Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]([OH:9])([CH2:7][OH:8])[CH:5]([OH:10])[CH:4]([OH:11])[CH:3]([OH:12])[CH:2]1[NH:13]C1C(O)C(O)C(O)C(CO)=C1>[Pt]=O>[CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1[NH2:13]
Reactant: OCC1=CC(NC2CC(O)(CO)C(O)C(O)C2O)C(O)C(O)C1O
Agent: O=[Pt]
Product: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 26 %

Procedure:
An aqueous solution (50 mL) of validoxylamine G (420 mg) was submitted to catalytic reduction at room temperature under atmospheric pressure in the presence of platinum oxide (20 mg). The catalyst was removed by filtration, and the filtrate was adsorbed onto a column of Amberlite CG-50 (NH4- form, 50 mL) followed by washing with water and then elution with 0.5N aqueous ammonia (200 mL). The eluate was concentrated under reduced pressure, and submitted to column chromatography on Dowex 1×2 (OH- form, 100 mL) and eluted with water. The eluate fractions (120-200 mL) were concentrated to dryness under reduced pressure, to give white powders of valiolamine (60 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.CCN(CC)CC.[C:23]([CH:25](C)[CH2:26][CH2:27][C:28]#[CH:29])#[N:24].C(=O)(O)[O-].[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.[Cu]I.O>[C:23]([CH2:25][CH2:26][CH2:27][C:28]#[C:29][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1)#[N:24]
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCC(C)C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1COc1cncc(C#CCCCC#N)c1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (816 mg, 3.00 mmol), bis(triphenylphosphine)palladium(II) chloride (42 mg, 0.06 mmol) and copper (I) iodide (10 mg, 0.06 mmol) in CH2C12 (6.0 mL) and NEt3 (2.0 mL) was added 5-cyanohexyne (0.481 mL, 4.5 mmol). The mixture was refluxed overnight then cooled to room temperature. Water (4 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH//MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (674 mg, 79%). MS (CI/NH3) m/z 284 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.66-2.10 (m, 6H), 2.26-2.87 (m, 1H), 2.48 (s, 3H), 2.54-2.71 (m, 6H), 3.08-3.16 (m, 1H), 3.89-4.03 (m, 2H), 7.20 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 8.24 (d, J=3.0 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH3:32])[C:9]1[C:10]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][N:27]=[CH:26]3)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH2:1]([N:8]([CH3:32])[C:9]1[C:10]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][N:27]=[CH:26]3)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)Cc3ccccc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(Cc1ccccc1)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of methyl 3-(benzyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylate (70 mg, 0.17 mmol) in methanol (20 ml) was added sodium hydroxide (33 mg, 0.82 mmol) in water (5 ml). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum to give a residue, which was dissolved in water (20 ml), and adjusted to pH 4 with HCl (3N). The solids were collected by filtration to afford 3-(benzyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (64.1 mg, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[K+].Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Cc1cc(Cl)ccn1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)ccn1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A mixture containing 1.4 mmol 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester, 4.8 mmol potassium fluoride, 1.4 mmol 4-chloro-2-picoline (commercial) and 0.03 mmol bis(tri-tert.-butylphosphine)palladium in 5 ml deglazed dioxane was stirred at 100° C. for 1.5 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed twice with water. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on a 20 g Flashpack cartridge (Eluent: Heptane/AcOEt) to afford the title compound as a yellow oil (69% yield). MS (m/e): 311.2 ([M+H]+, 100%)
Reaction SMILES: C(Cl)(C)C.[Mg].C(O[C:10]([CH3:14])([CH3:13])[CH:11]=[CH2:12])(=O)C.[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16].[H-].[Na+].[Cl-].[NH4+]>CCOCC.O1CCCC1>[C:15]([CH:17]([C:10]([CH3:14])([CH3:13])[CH:11]=[CH2:12])[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]
Reactant: CCOC(=O)CC#N
Reactant: C=CC(C)(C)OC(C)=O
