Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([CH3:32])([O:24][Si](CC)(CC)CC)[CH3:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O1CCCC1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:33][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])([CH3:32])[CH3:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC[Si](CC)(CC)OC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Yield: 61 %

Procedure:
In a flask containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methyl-2-triethylsilanyloxy-propyl)-1H-pyrazol-3-yl]-propionamide (80 mg, 0.14 mmol) was added tetrahydrofuran (2 mL), water (500 μL) and acetic acid (2 mL) and was stirred at 25° C. until complete by thin layer chromatography. It was then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organics were than combined and washed with a saturated aqueous solution of sodium bicarbonate (10 mL) and dried over magnesium sulfate, filtered and concentrated. Purification by AnaLogix Intelliflash system (4 g silica gel column, 15% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (40 mg, 63%) as a white foam: [α]31589=−8.2° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C22H30N3O4SCl (M+H)+ 468.1719, observed 468.1717; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.06-1.20 (m, 2H, CH2), 1.35-1.84 (m, 8 H, 4×CH2), 2.00-2.17 (m, 1H, CH), 3.34 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.92 (dd, J=8.3, 6.8 Hz, 1H, ArCH), 4.65 (s, 1H, OH), 6.45 (d, J=2.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.59 (dd, Jo=8.3 Hz, Jm=1.6 Hz, 1H, Ar), 7.70 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.3 Hz, 1H, Ar), 10.81 (s, 1H, NH).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][CH:15]=1.[CH3:7][C:8]1[C:17]([CH3:16])=[C:12]([CH3:13])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Cc1cccc(C)c1C
Product: c1ccc2ccccc2c1

Procedure:
The process of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 wherein said conversion is transalkylation of benzene and methylnaphthalene to form toluene and naphthalene or transalkylation of toluene and trimethylbenzene to form xylenes and said conversion conditions include a temperature of between about 650° F. and 1100° F., a pressure of between about 0 and about 1000 psig and a WHSV of between about 1 and about 20.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(-c2ccncc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccncc2)cc1Br
Temperature: 60 °C

Procedure:
Bromine (26.0 g. 163 mmol) is added to a stirred solution of 4-(4-methoxyphenyl)pyridine (13.6 g. 73.5 mmol) in acetic acid (500 mL) and heated at 60° C for 72 h. The mixture is then evaporated to dryness under reduced pressure and the residue is treated with aqueous ammonia (400 mL of 6M) and extracted with ethyl acetate (3×200 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 95% t-butylmethyl ether/4.5% methanol/0.5% aqueous NH3(25%)) and recrystallised from ether-cyclohexane to give 4-(3-bromo4-methoxyphenyl)pyridine as a pale-yellow crystalline solid, m.p. 82-84° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]#[N:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1.O>[CH2:28]([N:10]1[C:9]([CH2:8][NH:7][C:6](=[O:32])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]3[N:33]=[N:34][NH:35][N:26]=3)[CH:16]=2)[C:11]1=[O:27])[CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C#N)ccc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nn[nH]n3)ccc2c1=O
Temperature: 90 °C
Reaction time: 24 h
Yield: 37.9 %

Procedure:
To a solution (30 mL) of tert-butyl(6-cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.86 g, 2.0 mmol) in toluene were added sodium azide (0.16 g, 2.5 mmol) and triethylamine hydrochloride (0.28 g, 2.5 mmol) and the mixture was stirred at 90° C. for 24 h. The reaction mixture was poured into water (100 mL), acidified with 1N hydrochloric acid and extracted twice with ethyl acetate (50 mL). The extracts were combined and washed with saturated brine (15 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-diisopropyl ether (1:5) to give tert-butyl [2-isobutyl-1-oxo-4-phenyl-6-(2H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.36 g, 37%) as colorless crystals.
Reaction SMILES: [N:1]1C=CC=CC=1C(=O)CC(=O)CC(C1C=CC=CN=1)=O.[N:21]1([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32](=O)[CH2:33][C:34](=[O:49])[CH2:35][C:36]([C:38]3[CH:43]=[C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH:41]=[CH:40][N:39]=3)=O)[CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>CO>[N:21]1([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]3[NH:1][C:36]([C:38]4[CH:43]=[C:42]([N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)[CH:41]=[CH:40][N:39]=4)=[CH:35][C:34](=[O:49])[CH:33]=3)[CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(CC(=O)c1ccccn1)CC(=O)c1ccccn1
Reactant: O=C(CC(=O)c1cc(N2CCCC2)ccn1)CC(=O)c1cc(N2CCCC2)ccn1
Solvent: CO
Product: O=c1cc(-c2cc(N3CCCC3)ccn2)[nH]c(-c2cc(N3CCCC3)ccn2)c1

