 mg, 1.2 mmol), intermediate A (261 mg, 1.26 mmol), HATU (638 mg, 1.68 mmol), and N-methyl morpholine (330 μL, 3.00 mmol) was added DMF (5 mL) and the reaction was stirred for 2 hours. The mixture was concentrated, redissolved in a minimal amount of CH3CN, and water was added dropwise until a thick slurry was formed. The solids were isolated by filtration and washed with CH3CN to afford 320 mg (61% y). M+1=437.2
Reaction SMILES: C([C@H](NC([C:34]1[C:35]2C=[CH:37][NH:38][C:39]=2[CH:40]=[CH:41][CH:42]=1)=O)[C@H](O)C(N1[C@H](C(=O)NCC2C=CC=CC=2C)C(C)(C)SC1)=O)C1C=CC=CC=1.[C:43](Cl)(=O)[C:44](Cl)=O>>[CH2:44]1[CH2:43][CH2:40][CH:39]([N:38]=[C:37]=[N:38][CH:39]2[CH2:35][CH2:34][CH2:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc3[nH]ccc23)CSC1(C)C
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The synthesis of compounds with the general structure 27 is as follows. The boc-protected thiazolidine carboxylic acid 1 is converted to amino-ketones 26 with requisite grignard reagents 25 in the presence of oxalyl chloride. Final compounds 27 are obtained by a DCC-mediated coupling of 26 and 4 followed by deprotection of the P2 phenol. Final compounds were purified either by flash chromatography or preparative HPLC. Specific Method D
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[C:12]1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]([O-:45])(=[O:44])C.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[Cl:8][C:7]1[C:2]([C:42]([O:45][CH3:12])=[O:44])=[N:3][CH:4]=[C:5]([CH2:9][O:10][CH3:11])[CH:6]=1
Reactant: CC(=O)[O-]
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: COCc1cnc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COCc1cnc(C(=O)OC)c(Cl)c1
Temperature: 165 °C
Reaction time: 6 h

Procedure:
An autoclave was charged with 1.16 g (5.6 mmol) of 2,3-dichloro-5-(methoxymethyl)pyridine, 72 mg of 1,4-bis(diphenylphosphino)butane [3 mol percent based on the 2,3-dichloro-5-(methoxymethyl)pyridine], 8 mg of bis(triphenylphosphine)palladium(II) chloride [0.2 mol percent based on the 2,3-dichloro-5-(methoxymethyl)pyridine], 1.39 g (17 mmol) of sodium acetate and 16 ml of methanol. The autoclave is repeatedly flushed with carbon monoxide to replace the air by carbon monoxide. A carbon monoxide pressure of 15 bar was then applied to the autoclave. The reaction mixture was heated to 165° C. (bath temperature) and stirred for 6 hours. After cooling to room temperature, the crude product was concentrated under reduced pressure (30 mbar), chromotographed over silica gel 60 (eluent:hexane/ethyl acetate 3:1), analyzed by gas chromatography and characterized by 1H NMR and MS/GC-MS. The yield of the product was 1.05 g (87 percent) of a colorless oil. Other data concerning the product was:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10]1>>[O:9]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:10]1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC1CCOC1
Product: Brc1ccc(OCC2CCOC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahydrofuran-3-methanol by the method of Example 10 (b).
Reaction SMILES: [CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:2][CH2:3][C:4]#[CH:5].Cl[C:38](=[N:45][OH:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>ClCCl>[C:39]1([C:38]2[CH:5]=[C:4]([CH2:3][CH2:2][CH2:1][C:6]3[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]4[C:18]=3[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]4[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[O:46][N:45]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C#CCCCc1c2c3c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2nn1CCC)CCCC3
Reactant: ON=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2c1CCCc1cc(-c2ccccc2)no1)CCCC3
Temperature: 40 °C
Yield: 59.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of di(tert-butyl) 1-pent-4-ynyl-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (4.00 g, 8.05 mmol), prepared as described in Example 615, α-chlorobenzaldoxime (2.51 g, 16.1 mmol), prepared as described in Example 596, anhydrous triethylamine (1.7 mL, 12.1 mmol), and anhydrous dichloromethane (25 mL) was heated at 40° C. for 18 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with potassium carbonate, water, and brine, dried over sodium sulfate, and filtered. The filtrate was loaded onto a silica gel column (250 g) and eluted with a gradient of 30-40% ethyl acetate in hexanes. The fractions containing product were combined and concentrated under reduced pressure to provide 2.97 g of di(tert-butyl) 1-[3-(3-phenylisoxazol-5-yl)propyl]-2-propyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate as a pale yellow solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@@H:15]([OH:17])[C@H:14]([OH:18])[C@@H:13]([OH:19])[C@H:12]1[C:20]([OH:22])=[O:21])=O)C1C=CC=CC=1.[H][H].O>CO.[Pd].O.CO>[OH:19][C@@H:13]1[C@@H:14]([OH:18])[C@H:15]([OH:17])[CH2:16][NH:11][C@@H:12]1[C:20]([OH:22])=[O:21]
Reactant: [H][H]
Reactant: O=C(O)[C@@H]1[C@H](O)[C@@H](O)[C@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1NC[C@@H](O)[C@H](O)[C@H]1O
Yield: 72 %

Procedure:
To the solution of 2S,3S,4S,5R)-N-Benzyloxycarbonyl-3,4,5-trihydroxypiperidine-2-carboxylic acid (Example 40) (41.7 mg, 0.14 mmol) in MeOH (4 mL) was added Pd/C catalyst (5% wt, 60 mg). The reaction mixture was stirred under the atmosphere of hydrogen gas for 6 h. Catalyst was filtered through celite pad and volatiles were removed. Pure product was isolated by flash chromatography on silicagel using H2O-MeOH (2:98) as an eluent (16.7 mg, 72% yield). [α]D=−8.6° (C=0.21, H2O). 1H NMR (360 MHz, D2O+ two drops of MeOD-d4) δ 4.09-4.00 (m, 1H), 3.89-3.75 (m, 3H), 3.23 (dd, J=13.1, 1.9 Hz, 1H), 3.08 (dd, J=13.1, 3.8 Hz, 1H);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Br:37])[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:35])([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[Br:37][C:4]1[C:5]([C@@H:8]([NH:18][C:19](=[O:36])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([C:32]([F:33])([F:34])[F:35])=[N:22]2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][CH:7]=[C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 41C (35.6 mg, 0.06 mmol) was dissolved in 1 mL of methylene chloride and cooled to 0° C. To it was added 0.2 mL of pyridine followed by methanesulfonyl chloride (0.007 mL, 0.09 mmol). The reaction mixture was stirred at 0° C. for one hour. LCMS showed complete reaction. It was then partitioned between EtOAc and brine. The organic layer was separated, dried and concentrated to afford the title product. MS (m/z) 670.27 [M+H]+.