Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:15])([CH3:14])[O:12][B:11]([OH:16])[C:10]=2[CH:17]=1)=[O:4].[NH:30]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:31]([C:44](O)=[O:45])[CH2:32][CH2:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:50]([O:49][C:47]([NH:30][C@H:31]([C:44]([NH:1][C@H:2]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([CH3:15])([CH3:14])[O:12][B:11]([OH:16])[C:10]=2[CH:17]=1)=[O:4])=[O:45])[CH2:32][CH2:33][C:34]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:43])=[O:48])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CC1(C)OB(O)c2cc(NC(=O)[C@H](N)CCc3ccc(C(F)(F)F)cc3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of (R)-2-amino-N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(4-(trifluoromethyl)phenyl)butanamide (CLXIX) (1.2 g, 2.71 mmol) and Boc-Glu(OBzl)-OH (CLXX) (0.915 g, 2.71 mmol) in DCM (10 mL) was added DIPEA (1.39 mL, 8.13 mmol). To this solution was added HATU (1.03 g, 2.71 mmol) and the mixture was stirred at room temperature overnight. The mixture was washed with 2 N aqueous HCl, 1 M aqueous K2CO3, brine and dried over MgSO4. The solution was evaporated to dryness under vacuum to give (S)-benzyl 4-(tert-butoxycarbonylamino)-5-((R)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-4-(4-(trifluoromethyl)phenyl)butan-2-ylamino)-5-oxopentanoate as an orange foam (1.83 g, 2.52 mmol, 93% yield). 1H NMR (DMSO-d6) δ ppm 1.33 (s, 9H), 1.4 (s, 6H), 1.8-1.88 (m, 1H), 1.9-1.96 (m, 2H), 2.08 (brs, 1H), 2.42 (brs, 2H), 2.6-2.66 (m, 1H), 2.7-2.76 (m, 1H), 3.98-4.05 (m, 1H), 4.4 (brs, 1H), 5.07 (s, 2H), 7.1 (brs, 1H), 7.28-7.34 (m, 6H), 7.37-7.44 (m, 2H), 7.55-7.63 (m, 3H), 7.89 (s, 1H), 8.34 (brs, 1H), 9.0 (s, 1H), 9.86 (s, 1H); 19F NMR (DMSO-d6) δ ppm −60.11 (s, 3F); ESIMS found for C37H43BF3N3O8 m/z 726.7 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.CO[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[C@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C@H:29]2[C@@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:19][C:15]4[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=4)[C:12]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[NH:8][N:7]=4)=[O:21])[C:32]3=[O:40])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1cc(C2CC2)[nH]n1
Product: O=C(Nc1cc(C2CC2)[nH]n1)c1cccc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 5-cyclopropyl-1H-pyrazol-3-amine, 3-bromomethyl-benzoic acid methyl ester, (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C30H25ClN4O2: 508, observed (M+H)+: 509.2 1H NMR (400 MHz, MeOD-d4) δppm 0.54-0.77 (m, 2 H) 0.79-0.95 (m, 2 H) 1.62-1.77 (m, 1 H) 2.05 (s, 1H) 2.18-2.30 (m, 2 H) 3.23-3.31 (m, 1 H) 5.07-5.26 (m, 2 H) 6.09 (d, J=6.82 Hz, 1 H) 6.72 (t, J=7.58 Hz, 1H) 6.95 (d, J=7.83 Hz, 1 H) 7.05-7.14 (m, 1 H) 7.14-7.20 (m, 2 H) 7.30 (d, J=8.34 Hz, 2 H) 7.51 (t, J=7.71 Hz, 1 H) 7.62 (d, J=7.83 Hz, 1 H) 7.89 (d, J=7.83 Hz, 1 H) 7.94 (s, 1 H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:18](Cl)(Cl)=[O:19].Cl>ClCCl.C1(C)C=CC=CC=1>[N:2]([C@@H:3]([CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[C:18]=[O:19]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC[C@H](N=C=O)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To 25.00 g (137.62 mmol) of methyl(2S)-2-aminohexanoate hydrochloride in 458 mL of dichloromethane at 0° C. was added 44.52 mL (550.49 mmol) of pyridine. Then, 85.57 mL (165.14 mmol) of a 1.93 M solution of phosgene in toluene was added to the solution and the mixture was stirred at 0° C. for 3 h. The solution was poured into 1N hydrochloric acid at 0° C. and extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by vacuum distillation at 80° C. @ 2 torr to give 21.32 g (91%) of methyl(2S)-2-isocyanatohexanoate. Rf=0.46 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6)δ 4.37 (dd, J=7 Hz, J=5 Hz, 1H), 3.73 (s, 3H), 1.78-1.60 (m, 2H), 1.36-1.16 (m, 4H), 0.85 (t, J=7 Hz, 3H); ES-MS m/z 172 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=1[F:31]>C(Cl)Cl>[F:31][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:20]=1[NH:19][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)cc1F

Procedure:
A solution of hexadecanoyl chloride (20 g) in 100 ml of methylene chloride is slowly added with stirring to a solution of 20 g of ethyl 4-amino-3-fluorobenzoate in 100 ml of methylene chloride. The mixture is filtered and the filtrate is washed with dilute hydrochloric acid and water, dried and the solvent evaporated. Crystallization of the residue from acetonitrile affords ethyl 3-fluoro-4-(hexadecanoylamino)benzoate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[CH2:10]([N:17]=[C:18]=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[CH2:10]([N:17]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=[C:18]1[S:19][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: S=C=NCc1ccccc1
Reactant: Clc1ccc(CBr)cc1
Reactant: NNC(=O)c1ccco1
Product: Clc1ccc(CSc2nnc(-c3ccco3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-furancarboxylic acid hydrazide, benzyl isothiocyanate and 4-chlorobenzyl bromide as the starting materials. (M+H)+−382.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(O)(=O)C.C(O[BH3-])(=O)C.[Na+]>C(Cl)Cl>[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[I:9])[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: Nc1ccc(F)cc1I
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1CCC(Nc2ccc(F)cc2I)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-fluoro-2-iodoaniline and (18 g) 4-oxo-cyclohexanecarboxylic acid ethyl ester (20 g) in DCM (200 ml) is added acetic acid (4.4 ml) and 4 Å molecular sieves (5 g). After 2 h at rt, sodium acetoxyborohydride (50 g) is added and the suspension stirred overnight. The reaction is made slightly alkaline with KHCO3/NaHCO3(aq) and extracted with DCM to give crude 4-(4-fluoro-2-iodo-phenylamino)-cyclohexanecarboxylic acid ethyl ester.
