Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[NH:70][N:69]=[N:68][N:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[NH:70][N:69]=[N:68][N:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4nnn[nH]4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4nnn[nH]4)CS[C@H]23)cs1
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl]amino-3-(5-tetrazolyl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (942 mg: containing ca. 10% of byproduct) in a mixture of anisole (3 ml) and nitromethane (12 ml) cooling at -30° to -40° C. is added a solution of aluminum chloride (980 mg: 7.37 mMol.) in anisole (3 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is diluted with 1N-hydrochloric acid (7.5 ml) and water, washed with ethyl acetate, concentrated under reduced pressure to remove the organic solvents, and subjected to styrene-divinylbenzene copolymer chromatography (methanol: water=2:3). The resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl]amino-3-(tetrazol-5-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (289 mg). Yield: 28% (from 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl]amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[CH2:31]([C:38]([OH:40])=O)[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1.[NH2:41][C@H:42]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=1)[C:43]([N:45]1[CH2:48][C:47]([O:56][CH2:57][C:58]#[C:59][CH3:60])([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])[CH2:46]1)=[O:44].[OH-].[Na+]>CN(C)C=O>[CH2:57]([O:56][C:47]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])[CH2:48][N:45]([C:43](=[O:44])[C@H:42]([NH:41][C:38](=[O:40])[CH2:31][CH2:32][C:33]2[N:37]=[CH:36][NH:35][CH:34]=2)[CH2:61][C:62]2[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=2)[CH2:46]1)[C:58]#[C:59][CH3:60]
Reactant: CC#CCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#CCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
732 mg (2.3 mmol) of TBTU and 1 ml (7 mmol) of triethylamine are added to a solution of 408 mg (2.3 mmol) of desamino-histidine hydrochloride in 6 ml of dimethylformamide. After stirring for 10 min, 751 mg (1.8 mmol) of (R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolyl-azetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one in 6 ml of dimethylformamide are added. The reaction medium is stirred for 115 hours at ambient temperature and then a 1N aqueous solution of sodium hydroxide is added and the medium is extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography, elution being carried out with a 90/10 dichloro-methane/methanol mixture. 362 mg of N—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white solid with a yield of 40%.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22](C(OC(C)(C)C)=O)[N:23]=1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:18][O:17][C:13]1[N:12]=[C:11]2[CH:10]=[C:9]([C:19]3[C:20]4[S:33][CH:32]=[CH:31][C:21]=4[NH:22][N:23]=3)[NH:8][C:16]2=[CH:15][CH:14]=1
Reactant: COc1ccc2c(cc(-c3nn(C(=O)OC(C)(C)C)c4ccsc34)n2C(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-methoxy-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester [250 mg, 0.531 mmol, Intermediate (62)], anisole (1.0 mL), and dichloromethane (1.0 mL) at ambient temperature was added trifluoroacetic acid (1.0 mL) and the resulting solution heated at 45° C. After 1 hour, the green reaction solution was cooled to ambient temperature, basified with 5% aqueous potassium carbonate (30 mL), and the resulting mixture extracted twice with ethyl acetate (20 mL). The combined extracts were washed with water (20 mL) and brine (20 mL) successively, dried over magnesium sulfate, and concentrated in vacuo to an oily mixture. Trituration with ether/heptane (1:1) provided 5-methoxy-2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-pyrrolo[3,2-b]pyridine [107 mg, 74%, Example 60] as a tan powder. TLC Rf 0.52 (silica, ethyl acetate); mp: 234-236° C.; LC/MS: 271.02 (M+H), RT=2.03 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.32 (br s 1H), 11.67 (br s, 1H), 7.74 (d, J=5 Hz, 1H), 7.66 (d, J=9 Hz, 1H), 7.18 (d, J=5 Hz, 1H), 6.58-6.53 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([C:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1)(C)[C:7]([OH:9])=[O:8])=[O:4].N[C:18]([C:23]1[CH:28]=CC=C[CH:24]=1)(C)C(O)=O>>[C:23]([O:4][C:3]([N:5]1[CH2:13][CH2:12][CH:11]([CH:6]([C:7]([OH:9])=[O:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:16][CH2:15]1)=[O:2])([CH3:18])([CH3:24])[CH3:28]
Reactant: COC(=O)NC(C)(C(=O)O)c1ccccc1
Reactant: CC(N)(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97 %