Agent: CC(C)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(C)(C)C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
A mixture of 131 mg of dichloro(bis triphenylphosphine)nickel II, 1.5 ml of tetrahydrofuran and 372 μl of a 1.08N solution of magnesium isopropyl chloride in ether was stirred at room temperature for 10 minutes and then a solution of 128 mg of 3-acetoxy-3-methyl-but-1-ene in 2 ml of tetrahydrofuran was added thereto followed by addition of a suspension of 248 mg of ethyl cyanoacetate, 88 mg of a 55% dispersion of sodium hydride in oil and 6 ml of tetrahydrofuran. The mixture was stirred at room temperature for 48 hours and a solution of ammonium chloride was added thereto. The mixture was extracted with ether and the decanted organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 1--1 ether-petroleum ether mixture to obtain 126 mg of ethyl 2-cyano-3,3-dimethyl-pent-4-en-1-oate containing 95% of the desired isomer and 5% of ethyl 2-cyano-5-methyl-hex-4-en-1-oate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[CH3:28][O:29][C:30](=[O:45])[C@@H:31]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH2:33][C:34](O)=[O:35].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.C(#N)C>[CH3:28][O:29][C:30](=[O:45])[C@@H:31]([NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:32][CH2:33][C:34](=[O:35])[NH:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Yield: 14.6 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-methyl ester (370 mg, 0.70 mmol; 66% purity) described in Manufacturing Example 2-1 and methanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred for 5 hours at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated from the filtrate under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-methyl ester (300 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 0.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-methyl ester (crude, 220 mg), N-methylmorpholine (46 μL, 0.42 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (180 mg, 0.46 mmol) in this order at 0° C., which was stirrer overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1), so as to obtain the titled compound (37 mg).
Reaction SMILES: NN.O=C1C2C(=CC=CC=2)C(=O)[N:5]1[CH2:14][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17]>CO.C(OCC)C>[NH2:5][CH2:14][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)(C)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(C)(C)CN
Temperature: 65 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
Hydrazine (1.1 eq., 0.27 mL, 8.42 mmol) was added to the solution of methyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,2-dimethylpropanoate (0.2 g, 7.66 mmol) in methanol (60 mL) maintained under magnetic stirring at 65° C. After 5 hours the reaction mixture was allowed to cool to room temperature, diluted with diethyl ether and filtered. The filtrate was washed thoroughly with diethyl ether. The title compound was obtained after evaporation of the solvents and it was used in the next step without any further purification. (0.8 g, 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12]C)=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.Cl>[OH-].[K+]>[OH:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Temperature: 100 °C
Yield: 95.1 %

Procedure:
A mixture of 4,5-dimethoxy-2-nitrobenzoic acid (20.6 g, 90.7 mmol) in 20% KOH solution (136 mL) was heated at 100° C. for 12 hours. After it was cooled with ice, it was acidified with concentrated HCl to pH 2. It was filtered, washed with CH2Cl2 and EtOAc, and dried over vacuum to afford 5-hydroxy-4-methoxy-2-nitrobenzoic acid as solid (18.38 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ 7.29 (s, 1H), 6.90 (s, 1H), 4.8 (br, 1H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:18](O)=[O:19])[NH:13]3)=[CH:5][CH:4]=1.Cl.Cl.Cl.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C@@H:32]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)[CH3:33])[CH2:27][CH2:26]1>>[OH:40][CH:37]1[CH2:36][CH2:35][N:34]([C@@H:32]([CH3:33])[CH2:31][N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:18]([C:12]3[NH:13][C:14]4[C:10]([CH:11]=3)=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:17]=[CH:16][CH:15]=4)=[O:19])[CH2:30][CH2:29]2)[CH2:39][CH2:38]1