Reaction SMILES: [O:1]([CH2:8][CH:9]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.Cl.C(N[CH2:17][CH3:18])C.[CH2:19]([O:21]P([CH2:27][C:28]([OH:30])=[O:29])(OCC)=O)C.C([Li])CCC>O1CCCC1.CCOCC>[C:2]1([O:1][CH:8]=[CH:9][CH:19]=[O:21])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[O:1]([CH:8]=[CH:17][CH:18]=[CH:27][C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: O=CCOc1ccccc1
Reactant: CCNCC
Agent: C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)C=CC=COc1ccccc1
Product: O=CC=COc1ccccc1

Procedure:
2-Formylvinyl phenyl ether is prepared by treating phenoxyacetaldehyde with formaldehyde and diethylamine hydrochloride salt. The ether is then reacting with a solution of diethylphosphonoacetic acid and n-butyllithium in anhydrous tetrahydrofuran (THF) to form 5-phenoxy-2,4-pentadienoic acid. 5-Phenyl-2,4-pentadienal is obtained by first converting the carboxylic acid to a Weinreb amide using oxalyl chloride followed by N,O-dimethylhydroxylamine. Subsequently, reduction of the Weinreb amide with lithium aluminum hydride (LAH) in THF leads to the formation of 5-phenoxy-2,4-pentadienal. The synthesis is summarized in Scheme II.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[C:17]3[C:18]([OH:22])=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:23]([O:26][C@@H:27]1[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[O:36][C@@H:28]1OC(=N)C(Cl)(Cl)Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>ClCCl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]2[C:17]3[C:18]([O:22][C@@H:28]4[O:36][C@H:37]([CH2:48][O:49][C:50](=[O:52])[CH3:51])[C@@H:38]([O:44][C:45](=[O:47])[CH3:46])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:27]4[O:26][C:23](=[O:25])[CH3:24])=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)Nc1ccc(CCc2coc3cccc(O)c23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)c23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
To a mixture of 3-[2-(4-acetylaminophenyl)ethyl]-4-hydroxybenzofuran (30 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (64 mg) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.013 mL), and the mixture was stirred at room temperature for three days. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/3-1/2) to give 3-[2-(4-acetylaminophenyl)ethyl]-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)benzofuran (38 mg). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.02 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give the title compound (12 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.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>[CH:27]1([N:32]2[CH:36]=[C:35]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:34]=[N:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cnn(C3CCCC3)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC1Cc2ccc(-c3cnn(C4CCCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.5 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH=10) to afford the desired product (4.7 mg). LCMS (M+H)+: m/z=473.2.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2S[C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.NCCC(O)=[O:37].CO.C(Cl)Cl>C(O)(=O)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:37][C:29](/[CH:31]=[C:3]3/[NH:4][C:5](=[S:18])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:2]/3=[O:1])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1
Reactant: NCCC(=O)O
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)s1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)N1C(=O)/C(=C\c2ccc(-c3ccc(Br)cc3)o2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.053 g, 0.199 mmol) and 5-(4-bromophenyl)thiophene-2-carbaldehyde (0.050 g, 0.199 mmol) in acetic acid 5 mL is added β-alanine (1.8 mg, 0.020 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.060 g, 0.120 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.83 (dm, J=9.0 Hz, 2H), 7.44 (dm, J=9.3 Hz, 2H), 7.17 (m, 5H), 7.03 (s, 2H), 6.47 (s, 1H), 5.64 (d, J=8.7 Hz, 1H), 3.69 (m, 1H), 3.49 (m, 1H). MS (ES−, m/z): 495.2 (M−, 80.0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH:16]=O)=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][CH2:10][C:9]=2[CH2:16][N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(C)CCC(C=O)=C(c2ccc(Cl)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CCC(CN2CCN(C(=O)OC(C)(C)C)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
