Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[C:52]([NH2:57])[CH:51]=2)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>O1CCCC1>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[C:52]([NH:57][C:18](=[O:20])[CH2:17][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=3)[CH:51]=2)[CH2:47][CH2:48]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(F)c(F)c1
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of [tert-butoxycarbonyl-(3,4-difluorophenyl)-amino]-acetic acid (0.200 g) in tetrahydrofuran (2 ml) at 0° C. was added triethylamine (110 ul) followed by dropwise addition of isobutylchloroformate (100 ul). After stirring for 1 hr, triethylamine (150 ul) was added followed by 4-(3-amino-4-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.234 g) in tetrahydrofuran (2 ml), and the reaction warmed to room temperature and then heated at 58° C. overnight. After cooling to room temperature, the reaction mixture was filtered through Celite, the filtrate collected and the solvent removed in vacuo. Purification by NPHPLC (0-5% MeOH in CH2Cl2) afforded the sub-title compound as a pale yellow solid (0.300 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:19]([CH3:20])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[CH3:21])(C(C)(C)C)(C)C.[NH2:22][C:23]1[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=1[C:25]([NH:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)=[O:26]>CCO>[OH:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH3:21])=[CH:14][C:15]([C:16]2[N:27]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)[C:25](=[O:26])[C:24]3[C:23](=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:22]=2)=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCO
Product: COC(=O)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccccc3c2=O)cc1
Temperature: 25 °C
Yield: 34.1 %

Procedure:
Isatoic anhydride (4.0 g, 24.5 mmol) and methyl 4-aminobenzoate were combined and heated at 140° C. for 4 hours. The reaction was cool to room temperature and purified by flash chromatography on silica gel, eluting with 90-100% CH2Cl2 in heptane, to afford methyl 4-(2-aminobenzamido)benzoate (5.2 g, 78%). 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (1.0 g, 3.30 mmol) and anhydrous CuCl2 (1.3 g, 9.90 mmol) were added to a solution of methyl 4-(2-aminobenzamido)benzoate (0.900 g, 3.30 mmol) in anhydrous EtOH (70 mL) and heated to reflux for 6 hours, before being cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% MeOH in CH2Cl2, followed by further purification on silica gel, eluting with 30-100% EtOAc in heptane, afforded the title compound as a white solid (0.500 g, 34%). 1H-NMR (300 MHz, DMSO-d6): δ 8.18 (dd, J=7.9, 1.1 Hz, 1H), 7.88-7.93 (m, 3H), 7.75 (d, J=6.7 Hz, 1H), 7.57-7.62 (m, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.03 (s, 2H), 4.82 (t, J=5.5 Hz, 1H), 3.84 (s, 3H), 3.60-3.72 (m, 4H), 2.07 (s, 6H). MS (APCI) m/z: 445 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].N>CO.[Ni]>[N:1]1([C:7]2[N:12]=[C:11]([CH2:13][NH2:14])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccnc(N2CCOCC2)n1
Agent: [Ni]
Agent: N
Agent: [OH-]
Solvent: CO
Product: NCc1ccnc(N2CCOCC2)n1
Reaction time: 2 h

Procedure:
A solution of 2-morpholin-4-yl-pyrimidine-4-carbonitrile (0.28 g, 1.47 mmol) in MeOH and 28% aqueous ammonia hydroxide (2.0 mL, 1.40 mmol) was hydrogenated over Raney-Ni catalyst using a continuous flow apparatus (conditions: 1 mL/minute, 25° C., 10 bar). After 2 hours, the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5% MeOH in CH2Cl2. The major fractions were combined and the solvent was concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C.[C:27]1([CH:34]=[CH:33][CH:32]=[C:30]([OH:31])[CH:29]=1)[OH:28]>O>[OH:28][C:27]1[CH:29]=[C:30]([OH:31])[CH:32]=[CH:33][C:34]=1[C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Oc1cccc(O)c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Oc1ccc(C23CC4CC(CC(C4)C2)C3)c(O)c1
Reaction time: 3 h
Yield: 86 %