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)O)cc23)cc1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(C[C@H](C)N5CCC(O)CC5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-phenyl)-1H-indole-2-carboxylic acid, 128 (see example 141) and amine 50.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH3:55][NH2:56]>>[CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][NH:17][C@@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:56][CH3:55])=[O:51])[CH2:15]2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CN
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)C(=O)O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(C)(C)C(=O)NC)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1

Procedure:
According to general procedure D, 1.0 mmol of 3-[(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid are reacted with methylamine (8M in EtOH) to afford the title compound which is identified based on its Rf value.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:16])[NH:11][CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][NH:11][C:10]2=[O:16]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(=O)NC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC2CCC1N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (108 mg, 0.48 mmol) in DCM (0.5 mL) at 0° C. was added dropwise, TFA (0.5 ml) and the reaction mixture stirred for 30 min. The reaction was warmed to RT and stirred for 1 h before being concentrated in vacuo and triturated with diethyl ether. The resultant residue was subjected to flash chromatography (Isolute NH2, 50% methanol in DCM) to give 3,8-Diaza-bicyclo[3.2.1]octan-2-one as a white solid (69 mg, quantitative). LCMS): RT=0.32 min, [M+H]+=127. 1H NMR 400 MHz (DMSO-d6) δ: 7.02 (1H, br, s), 3.53 (1H, m), 3.24 (1H, dd, J=11.00, 4.14 Hz), 2.80-2.79 (1H, m), 2.77 (1H, m), 1.78 (3H, m), 1.57-1.56 (1H, m).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:16](=[O:17])[N:15]2[C@@H:11]1[C@@H:12]([CH3:41])[C:13]([S:24][C@@H:25]1[CH2:29][N:28](C(OCC=C)=O)[C@H:27]([CH2:36][O:37][CH2:38][CH2:39][F:40])[CH2:26]1)=[C:14]2[C:18]([O:20]CC=C)=[O:19])[CH3:9])=O)C=C.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>O1CCCC1.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.C(OCC)(=O)C>[F:40][CH2:39][CH2:38][O:37][CH2:36][C@@H:27]1[CH2:26][C@H:25]([S:24][C:13]2[C@H:12]([CH3:41])[C@H:11]3[N:15]([C:16](=[O:17])[C@@H:10]3[C@H:8]([OH:7])[CH3:9])[C:14]=2[C:18]([OH:20])=[O:19])[CH2:29][NH:28]1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](COCCF)N(C(=O)OCC=C)C3)[C@H](C)[C@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCF)C3)[C@H](C)[C@H]12
Yield: 8.3 %

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyl)oxymethylpyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (372 mg) in a mixture of tetrahydrofuran (3.2 ml), ethanol (1.6 ml) and water (800 μl) were added triphenylphosphine (17 mg), morpholine (216 μl) and tetrakis(triphenylphosphine)palladium(0) (72 mg) at room temperature for 3 hours under nitrogen atmosphere. The reaction mixture was poured into a mixture of ethyl acetate (40 ml) and water (20 ml). The aqueous layer was separated and concentrated in vacuo to give a residual solution, which was chromatographed on "Diaion HP-20" eluting in turn with water and 10% aqueous acetone. The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2-fluoroethyl)oxymethylpyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid (20 mg).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]#[N:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(O)(C(F)(F)F)=O>>[NH2:27][CH2:26][CH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:2]([Br:1])[C:3]1=[O:28]
Reactant: N#CCc1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)c1

Procedure:
The title compound was prepared from compound of Example 97 by a procedure similar to the one described for Example 99, as the TFA salt (0.13 g, 33%): mp 70-74° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.21 (br s, 1H), 6.60-6.50 (m, 1H), 7.52 (d, J=6 Hz, 1H), 7.30 7.10 (m, 3H), 7.01 (d, J=9 Hz, 1H), 6.94-6.85 (m, 2H), 6.20 (d, J=6 Hz, 1H), 5.20 (s, 2H), 5.05 (s, 2H), 3.23 (br s, 2H), 2.97 (t, J=8 Hz, 2H), 2.05 (br s, 2H). ESHRMS m/z 449.0698 (M+H C21H20BrF2N2O2 requires 449.0671).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.C(Cl)(Cl)Cl.CC#N.I([O-])(=O)(=O)=[O:26].[Na+]>O.O.[Ru](=O)=O>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:10](=[O:26])[C:5]2=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1=O