Procedure:
This compound is prepared in a manner analogous to that described in Example 1, Step 2 for 1,5-di-pyridin-2-yl-pentane-1,3,5-trione, but instead the pyrrolidine-substituted triketone from Example 21 is used. Pure 4,4″-di-pyrrolidin-1-yl-1′H-[2,2′;6′,2″]terpyridin-4′-one can be obtained by recrystallisation from methanol in the form of an almost colourless solid. 1.81-2.05 (m, 8H); 3.17-3.33 (m, 8H); 6.32 (dd, 2H, J=5.7, 2.3 Hz); 6.84 (d, 2H, J=2.3 Hz); 6.90 (s, 2H); 8.19 (d, 2H, J=5.7 Hz). MS (EI pos., 70 eV), m/z=387 ([M+]), 359 (100); 358 (85); 330 (20); 28 (60).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH:9]([NH2:11])C)[CH:5]=[N:4]1)[CH3:2].[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:27](O)=[O:28])[CH:23]=2)[N:18]=1)([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([CH2:9][NH:11][C:27]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25]3)=[O:28])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(C)N)c1C
Reactant: CC(C)(c1ccc2cc(C(=O)O)ccc2n1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1ncc(CNC(=O)c2ccc3nc(C(C)(C)C(F)(F)F)ccc3c2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
To a DMF (3 ml) solution of 1-(1-ethyl-5-methyl-1H-pyrazol-4-yl)ethanamine (95 mg, 0.62 mmol), (2,2,2-trifluoro-1,1-dimethylethyl)quinoline-6-carboxylic acid (176 mg, 0.62 mmol), HBTU (284 mg, 0.748 mmol) and triethylamine (0.434 ml, 3.12 mmol) were added and the mixture was stirred for 3 hours at room temperature. The reaction was quenched with sat. NaHCO3 aq and water, and the product was extracted with EtOAc/hexane (4:1) (3×20 ml). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography, using EtOAc/hexane (2:1) to give the title product (31 mg, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 1.27 (3H, t) 1.49 (3H, d), 1.71 (6H, s), 2.25 (3H, s), 4.01 (1H, q), 5.19 (1H, m), 7.44 (1H, s), 7.86 (1H, d), 8.06 (1H, d), 8.20 (1H, d), 8.51 (1H, d), 8.53 (1H, bs) 8.86 (1H, d). LCMS (ESI) RT=3.11 mins, m/z 417 (M−H)−, 419 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][CH:9]([CH2:12]Br)[CH2:10]Br)=[CH:5][CH:4]=1.[CH3:16][NH2:17]>O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][CH:9]2[CH2:12][N:17]([CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COC(CBr)CBr)cc1
Reactant: CN
Solvent: O
Product: COc1ccc(COC2CN(C)C2)cc1
Temperature: 90 °C

Procedure:
33.7 Parts of 2-(p-methoxybenzyloxy)-1,3-dibromo-propane, 70 parts of monomethylamine and 70 parts of water were added to an autoclave, and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result, 11.7 parts of 3-(p-methoxybenzyloxy)-1-methylazetidine boiling at 85°-87° C. under 2 mm Hg were obtained.
Reaction SMILES: [C:1]([CH2:9][CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1[N:20]=[N:21][CH:22]=CC=1CC(C)C.C([NH:31][NH2:32])=O>>[CH2:14]([C:10]1[C:11]2[N:31]([CH:22]=[N:21][N:20]=2)[N:32]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CC(CC(=O)c1ccccc1)C(=O)O
Reactant: NNC=O
Reactant: CC(C)Cc1ccnnc1Cl
Product: CC(C)Cc1cc(-c2ccccc2)nn2cnnc12

