Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])[CH3:2].O[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.4 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylate ethyl ester [compound of formula (II)] (10.90 g, 26.75 mmol) prepared in Step 4 of Example 1 was dissolved in tetrahydrofuran:benzene (270 ml:90 ml). Then, 4-(2-hydroxyethyl)morpholine (5.83 g, 44.45 mmol) and triphenylphosphine (11.66 g, 44.45 mmol) were added thereto. Diisopropylazodicarboxylate (8.99 g, 44.45 mmol) was added dropwise to the mixture at 0° C., and stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate) to obtain the title compound (14 g, yield 93%) as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=3)[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: Cc1ccc2nc(-c3cccc(Cl)c3)oc(=O)c2c1
Yield: 91.1 %

Procedure:
When the reaction conditions of Example 1 are employed but 11.3 g of 5-methylanthranilic acid and 13.1 g of 3-chlorobenzoyl chloride are used, 18.5 g (91%) of 6-methyl-2-(m-chlorophenyl)-4H-3,1-benzoxazin-4-one of melting point 160°-162° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.Cl[CH2:18][C:19]([NH:21][CH3:22])=[O:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:22][NH:21][C:19](=[O:20])[CH2:18][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)COc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.0 mmol), 2-chloro-N-methylacetamide (129 mg, 1.2 mmol), and K2CO3 (207 mg, 1.5 mmol) in DMF (1.5 mL) was stirred at 80° C. overnight. The mixture was poured into water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to give the title compound in the yield of 72%. MS (m/z): 292 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:12]1[C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.Cl>ClC(Cl)C>[C:1]([C:20]1[CH:21]=[CH:22][C:23]2[S:24][C:25]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:17][C:18]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc2c(c1)Sc1ccccc1S2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (22.4 g) in dichloroethane (75 ml) was added to a suspension of aluminium chloride (58.4 g) in dichloroethane (100 ml) at 0° C. This was then added to a solution of thianthrene (43.2 g) in dichloroethane (600 ml) at 0° C. The reaction mixture was stirred for 1 hour at 0° C, then allowed to warm to room temperature and poured onto ice and concentrated hydrochloric acid. The organic layer was separated and the aqueous extracted with dichloroethane. The combined extracts were washed, dried and evaporated to give a brown oily product of crude 2-acetylthianthrene. This was heated to 90° C. for 2.5 hours with sodium hypochlorite solution (containing 14% available chlorine) (270 ml), normal sodium hydroxide solution (600 ml) and 1,4 dioxan (600 ml). After standing for 16 hours fine needles were filtered from the reaction mixture. These were washed and dried to give thianthrene, m.pt. 155° C. The reaction liquors were poured onto ice and concentrated hydrochloric acid. The precipitated solid was filtered off, washed with water, and dissolved in 0.5 Normal sodium hydroxide solution. The mixture was filtered from some insoluble material, and the alkaline filtrates re-acidified with concentrated hydrochloric acid. The precipitated solid was washed with water, and dried in vacuo to yield thianthrene-2-carboxylic acid, m.pt. ca. 220° C. Recrystallisation from glacial acetic acid and acetonitrile raised the melting point to 227°-8° C.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[Na+].[H-].[Na+]>O.CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:3]2[N:2]=[N:1][C:5]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)=[N:4]2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncccc1-c1nn[nH]n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncccc1-c1nnn(Cc2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 17.2 %

Procedure:
To a solution of 3-(2H-tetrazol-5-yl)-pyridin-2-ylamine (100 mg) described in Manufacturing Example 5-1, 4-benzyloxybenzyl chloride (172 mg), sodium iodide (111 mg), and DMF (3 mL) was added NaH (18 mg), which was stirred for 40 minutes at 60° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1, then 2:1, then 1:1). Ethyl acetate was added to the resulting residue, and the solids were filtered off to obtain the titled compound (38 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](OB(O)O)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:16][CH:15]=1
Reactant: COc1ccc(OB(O)O)cc1
Reactant: Brc1cnc2ccccc2c1
Product: COc1ccc(-c2cnc3ccccc3c2)cc1
Reaction time: 18 h
Yield: 89 %