Procedure:
Into a four-neck flask having an inner volume of 500 ml and equipped with a reflux condenser, a stirrer, a thermometer, and a nitrogen inlet were charged 28.1 g (0.18 mol) of 1-adamantanol, 8.8 g (0.05 mol) of p-toluenesulfonic acid monohydrate, and 35 ml of ethanol. After the atmosphere was displaced by nitrogen, 39.6 g (0.36 mol) of resorcinol was added. The mixture in the flask was placed in an oil bath at 90° C. and heated and agitated for 3 hours. The reaction solution was cooled, added with 200 ml of pure water, agitated for 30 minutes, and then filtered to obtain a solid material. The material was dried under reduced pressure, then recrystallized from a methanol/toluene mixture solvent. The crystals obtained were collected with washing by toluene, and then dried under reduced pressure until constant weight to obtain the target compound (yield 86%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[OH:13].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([NH2:10])[C:3]=1[OH:13]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c(O)c(F)c1F
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(O)c(F)c1F
Yield: 98.9 %

Procedure:
A solution of 2,3-difluoro-4-methyl-6-nitrophenol (1.2 g, 6.35 mmol) (D44) in ethanol (120 mL) was hydrogenated using a 10% Pd/C cartridge in the H-cube™ hydrogenator at 1 mL/min and full hydrogen at 25° C. Evaporation gave 2,3-difluoro-4-methyl-6-aminophenol (1.0 g, 6.28 mmol, 99% yield) as a fawn solid.
Reaction SMILES: [NH2:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([C:10](=[O:12])[CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:20]([NH:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([C:10](=[O:12])[CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(N)sc2c1CCN(C(C)=O)C2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1sc2c(c1C(=O)OCC)CCN(C(C)=O)C2
Temperature: 0 °C
Yield: 91.6 %

Procedure:
5.0 g (18.6 mmol) of 2-amino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 50 ml of toluene were mixed with 3.0 g (28 mmol) of ethyl chloroformate and 2.6 g (18.6 mmol) of finely powdered potassium carbonate and refluxed for 2 h. The reaction mixture was then taken up in ice/water, the toluene phase was separated off, and the aqueous phase was back-extracted with toluene. The combined organic phases were dried and then concentrated. 5.8 g (92%) of product were isolated as an oil which slowly crystallizes somewhat.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][Br:7].C(O)C.[O-]S(S([O-])=O)=O.[Na+].[Na+]>O>[NH2:12][C:10]1[CH:9]=[CH:8][C:3]([O:4][CH2:5][CH2:6][Br:7])=[C:2]([Cl:1])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)c(Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.5 %

Procedure:
To 11 g (0.040 mol) of the 1-(2-chloro-4-nitrophenoxy)-2-bromoethane produced in Example 5-(1), ethanol (170 ml) was added and dissolved therein; to the resulting solution, Na2S2O4 (27.6 g, 0.158 mol) as dissolved in water (50 ml) was added dropwise, followed by stirring at room temperature for 20 min. The solvent was evaporated and the residue was diluted with an aqueous solution of sodium bicarbonate and two extractions were conducted with ethyl acetate. The organic extracts were dried with sodium sulfate and the solvent was evaporated, with the residue being purified by being subjected to column chromatography on silica gel using, as an eluent, n-hexane containing ethyl acetate (25%) to yield the end compound 1-(4-amino-2-chlorophenoxy)-2-bromoethane (2.35 g) as a pale yellow solid mass.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH3:40])([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:37]([C:34]3([CH3:40])[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]3)=[O:38])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
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: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 8, Step A; 25 mg, 0.075 mmol), 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (22 mg, 0.090 mmol), and HATU (34 mg, 0.090 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.039 mL, 0.23 mmol) was added to the reaction dropwise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 80% acetonitrile/water to yield the final product as a yellowish powder (28 mg, 67% yield). MS (apci) m/z=557.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10]([O:12]C)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[K+]>CO>[CH3:1][O:2][C:3]([C:5]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)OC)CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.5 %