Procedure:
4-(Carboxy-methoxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 97%) was prepared following the procedure for 2-Methoxycarbonylamino-2-phenyl-propionic acid, substituting 4-(Amino-carboxy-methyl)-piperidine-1-carboxylic acid tert-butyl ester for 2-Amino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C14H24N2O6: 316.16 (M+); Found: 339.02 (M+Na+).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:9][C:10]1([CH2:14]O)[CH2:13][O:12][CH2:11]1.Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:9][C:10]1([CH2:14][O:7][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[CH2:13][O:12][CH2:11]1
Reactant: C#CCCCC(=O)O
Reactant: CC1(CO)COC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C#CCCCC(=O)OCC1(C)COC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.4 %

Procedure:
To a solution of 5-hexynoic acid (10.0 g) and 3-methyl-3-oxetane methanol (10.0 g) in methylene chloride (50 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.5 g), and 4-dimethylaminopyridine (1.09 g) were added under cooling with ice. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into iced water and extracted with ethyl acetate. The orgnic layer was washed by water and an aqueous saturated solution of sodium chloride, sucessively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (16.7 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]2[CH:16]=[CH:15][NH:14][N:13]2[CH3:17])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]2[CH:16]=[CH:15][NH:14][N:13]2[CH3:17])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C2C=CNN2C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1NC=CC1c1ccc(C(=O)O)c(Cl)c1

Procedure:
The tide compound was prepared in the same manner as described in Example 70, employing 2-chloro-4-(2-methyl-1H-pyrazol-3yl)-benzoic acid, methyl ester (0.464 g) and 2.5N sodium hydroxide (1.04 ml). 1H NMR (300 MHz), (DMSO-d6) δ: 3.89 (s, 3H), 6.56 (d, 1H), 7.49 (d, 1H), 7.59-7.90 (m, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:31]I>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)([CH2:16][N:17]([CH3:31])[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)(c2ccc(I)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC1(c2ccc(I)cc2)CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a flask containing sodium hydride (0.07 g, 2.9 mmol, 5 eq.) under Ar at 0° C. was added a solution of 4-(4-iodo-phenyl)-4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.298 g, 0.58 mmol) in DMF (5 mL). The resulting mixture was warmed to room temperature and stirred for 2 h, heated to 35° C. for 0.5 h and CH3I (0.36 mL, 5.8 mmol, 10 eq.) was added. The mixture heated at 35° C. for a further 2 h. The reaction was diluted with EtOAc (25 mL) and washed with saturated NaHCO3 (25 mL) and saturated brine (25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by flash column chromatography by eluting with 30% EtOAc/hexanes to give 4-(4-iodo-phenyl)-4-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (0.022 g, 0.42 mmol, 72%). 1H NMR (CDCl3): δ 7.83 (d, 2H), 7.20 (d, 2H), 3.93 (m, 2H), 3.78 (m, 1H), 3.53 (m, 1H), 3.07 (m, 2H), 2.60 (m, 3H), 2.24 (m, 2H), 1.93 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:33][CH2:34]SC)[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[CH2:18][C@H:17]1[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:33][CH2:34][N:15]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[CH2:18][C@H:17]2[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CC[C@H](NC(=O)[C@H](CCSC)NC(=O)OCc2ccccc2)[C@H](CNC(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A sample of the product from Step 7 was dissolved in iodomethane (30 ml) and stirred at room temperature for two days. The reaction mixture was evaporated and dried in vacuo. The residue was dissolved in CH2Cl2 and evaporated. The process was repeated four more times. The resulting residue was dried in vacuo to yield a yellow foamy solid which was then taken in DMF (20 ml) and treated with Cs2CO3 (6.36 g, 19.52 mmol). The reaction mixture was stirred at room temperature overnight. It was diluted with EtOAc and washed with water (2×). The combined aqueous layer was extracted with EtOAc (2×). The combined organic layer was then washed with brine and dried over anhydrous MgSO4. The solution was then concentrated and chromatographed to yield tert-butyl ((1S,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-methoxycyclohexyl)methylcarbamate as a white foamy solid. LC/MS found [M+H]+=476.4
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[C:4]([CH:13]=O)[CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[C:4]([CH2:13][C:23]2[S:22][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:25][CH:24]=2)[CH:3]=1
Reactant: O=Cc1cc(Br)c2ccccc2c1F
Reactant: c1ccc(-c2cccs2)nc1
Product: Fc1c(Cc2ccc(-c3ccccn3)s2)cc(Br)c2ccccc12