To a 2 L three neck RB flask provided with a mechanical stirrer were charged a solution of 4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carbaldehyde (50.0 g) in toluene (250 mL), BOC-piperazine (48.2 g) and anhydrous THF (250 mL). The yellow solution was stirred at 20° C. for 5 min. Sodium triacetoxyborohydride (52.7 g) was added in portion (note: the internal temperature rose to ˜29.5° C. in 15 min cooling may be needed). The yellow mixture was stirred at ˜25° C. for NLT 4 hrs. A conversion of starting material to product of 99.5% was observed by HPLC after a 3 hour reaction time.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:3][OH:2])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a chilled solution of 4-(4-chloro-phenyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (700 mg, 1.98 mmol) in 6 ml ether was added dropwise 2 ml lithium aluminium hydride 1M solution in ether. The reaction was stirred at 0° C. for 3 hours, then water (100 ml) was slowly added. The resulting gel was filtered and the aqueous filtrate was extracted three times with ether. The combined organic layers were dried with magnesium sulfate and concentrated under vacuum. Recovered oil was purified by silica gel chromatography, eluting with hexane-ethyl acetate (6:4) to give the title compound (297 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:29]([C:14]1[C:15](=[O:28])[N:16]([CH2:19][C:20](=[O:27])[N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:17]2[C:12]([C:13]=1[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:30])[CH3:36]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.4 (1H, br), 10.18 (1H, m), 8.55 (1H, s), 7.15 (2H, dd, J=8.4, 5.5 Hz), 7.02 (2H, t, J=8.4 Hz), 6.98 (1H, s), 4.94 (2H, s), 4.11 (2H, s), 3.61 (4H, m), 3.59-3.43 (6H, m), 1.68 (2H, m), 1.54 (4H, m), 1.21 (3H, t, J=7 Hz); HRMS calcd for C27H31FN4O5+H+: 511.2357. Found: 511.2366.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.C(N(C(C)C)CC)(C)C.[C:36](=O)([O:46]C1C=CC([N+]([O-])=O)=CC=1)[O:37][CH2:38][C@@H:39]1[CH2:43][O:42][C:41]([CH3:45])([CH3:44])[O:40]1>O1CCCC1.ClCCl>[CH3:44][C:41]1([CH3:45])[O:40][C@H:39]([CH2:38][O:37][C:36]([NH:2][C@@H:3]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][N:20]5[CH:24]=[CH:23][N:22]=[N:21]5)[O:16][C:15]4=[O:25])=[CH:10][C:9]=3[F:26])[CH2:4]2)=[O:46])[CH2:43][O:42]1
Reactant: N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reactant: CC1(C)OC[C@@H](COC(=O)Oc2ccc([N+](=O)[O-])cc2)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](COC(=O)N[C@@H]2CCN(c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)C2)O1
Yield: 51.8 %

Procedure:
(5R)-3-(4-((3R)-3-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (400 mg, 1.05 mM) was suspended in tetrahydrofuran (10 ml) and treated with diisopropylethylamine (176 mg, 1.36 mM) and (4S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl 4-nitrophenyl carbonate (429 mg, 1.44 mM) dissolved in dichloromethane (5 ml). The mixture was stirred vigorously at ambient temperature for 18 hours, with the addition of two further portions of diisopropylethylamine (137 mg, 1.06 mM). Solvent was evaporated, the residue redissolved in ethyl acetate (20 ml), washed with water (3×20 ml), and dried (magnesium sulfate). After removal of the solvent, the residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (273 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(C)nn3c(-c4ccc(F)c(F)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 85 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
(S)-(1-(7-(3,4-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (62 mg), 4-methoxyphenylboronic acid (27 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (8 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred for 6 hours under argon atmosphere at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure, concentrated and purified by column chromatography to yield the target compound (58 mg).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1([F:30])[CH2:29][NH:28][CH2:27]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:28]3[CH2:29][C:26]([F:30])([F:25])[CH2:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: FC1(F)CNC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(F)(F)C3)ccc2n1CC1CCOCC1
Yield: 66.3 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (90 mg, 0.24 mmol), 3,3-difluoroazetidine (45 mg, 0.49 mmol) and DMAP (59 mg, 0.49 mmol) in MeCN (10 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 68 mg (66%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.46-1.63 (m, 4 H), 1.65 (s, 9 H), 2.27-2.44 (m, 1 H), 3.30-3.39 (m, 2 H), 3.89-3.98 (m, 2 H), 4.20 (t, J=12.30 Hz, 4 H), 4.51 (d, J=7.62 Hz, 2 H), 7.93 (dd, J=8.69, 1.66 Hz, 1 H), 8.05 (d, J=8.79 Hz, 1 H), 8.19 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=427.8; Anal. Calcd for C20H27F2N3O3S+1.10 TFA+0.3 CH3CN (565.26): C, 48.45; H, 5.17; N, 8.18. Found: C, 48.42; H, 4.86; N, 8.20.