Procedure:
To a solution of cyclopentane-1,1-dicarboxylic acid dimethyl ester (4.0 g, 21.5 mmol) in MeOH (25 mL) is added potassium hydroxide (1.32 g, 23.7 mmol). The mixture is stirred at room temperature for 15 hours and concentrated under reduced pressure. To the obtained residue, aqueous 1M HCl (50 mL) is added and the solution is extracted with AcOEt. The organic layer is washed with H2O, dried over Na2SO4, and concentrated under reduced pressure to give cyclopentane-1,1-dicarboxylic acid methyl ester (3.72 g, quant.); TLC (dichloromethane/MeOH, 10:1) Rf 0.25, 1H NMR (400 MHz, chloroform-d) δ ppm 1.67-1.74 (m, 4H), 2.17-2.25 (m, 4H), 3.75 (s, 3H).
Reaction SMILES: [C:1]([C@H:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].[OH:28]O.[OH-].[Na+].Cl>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C@H:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:28])[NH2:2]
Reactant: N#C[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: NC(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
In 12 ml of dichloromethane is dissolved 1.06 g of (3S,4S)-4-cyano-3-triphenylmethylamino-2-azetidinone and, following addition of 1.02 g of tetra-n-butylammonium hydrogen sulfate, 0.68 ml of 30% aqueous hydrogen peroxide and 4.5 ml of 1 N sodium hydroxide are added under ice-cooling and stirring. The mixture is stirred vigorously for 50 minutes and poured into ice water containing 1.3 ml of 1 N hydrochloric acid. After phase separation, the aqueous layer is extracted twice with chloroform. The organic layers are combined and washed with an aqueous solution of sodium thiosulfate and sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is chromatographed on a silica gel column [eluant: chloroform-ethyl acetate-methanol (50:50:5)] to give 0.223 g of (3S,4S)-4-carbamoyl-3-triphenylmethylamino-2-azetidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=S)=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[NH3:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[NH:29])=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: Cc1ccc(OCc2c(F)cccc2Cl)c(NC(=S)Nc2ccc(Cl)cc2)n1
Reactant: N
Product: Cc1ccc(OCc2c(F)cccc2Cl)c(NC(=N)Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.58 g, 0.0027 mol), N-[3-(2-chloro-6-fluorobenzyloxy)-6-methylpyrid-2-yl]-N'-4-chlorophenylthiourea (1.00 g, 0.0023 mol) and methanolic ammonia solution (30 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.52 g (54%), m.p. 148°-149 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26](CC1C=CC(OC)=CC=1)[CH2:25][CH2:24][CH2:23]2.Cl>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH2:25][CH2:24][CH2:23]2
Reactant: COc1ccc(CN2CCCc3cc(Cc4cc([C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)ccc4Cl)ccc32)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)CCCN4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 18 h
Yield: 70.5 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-{4-chloro-3-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-ylmethyl]-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (135 mg, 0.25 mmol) in methanol (5 mL) was added 10% palladium on charcoal (60 mg), 0.05 mL conc. HCl and stirred under hydrogen balloon pressure for 18 h. Reaction mixture was filtered through celite bed, washed with methanol and concentrated. The resulting residue was purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (74 mg).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][C:20](=[N:22][O:23][CH3:24])[CH2:19][C@H:18]1[C:25]([OH:27])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:28](=[N:31]O)([NH2:30])[CH3:29]>C(Cl)Cl.C1COCC1>[CH3:24][O:23][N:22]=[C:20]1[CH2:21][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[C@H:18]([C:25]2[O:27][N:31]=[C:28]([CH3:29])[N:30]=2)[CH2:19]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(N)=NO
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON=C1C[C@@H](c2nc(C)no2)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 59 %