Procedure:
Following the general procedure of Example 4, 3-benzoyl-2-isobutyl-propionic acid is converted to 3-chloro-4-isobutylpyridazine which is treated with N-formylhydrazine to give the title compound.
Reaction SMILES: [OH:1][P:2]([O:5][P:6]([O:9][P:10]([OH:13])([OH:12])=[O:11])([OH:8])=[O:7])(=[O:4])[OH:3].[N+]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)([O-])=O.[NH2:26]C1C=C2C(=CC=1)NC=C2>>[OH:13][P:10]([O:9][P:6]([O:5][P:2]([OH:4])([OH:3])=[O:1])([OH:8])=[O:7])(=[O:11])[OH:12].[NH2:26][C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:25][CH:24]=2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: O=P(O)(O)OP(=O)(O)OP(=O)(O)O
Product: Nc1cc2ccccc2[nH]1

Procedure:
Amino-indole triphosphate was prepared from 5-nitro-indole triphosphate by hydrogenation reaction. The extinction coefficient for 5-amino-indole is 5830 M−1 cm−1 at 270 nm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C@@H:10]([NH:14][C:15]([O:17][CH3:18])=[O:16])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1>ClCCl.C([SiH](CC)CC)C.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C@@H:10]([NH:14][C:15]([O:17][CH3:18])=[O:16])[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](CC(=O)c1ccc(Br)cc1)C(=O)O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](CCc1ccc(Br)cc1)C(=O)O
Reaction time: 5.5 h
Yield: 74 %

Procedure:
A solution of (R)-4-bromo-α-[(methoxycarbonyl)amino]-γ-oxobenzenebutanoic acid (2) (74.35 g) in dichloromethane and triethylsilane (182 ml) was cooled to 0° C. and titanium tetrachloride (99.0 ml) was added dropwise over a period of 15 minutes with stirring. After 5.5 hours, triethylsilane (72 ml) was added, and the mixture was stirred at room temperature for 17 hours and at reflux on the steam bath for 3 hours. The mixture was cooled and poured onto ice. The mixture was extracted twice with diethylether. The combined ether extracts were washed with water and extracted 3 times with 250 ml portions of 10% sodium carbonate solution. The combined extracts were washed with diethylether, cooled in ice, and acidified with concentrated hydrochloric acid. The precipitate was filtered, washed with water, and dried under vacuum to leave a white solid. Crystallization from ethyl acetate/hexane gave the title compound as white crystals (52.7 g, 74%, m.p. 136-137° C.). [α]D =-12° (25° C., CH3OH, c=0.8709).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[O:22])(=[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].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl.[NH2:62][C@H:63]([C:76]([O:78][CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)=[O:77])[CH2:64][CH2:65][C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67]>O1CCOCC1>[C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:62][C@H:63]([C:76]([O:78][CH2:79][C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1)=[O:77])[CH2:64][CH2:65][C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])=[O:28])=[O:22])(=[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]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
N-(3-hexadecanoyloxyoctadecanoyl)-β-alanine (1.47 g) prepared by the method of Preparation B-5 and N,N'-dicyclohexylcarbodiimide (412 mg) were added to a mixed solution of dichloromethane (20 ml) and dioxane (20 ml). The resulting mixture was stirred for 15 minutes. Then, a solution of dibenzyl L-glutamate (650 mg) in dioxane (10 ml) was added thereto over a period of 30 minutes. The mixture was stirred for 2 hours at room temperature and allowed to stand overnight. The precipitated N,N'-dicyclohexylurea was removed off by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to afford crystals of dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-glutamate (850 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[CH3:34][C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>C(Cl)Cl>[CH3:15][C:14]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:22][C:42](=[O:43])[N:41]([C:37]2[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(O)c2ccccc2)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cccc(N2CCC(C)(c3ccccc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (1 g, 3.12 mmol) and DBU (1.4 g, 9.26 mmol) in CH2Cl2 (15 mL) was added a solution of 3-methylphenyl isocyanate (623 mg, 4.68 mmol) in CH2Cl2 (5 mL) at 0° C. over 0.5 h. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography and then by preparative HPLC to afford 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one. LC-MS Method 2, tR=2.706 min, m/z=282. 1H NMR (CDCl3) 1.75 (s, 3H), 2.30 (s, 3H), 2.35-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 6.95 (m, 2H), 7.05 (m, 1H), 7.20-7.30 (m, 1H), 7.35 (m, 1H), 7.42-7.50 (m, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[Cl:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>C(OC(=O)C)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH:14][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=2)[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(CCl)cc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CCl)cc3)C2SC1