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (4.13 ml) in tetrahydrofuran (40 ml) was cooled to −78° C. under argon atmosphere, and added dropwise thereto was n-butyl lithium (2.44 M hexane solution, 10.0 ml). The mixture was stirred at the same temperature for 30 minutes, and added dropwise thereto at −78° C. was a solution of 1-bromo-4-fluoronaphthalene (5.0 g) in tetrahydrofuran (20 ml). The mixture was stirred at the same temperature for 1 hour, and added dropwise thereto at −78° C. was N,N-dimethylformamide (5.16 ml). The mixture was stirred at the same temperature for 1 hour, and added thereto was a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from diisopropyl ether and hexane to give 4-bromo-1-fluoro-2-naphthaldehyde (4.43 g) as pale yellow crystals. APCI-Mass m/Z 267/269 (M+NH4). (2) The above 4-bromo-1-fluoro-2-naphthaldehyde and 2-(2-pyridyl)thiophene were treated in a manner similar to Reference Example 120 to give the desired 4-bromo-1-fluoro-2-(5-(2-pyridyl)-2-thienylmethyl)naphthalene as colorless powder. APCI-Mass m/Z 398/400 (M+H).
Reaction SMILES: O=O.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.CO>O1CCCC1.[Rh]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(F)cc1
Agent: [Rh]
Agent: O=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Rhodium-catalyzed hydrogenation. -- A catalyst solution was prepared in a glove box (O2 content <1 ppm) by dissolving 0.01045 g (0.0257 mmol) of [Rh(COD)2 ]BF4 and 0.01861 g (0.0257 mmol) of (R,S)-BPPFA-EPIP in 20 ml of tetrahydrofuran and stirring at RT for 15 minutes. Then, 5.0 g (25.75 mmol) of 2-(p-fluorophenyl)-3-methylcrotonic acid, 13 ml of methanol and 33 ml of tetrahydrofuran were placed in a 185 ml autoclave and the catalyst solution prepared above was added. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under a constant pressure of 50 bar. The conversion was 100% after 24 hours. The hydrogenation solution was evaporated at 50°/200 mbar and the residue was distilled at 108-110°/0.01 mbar. There were obtained 4.8 g (97%) of (S)-2-(p-fluorophenyl)-3-methylbutyric acid as a colorless oil which solidified at RT; 98.2% ee.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[N:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]([C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])[S:29][CH:30]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:27]=[C:28]([C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:14](=[O:16])[C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=4)[N:13]=3)[S:29][CH:30]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)n1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)n1)c1nc(-c2ccc(Cl)cc2)cs1
Yield: 56 %

Procedure:
This compound was synthesized from 6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinic acid and 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine as described in example 8 step 6 (55 mg, yield 56%). 1H NMR (400 MHz, CDCl3) δ 8.87-8.85 (m, 1H), 8.43-8.41 (dd, J=7.8 Hz, 1 Hz, 1H), 8.27-8.24 (dd, J=7.8 Hz, 1.3 Hz, 1H), 8.10-8.06 (m, 1H), 7.89-7.87 (d, J=8.5 Hz, 2H), 7.41 (s, 1H), 7.32-7.29 (d, J=8.8 Hz, 2H), 3.91-3.89 (d, J=6.5 Hz, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated for C22H17ClF3N6O2S: 507.07. found: 508.0 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=O)C.CO[NH:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:20][NH:19][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:3]
Reactant: CNOC
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1C
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 5-chloro-1-methyl-1H-indole-2-carboxylic acid ethyl ester (1.27 g, 5.3 mmol) in toluene (10 mL) was added O,N-dimethyl-hydroxylamine (9.6 mL of a 1 M solution in toluene, 9.6 mmol). The resulting mixture was heated to reflux overnight after which the reaction was cooled to room temperature and quenched by the addition of 10% aqueous K2CO3 (50 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound (2.12 g, 96%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.27 (m, 2H), 6.73 (s, 1H), 6.13 (s, 1H), 4.03 (s, 3H), 3.01 (d, J=4.9 Hz, 3H); MS (ESI) m/e 222 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:20](B(O)O)[CH2:21][CH2:22][CH3:23]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CCCCB(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
A 4 mL vial was charged with 4-tert-butylbromobenzene (213 mg, 1.00 mmol), Pd(dba)2 (5.8 mg, 0.01 mmol, 1 mol %), Ph5FcP(t-Bu)2 (14.2 mg, 0.02 mmol, 2 mol %), K3PO4 (430 mg, 2.02 mmol, powdered) and n-butylboronic acid (124 mg, 1.21 mmol). Anhydrous toluene (2 mL) and a stirring bar were added, and the vial was then sealed with a cap containing a PTFE septum and removed from the drybox. The reaction mixture was stirred at 100° C. for 2.5 h. After the starting aryl halide was consumed as determined by GC, the reaction solution was cooled to room temperature. The reaction solution was then adsorbed onto silica gel directly, and the product was isolated by eluting with ethyl acetate/hexanes to give 175 mg (92%) of 4-tert-butyl-1-n-butylbenzene as colorless oil. Kugelrohl distillation was used for further purification.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:27](=[O:28])[NH:26][C:25]4[CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]5[CH:41]=[CH:40][C:39]([N:42]6[CH2:47][CH2:46][O:45][CH2:44][CH2:43]6)=[CH:38][CH:37]=5)[CH:31]=[CH:32][C:24]=4[NH:23][C:22]=3[CH:48]=2)=[CH:14][C:13]=1[O:49][CH3:50])(C(C)(C)C)(C)C.CO.O.[F-].C([N+](CC)(CC)CC)C>O1CCOCC1>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:27](=[O:28])[NH:26][C:25]4[CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]5[CH:41]=[CH:40][C:39]([N:42]6[CH2:43][CH2:44][O:45][CH2:46][CH2:47]6)=[CH:38][CH:37]=5)[CH:31]=[CH:32][C:24]=4[NH:23][C:22]=3[CH:48]=2)=[CH:14][C:13]=1[O:49][CH3:50]
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OCCO[Si](C)(C)C(C)(C)C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OCCO
Temperature: 25 °C