Procedure:
The compound is prepared by the reaction of 3-bromoquinoline (500 mg, 2.40 mmol, 1 eq) with 4-methoxyphenylboric acid (365 mg, 2.40 mmol, 1 eq) according to method A in 18 h. Purification by column chromatography with a mixture of hexane/ethyl acetate 9/1 yielded the desired product as a white solid in a yield of 89% (504 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1>>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2cccnc2C)nn1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cccnc4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 9 was prepared by coupling 4-methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid (5:3 mixture with 4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid) with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. Preparative HPLC was used to separate N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide from N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide. ESI MS m/z 549 [C28H32N6O4S+H]+.
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][C@@H:9]1[O:14][C:13]2[CH:15]=[C:16]3[C:21](=[CH:22][C:12]=2[NH:11][C:10]1=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]3)(C)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C)C=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:6][CH2:7][CH2:8][C@@H:9]3[O:14][C:13]4[CH:15]=[C:16]5[C:21](=[CH:22][C:12]=4[NH:11][C:10]3=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]5)[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC[C@@H]1Oc2cc3c(cc2NC1=O)CCCC3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cc3c(cc2O[C@H]1CCCN1CCN(c2ccc(F)cc2)CC1)CCCC3
Yield: 59.7 %

Procedure:
A mixture of (S)-6,7,8,9-tetrahydro-2-(3-mesyloxypropyl)-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (1.02g), 1-(4-fluorophenylpiperazine (0.83g), triethylamine (0.43 ml) and dimethylformamide (15 ml) was stirred at 70° C. for 2 hours. The solvent was distilled off and the residue was purified by column chromatography on silica gel (60 g) with ethyl acetate-hexane (3:1, v/v) to yield crystals of (S)-(-)-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6,7,8,9-tetrahydro-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one (0.76 g, 59.6%). Repeated recrystallization from MeOH gave colorless crystals, m.p. 155.5°-156.6° C. [α]D26 -19.9° (c=1.2, CHCl3).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:20][OH:21])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Product: ON=C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
1-(4-Trifluoromethylbenzyl)-4-piperidone oxime is prepared from 1-(4-trifluoromethylbenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:24]=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:24]([NH:23][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:25])[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1C=CC(NC(=O)Nc3ccccc3)C1)c1cccc(Cl)c21
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a stirred solution of 5-(4amino-cyclopent-2-enyl)9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (50 mg, 0.16 mmol) in CH2Cl2 (2 mL) was added isocyanatobenzene (0.018 mL, 0.18 mmol) and DMAP (catalytic amount) and stirred at r.t for 2 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the tide compound (35 mg, 50%). Mass Spectrum (M) (m/z) 433.3 (M−1). Anal. Calc. For C23H19ClN4O3; Theoretical: C, 63.52, H, 4.40, N, 12.88%; Found: C, 63.82, H, 4.45, N, 12.49%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14]([OH:16])=O)=[C:8]([CH3:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH:21]1([CH2:24][NH2:25])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][NH:25][C:14]([C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]([CH3:12])[C:8]=2[CH3:13])=[O:16])[CH2:23][CH2:22]1
Reactant: NCC1CC1
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(C(=O)NCC3CC3)c(C)n(C)c2c1
Yield: 38.4 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid 16c (0.80, 3.65 mmole) with SOCl2 (0.799 ml, 10.95 mmole) and cyclopropylmethylamine (0.38 ml, 4.38 mmole) in a manner as previously described for example 9d to give a pale yellow solid (0.382 g, 38%). 1H NMR (300 MHz, CD3OD) δ7.50 (1H, d, J=8.7 Hz), 6.81 (1H, d, J=2.2 Hz), 6.69 (1H, dd, J=2.2, 8.7 Hz), 3.74 (3H, s), 3.56 (3H, s), 3.20 (2H, m), 2.50 (3H, m), 1.07 (1H, m), 0.44 (2H, m), 0.21 (2H, m); ESIMS (MH+): 273.10.
Reaction SMILES: [C:1]([O-:4])([O-:3])=[O:2].[K+].[K+].O[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[CH:10][CH:9]=1>O1CCCC1>[C:16]([O:2][C:1]([O:4][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[CH:10][CH:9]=1)=[O:3])([CH3:18])([CH3:17])[CH3:15]
Reactant: C=C(C)C(=O)Nc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccc(OC(=O)OC(C)(C)C)cc1