Procedure:
Diisopropylcarbodiimide (3.16 g, 25.17 mmol) was added to a solution of (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2, 6.50 g, 25.17 mmol) and acetamidoxime (Intermediate 7, 1.86 g, 25.17 mmol) in DCM (55 ml) and stirred overnight at room temperature (DCM-insoluble amidoximes were pre-dissolved in THF, to which was added a solution of DIC and Intermediate 2 in DCM). After filtering at the pump, and evaporation in vacuo, the residue was dissolved in pyridine (60 ml) and refluxed for one hour, then cooled and allowed to stand overnight, then evaporated in vacuo. The crude product was then dissolved in DCM (50 ml) and washed with sat. NaHCO3(aq) (2×50 ml) and then 1M HCl(aq) (2×50 ml), dried over magnesium sulphate and evaporated in vacuo (crude yield 70%). Silica gel chromatography, eluting with 15% ethyl acetate in hexanes gave the desired compound, tert-butyl (2S,4EZ)-4-(methoxyimino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyrrolidinecarboxylate (4.4 g, 60% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1.CON(C)[C:19](=[O:31])[CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].Cl>C1COCC1.CCCCC>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[C:19](=[O:31])[CH2:20][CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:13]1
Reactant: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Reactant: CC1(C)COC(c2ccc(F)cc2Br)=N1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(CCC(=O)c1cc(F)ccc1C1=NC(C)(C)CO1)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A stirred solution of 2-(2-bromo-4-fluorophenyl)-4,4-dimethyl-4,5-dihydrooxazole (1.2 g, 4.7 mmol) in dry THF (6 mL) was cooled to −78° C. and a solution of tert-buLi (1.7 M in pentane, 5.5 mL, 9.3 mmol) was added drop wise. After 30 min, a solution of tert-butyl 3-(methoxy(methyl)amino)-3-oxopropyl(methyl)carbamate (0.77 g, 3.1 mmol) in dry THF (5 mL) was added. The cooling bath was allowed to warm to −20° C. and the reaction mixture was stirred between −20° C. and 0° C. for 4 h. After warming to room temperature, the mixture was added 0.2N HCl (50 mL). The mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 0% ethyl acetate in hexanes to 60% ethyl acetate in hexanes) to give product (0.72 g, 61%). 1H NMR (CDCl3) 7.62 (brs, 1H), 6.88 (t, J=7.5 Hz, 1H), 6.79 (brs, 1H), 3.80-4.00 (m, 2H), 3.30 (t, J=7.0 Hz, 2H), 2.76 (brs, 2H), 2.59 (s, 3H), 1.13 (s, 15H); MS EI m/z 379 (M+H)+.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27](OC)=[O:28])(=[O:20])=[O:19])=[O:16])[N:8]=1>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([S:18][CH2:21][CH2:22][CH2:23][CH3:24])=[O:28])(=[O:19])=[O:20])=[O:16])[N:8]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCCSC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Temperature: 80 °C
Yield: 109.6 %

Procedure:
Trimethylaluminum (1.5 ml) (2M) was charged via syringe to 5.0 ml dry toluene under nitrogen atmosphere and 0.54 g (0.006 mole) N-butanethiol in 2.0 ml toluene was added dropwise. N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide (0.95 g) was added portionwise and the mixture warmed to 80° C. for 3 hr. After cooling to room temperature, the mixture was quenched with 25 ml of 10% HCl. Methylene chloride was added, separated, dried over magnesium sulfate, filtered and evaporated to give a crude oil. Trituration with hexanes gave 0.6 g white solid, m.p. 115°-120° C., showing infrared absorption peaks at 1725, 1680, 1600, 1560 cm-1 consistent for N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-(N-butylthio)carbonylbenzenesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]1.[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][CH:27]=1.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[N:10]=[CH:9]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO)c3)c(F)c2)C(=O)O1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(Cn4cnc5ccccc54)c3)c(F)c2)C(=O)O1
Yield: 37.3 %

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-hydroxymethylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide (104 mg, 0.3 mM) and benzimidazole (71 mg, 0.6 mM) were suspended in dry acetonitrile (6 ml) under argon, and NAN-dimethylformamide dineopentyl acetal (208 mg, 0.9 mM) added. The mixture was refluxed for 8 hours. Solvent was evaporated, and the residue dissolved in dichloromethane and chrornatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 20% methanol in dichnoromethane. Relevant fractions were combined and evaporated to give the title product (50 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and (4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methanamine. LCMS (MIFF): m/z=451.2, tR (minutes, Method D)=0.79
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:11])[O:9][CH:10]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O.C1C=CC(C(OOC(C2C=CC=CC=2)=O)=O)=CC=1>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][Br:12])[O:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1coc(CBr)n1
Yield: 10.3 %

Procedure:
To a stirred solution of 1.74 g (11 mmol) of 2-methyl-oxazole-4-carboxylic acid ethyl ester in 15 mL tetrachloromethane at RT, 2.994 g (17 mmol, 1.5 eq) N-bromosuccinimide and 50 mg (0.2 mmol, 0.02 eq) benzoyl peroxyde were added. The reaction mixture was stirred under reflux overnight. The reaction mixture was filtered, the filtrate was extracted with CH2Cl2 and Na2S2O3 solution. The combined organic phases were dried over Na2SO4, filtered and evaporated to dryness to yield 265 mg (10%) of 2-bromomethyl-oxazole-4-carboxylic acid ethyl ester as an yellow oil, MS: 235 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])(=[O:12])=[O:11])=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:21][C:22]([OH:24])=[O:23])[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2C)cn1
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1

Procedure:
prepared by reaction of N-(6-methoxy-pyridin-3-yl)-2-methyl-benzenesulfonamide with tert-butyl bromoacetate