Procedure:
A mixture of Example 609A (23 mg, 0.033 mmol) in 1:1 MeOH:dioxane (2 mL) was treated with tetraethylammonium fluoride hydrate (49.4 mg, 0.33 mmol) at 50° C. for 24 hours. The reaction was then cooled to room temperature, concentrated, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was purified by preparative HPLC to provide the title compound. MS (ESI) m/e 582 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.75 (s, 1H), 7.84 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.25 (d, J=1.4 Hz, 1H), 7.15-7.20 (m, 3H), 7.07 (m, 1H), 6.80-6.96 (m, 7H), 4.00-4.06 (m, 4H), 3.85 (s, 3H), 3.70-3.75 (m, 6H), 2.96-2.99 (m, 4H), 2.86 (t, J=6.4 Hz, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]1=[O:17])=O)(C)(C)C.[ClH:18]>CCOC(C)=O>[ClH:18].[NH2:8][C@H:9]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]1=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(C)(C)OC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CC[C@H](N)C(=O)O1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
3(S)-(t-Butoxycarbonyl)amino-6,6-dimethyltetrahydropyran-2-one (0.36 g, 1.48 mmol) was dissolved in EtOAc (30 mL) and treated with HCl gas at -50° C. for 20 min and stirred at -30° to -50° C. for 20 min. Argon was bubbled into the soln for 10 min, then the soln was concentrated to give 0.265 g (100%) of the title compound as a white solid. 1H NMR (CD3OD) δ 4.05-4.15 (m, 1H), 2.2-2.32 (m, 1H), 2.0-2.15 (m, 3H), 1.48 (s, 3H), 1.43 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13](Br)[N:12]=2)=[O:10])[NH:6][N:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:12]=2)=[O:10])[NH:6][N:7]=1
Reactant: C1CCNC1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Solvent: C1CCOC1
Product: Nc1nc(C(F)(F)F)c(N2CCCC2)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1

Procedure:
To a stirred solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide (Example 1) (40 mg, 0.095 mmol) in dry THF (2 ml) was added pyrrolidine (7.89 μL, 0.095 mmol). The resulting mixture was heated using microwave radiation at 120° C. for 35 minutes. The reaction mixture was partitioned between EtOAc (50 ml) and water (30 ml) and the organic portion was separated, (MgSO4) and concentrated in vacuo to give the crude product as an orange oil. The crude product was purified using preparative TLC eluting with DCM: 1% MeOH to afford the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH:27]([F:29])[F:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)/[CH:21]=[CH:22]/[N:23](C)C)=[CH:16][CH:15]=3.O.[NH2:35]N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH:27]([F:29])[F:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[CH:22][NH:23][N:35]=1)=[CH:16][CH:15]=3
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C(F)F)c21

Procedure:
The process is carried out as indicated in Example 40 above, with the compound from Example 151B, 3-(2,4-dichlorophenyl)-9-difluoromethyl-6-((E)-3-dimethylamino-acryloyl)-1-methyl-1,9-dihydropyrido[2,3-b]indol-2-one, and hydrazine monohydrate.