Procedure:
K2CO3 (30 g) is added to a solution of 20.0 g (0.112 tool) of N-(4-hydroxyphenyl)methacrylamide in tetrahydrofuran (THF). A solution of 27 g (0.124 tool) of di-tert-butyl pyrocarbonate (di-tert-butyl dicarbonate) in THF is then added at room temperature while stirring. The reaction is complete after a few hours. The reaction mixture is poured onto ice and extracted with ethyl acetate, the organic phase is dried and the solvent is distilled off. A white crystalline product is obtained which is recrystallized from diisopropyl ether.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=1[C@H:26]([OH:29])[CH2:27][OH:28].Cl.C(OCC)C>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=1[C@H:26]([OH:29])[CH2:27][O:28][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CCOC(=O)CCc1ccc(Cl)c([C@H](O)CO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)CCc1ccc(Cl)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
p-Toluenesulfonyl chloride (1.08 g, 5.69 mmol) in pyridine (15 mL) was added drop wise over 30 min to a cooled (0° C.) solution of ethyl 3-{4-chloro-3-[(1S)-1,2-dihydroxyethyl]phenyl}propanoate (1.41 g, 5.17 mmol) in pyridine (20 mL) under N2. The solution slowly warmed to rt overnight. After 16 h, 1N HCl and ethyl ether were added. The organic layer was isolated and the aqueous layer washed with ethyl ether (2×). The combined organic fractions were washed with 1N HCl, 10% aqueous Cu2SO4, brine, dried (Na2SO4), and concentrated. The crude product was purified by Biotage chromatography (0%-10% EtOAc/Hexanes) to afford 1.77 g of product as an oil (80%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.81 (d, J=8.08 Hz, 2 H) 7.43 (d, J=2.27 Hz, 1 H) 7.36 (d, J=8.34 Hz, 2 H) 7.22 (d, J=8.08 Hz, 1 H) 7.10 (dd, J=8.21, 1.89 Hz, 1 H) 5.34 (td, J=5.62, 2.91 Hz, 1 H) 4.28 (dd, J=10.61, 2.53 Hz, 1 H) 4.14 (q, J=7.24 Hz, 2 H) 3.98 (dd, J=10.61, 8.34 Hz, 1 H) 2.93 (t, J=7.71 Hz, 2 H) 2.60 (t, J=7.83 Hz, 2 H) 2.47 (s, 3 H) 1.25 (t, J=7.07 Hz, 3 H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([NH:9][S:10]([C:13]1[CH:18]=[C:17]([CH2:19][NH2:20])[CH:16]=[CH:15][C:14]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:12])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([NH:9][S:10]([C:13]1[CH:18]=[C:17]([CH2:19][NH:20][C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:12])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(CN)cc1S(=O)(=O)NC(C)(C)C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(C)=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
0.63 g (8 mmol) of acetyl chloride dissolved in 10 ml of dichloromethane is added dropwise to a solution, cooled to 0° C., of 2.01 g (6.7 mmol) of N-tert-butyl-5-aminomethyl-2-methoxycarbonylbenzenesulfonamide and 0.93 ml (6.7 mmol) of triethylamine in 30 ml of dichloromethane, and the mixture is then stirred at room temperature for 2 h. The reaction solution is washed with water, dried and evaporated to dryness i.v. 2.1 g (91%) of N-tertbutyl-5-acetamidomethyl-2-methoxycarbonylbenzenesulfonamide are obtained as a viscous oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][C:12]=2[F:28])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:13][C:12]=2[F:28])=[CH:7][CH:6]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CN=[N+]=[N-])cc3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CN)cc3)c(F)c2)C(=O)O1
Temperature: 52.5 °C
Yield: 87.1 %