Procedure:
A mixture of 1 g of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of p-chloromethylphenylacetyl chloride in 45 ml of ethylacetate is refluxed for about 2 hours after which the solvent is removed under vacuum yielding a yellow-brown amorphous product which is chromatographed on silica gel using benzene-acetone as the eluant to give 3-[(acetyloxy)methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 164°-165° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si](C(C)C)(C(C)C)C(C)C)=[CH:4][C:3]=1[C:21]([OH:23])=[O:22].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)O)c(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1cc2cc[nH]c2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.5 %

Procedure:
6-Fluoro-1-(triisopropylsilyl)-1H-indole-5-carboxylic acid (4.36 g, 13.00 mmol) was treated with THF (30 mL) and tetra-n-butylammonium fluoride (1.0 M in THF, 13.0 mL, 13.00 mmol) and stirred at RT for 15 min. The reaction mixture was diluted with Et2O (30 mL) resulting in a suspension which was collected by filtration affording 6-fluoro-1H-indole-5-carboxylic acid (2.41 g) as a white crystalline solid. MS (ESI, pos. ion) m/z: 180.1 (M+H)+. The crude material was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][P:5]([CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)(=[O:8])[O:4][CH2:3]1.C(OC(=O)[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:29][C:28]=1[NH2:38])(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[CH:29][C:28]=1[NH:38][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([CH2:9][P:5]2(=[O:8])[O:6][CH2:7][C:2]([CH3:19])([CH3:1])[CH2:3][O:4]2)=[CH:11][CH:12]=1
Reactant: CC1(C)COP(=O)(Cc2ccc(C(=O)O)cc2)OC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC1(C)COP(=O)(Cc2ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cc2)OC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(5,5-Dimethyl-2-oxo-2λ5-[1,3,2]dioxaphosphinan-2-ylmethyl)-benzoic acid (100 mg, 0.35 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (123 mg, 0.42 mmol), EDC (81 mg, 0.42 mmol), HOBT (54 mg, 0.35 mmol), and DIPEA (136 mg, 1.05 mmol) were combined and diluted with DMF (1.4 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined and concentrated in vacuo. The residue was diluted with 10:1 DCM:TFA and stirred at ambient temperature for 2 hours. The mixture was then concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) δ 9.85 (s, 1H), 7.93 (d, J=7.2 Hz, 2H), 7.50 (s, 1H), 7.43 (d, J=7.2 Hz, 2H), 7.34-7.40 (m, 2H), 7.28-7.30 (m, 1H), 7.03-7.06 (m, 1H), 6.90-6.92 (m, 1H), 4.20-4.25 (m, 2H), 4.01 (br-s, 2H), 3.87-3.94 (m, 2H), 3.52 (d, J=20.4 Hz, 2H), 1.08 (s, 3H), 0.84 (s, 3H). MS: cal'd 457 (MH+), exp 457 (MH+).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH:22]([SH:24])[CH3:23].Cl>CN(C)C(=O)C>[CH:22]([S:24][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:23])[CH3:21]
Reactant: CC(C)S
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 90 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid in 6 ml N,N-dimethylacetamide were added 15.2 mol cesium carbonate and 10.1 mmol 2-propanethiol and the mixture was stirred at 90° C. for 3 h. The reaction mixture was then cooled to room temperature and acidified to pH 1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light yellow liquid which was used in the next step without further purification (yield 99%). EI-MS (m/e): 274.1 (M+, 35%), 232.1 ([M-C3H6]+, 30%, 214.1 (M-C3H6—H2O)+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][CH2:37][CH:38]([OH:50])[CH2:39][N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:36][CH2:37][CH:38]([OH:50])[CH2:39][N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41]1)=[O:9]
Reactant: Nc1ccc(F)c(C(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
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: Nc1ccc(F)c(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 17 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
The solution of 5-amino-2-fluorobenzoic acid (200 mg, 1.29 mmol) and HATU (490 mg, 1.29 mmol) in DCM (15 mL) was stirred at 17° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (265 mg, 1.29 mmol) and DIPEA (333 mg, 2.58 mmol) was added and the resulting solution was stirred at 17° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give desired product (372 mg, Yield 84%).