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a vigorously stirred solution of tert-butyl 3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (1.0 g, 3.3 mmol) in 1:1 CHCl3:MeCN (25 mL) was added ruthenium (IV) oxide hydrate (65 mg, 0.43 mmol) and sodium metaperiodate (3.3 g, 15.5 mmol) in water (31 mL). After 1 h, additional ruthenium (IV) oxide hydrate (50 mg) was added. After another hour, a final portion of ruthenium (IV) oxide hydrate (30 mg) was added. Stirring was maintained for 30 minutes and then water was added. The entire mixture was extracted with CHCl3. The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a green oil. Purification by chromatography (SiO2; hexanes—100% EtOAc) provided the desired product as a white solid (663 mg, 63%). MS (ESI): mass calcd. for C10H13BrN4O3, 316.0; m/z found, 317.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.41-4.28 (m, 2H), 4.26-4.22 (m, 2H), 1.58 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][OH:35])[CH2:33][O:32][CH2:31]1>C(#N)C>[OH:35][CH2:34][C:30]1([CH2:29][O:1][C:2]2[C:3]([O:20][CH3:21])=[C:4]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[C:15](=[O:19])[O:14][CH2:13]4)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:33][O:32][CH2:31]1
Reactant: OCC1(CBr)COC1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 23.2 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (151 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (25 mg, 23.2%).
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-:5])=[O:4].[Na+].Cl>CCOC(C)=O>[F:13][C:2]([F:1])([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])C(F)(F)c1ncc(F)cn1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C(F)(F)c1ncc(F)cn1
Yield: 78.1 %

Procedure:
To sodium 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate from Example 3 step C (2.97 g, 13.87 mmol) was added EtOAc (100 mL) and 4 N HCl (100 mL) and the mixture shaken and partitioned. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. Hexanes was added to the residue and the mixture again concentrated under reduced pressure to afford 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetic acid (2.08 g, 78%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][N:13]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:12]2)[CH2:9]1)=[O:7]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(CNC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(C1)CN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
2,6-Diaza-spiro[3.3]heptane-2-carboxylic acid 2,4-dichloro-benzylamide (245 mg, 416 μmol) and triethylamine (200 mg, 198 mmol) were dissolved in dichloromethane (5 mL) followed by benzoyl chloride (70 mg, 499 μmol) and the reaction mixture was stirred for 1 h at ambient temperature. The crude reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; methanol:dichloromethane 0:1 to 1:19) to give the title compound (106 mg, 63%) as a colorless solid. MS (EI) m/e: 404.1 (M+H)+.
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH:20](=[O:24])[CH2:21][CH2:22][CH3:23]>O1CCCC1>[OH:24][CH:20]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCCC=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)OCC)cc1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
At −40° C., isopropylmagnesium chloride lithium chloride (15.3 mL, 1.3 M in THF, 19.9 mmol) was added dropwise to a solution of ethyl 4-iodobenzoate (5000 mg, 18.11 mmol) in tetrahydrofuran (30 mL). The solution was stirred at −40° C. for 40 minutes. Butyraldehyde (1830 mg, 25.4 mmol) was added. The mixture was allowed to warm to room temperature over 3 hours. The reaction was quenched with 1N HCl and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1-hydroxybutyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 4.83-4.66 (m, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.86 (d, J=3.7 Hz, 1H), 1.83-1.61 (m, 2H), 1.51-1.42 (m, 1H), 1.39 (t, J=7.2 Hz, 3H), 1.36-1.23 (m, 1H), 0.94 (t, J=7.6 Hz, 3H).