Procedure:
A solution of 53 (7.16 g, 18.69 mmol) in tetrahydrofaran (THF) (100 mL) was treated with triphenylphosphine (PPh3, 5.88 g, 22.43 mmol, 1.2 equiv) and H2O (3.6 g, 3.6 mL, 0.2 mmol, 11.0 equiv) at 25° C., and the resulting reaction mixture was warmed to 50-55° C. for 12 h. When TLC and HPLC showed the reduction reaction was complete, the reaction mixture was cooled to room temperature before the solvents were removed in vacuo. The residue was directly purified by flash column chromatography (0-15% MeOH-CH2Cl2 gradient elution) to afford the desired N-[3-(4′-Aminomethyl-2-fluoro-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 54 (5.82 g, 87% yield) as off-white crystals, which were of sufficient purity to be directly used in subsequent reactions. 1 H NMR (300 MHz, DMSO-d6) δ1.85 (s, 3H, COCH3), 3.04 (br. s, 2 H, NH2), 3.44 (t, 2 H, J=5.4 Hz), 3.78 (m, 3 H), 4.18 (t, 1 H, J=9.1 Hz), 4.77 (m, 1 H), 7.25-7.60 (m, 7 H, aromatic-H), 8.20 (t, 1 H, J=5.8 Hz, NHCOCH3). LCMS (ESI) m/e 359 (M+2 H)2+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S(Cl)([Cl:15])=O.Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:15])=[O:8]
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(Cl)c1
Yield: 99.7 %

Procedure:
A solution of trans-3-chlorocinnamic acid (25.5 g) and thionyl chloride (33.6 g) in dry benzene (300 ml) was heated at reflux until the evolution of HCl and SO2 had ceased. Excess thionyl chloride and benzene were removed by distillation under reduced pressure to give trans-3-chlorocinnamoyl chloride (28 g) as an oil. A solution of trans-3-cinnamoyl chloride (4.0 g) in dry toluene (75 ml) was added with stirring to a solution of pyrrolidine (4.3 g) in dry benzene (75 ml) at ambient temperature. The reaction mixture was allowed to stir for 10 hr., after which time excess pyrrolidine and solvents were removed under reduced pressure. The residue was triturated with water, filtered, and recrystallized from ethanol/water as follows: the wet solid was dissolved in warm (40 - 45° C) ethanol (90 ml), the resulting solution filtered, and water (ca. 900 ml) added giving crystalline trans-1-(3-chlorocinnamoyl)pyrrolidine, m.p. 137 - 138° C. Elemental analysis, NMR, and IR spectra are consistent with the assigned structure.
Reaction SMILES: [C:1]1([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:22]([NH:25]C(=O)OC(C)(C)C)(=[O:24])=[O:23])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:22](=[O:23])(=[O:24])[NH2:25])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of Compound 46a (1.16 g, 2.3 mmol) in DCM (10 mL) was added TFA (5 mL) and the reaction mixture stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure then evaporated under reduced pressure from toluene (2×). The residue was diluted with 1.5 M K3PO4 then extracted with DCM (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1 to 15% MeOH/DCM to give Compound 46b (68 mg, 74% yield) as a pale brown solid. LCMS=1.71 min using analytical method (B), 402.0 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.5, 1.8 Hz, 1H), 7.73-7.65 (m, 2H), 7.47 (t, J=7.7 Hz, 2H), 7.41-7.32 (m, 1H), 4.47 (s, 2H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:18][CH:17]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Nc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cnc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C

Procedure:
Under an argon atmosphere 50 mL 2 M Na2CO3 solution and 1.2 g (1.0 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 8.7 g (50.0 mmol) 5-bromo-pyrazin-2-ylamine and 8.0 g (50.0 mmol) 4-chlorophenyl-boric acid in 150 mL 1,4-dioxane and 50 mL MeOH and the reaction mixture is heated to 110° C. for 2.5 h. The mixture is evaporated down i.vac., the residue is combined with water, extracted exhaustively with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: DCM to DCM/MeOH 20:1).