Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH:34]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1)[CH2:34][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1)[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cnc(CNCCCCN(C)C(=O)OC(C)(C)C)c(C)c1
Reactant: O=Cc1nccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN(C)C(=O)OC(C)(C)C)Cc2nccc3ccccc23)c(C)c1

Procedure:
Using General Procedure B: Reaction of {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester and 1-isoquinoline-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-amino]-butyl}-methyl-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[OH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][OH:27])=[CH:30][CH:31]=2)[CH:3]=1)=[O:15]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CO)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (2.5 g, 5.98 mmol), (4-(hydroxymethyl)phenyl)boronic acid (1 g, 6.57 mmol) and Pd(PPh3)4 (0.69 g, 0.597 mmol) in 1,4-dioxane (30 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 (2.3 g, 21.69 mmol) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (2.6 g, 96.3%).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11]2)[CH2:6]1)=[O:4]>C(O)C.[Pd]>[CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6]1)=[O:4]
Reactant: CNC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)N1CCC(N2CCNCC2)C1
Reaction time: 7 h

Procedure:
45-4 (0.10 g, 0.30 mmol) was dissolved in 10 mL of absolute ethanol. To this solution was added 10% Pd/C catalyst. This was then hydrogenolyzed for 7 hours at 60 psi. The catalyst was then filtered off and the filtrate was evaporated to an oil and flushed with methanol to afford 45-5. 1H-NMR (CD3OD): 3.62(m, 2H); 3.49(m, 2H); 3.24(t, 4H); 3.14(m, 1H); 3.03(m, 1H); 2.82(m, 2H); 2.72(complex, 4H); 2.20(m, 1H); 1.86(m, 1H).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:29]=[CH:28][C:27]4[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH3:31][O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:32][CH3:33])[N:21]=[C:20]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:34])=[O:5])=[CH:12][CH:11]=3)[CH2:19][CH2:18]1)[N:29]=[CH:28]2
Reactant: COc1cc2cnc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc2cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2cnc(N3CCC(Nc4ccc(C(=O)O)cc4)CC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 168.8 %

Procedure:
A solution of (13) (0.014 g, 0.029 mmol) in trifluoroacetic acid (3 mL) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was evaporated to a yellow solid residue (0.020 g, quantitative yield); 1H NMR (DMSO) δ 8.95 (s, 1H), 7.66 (d, 2H, J=8.7), 7.23 (s, 1H), 6.94 (s, 1H), 6.62 (d, 2H, J=8.8), 4.67 (d, 2H, J=13.6), 3.90 (s, 3H), 3.83 (s, 3H), 3.64 (m, 1H), 3.19 (t, 2H, J=11.5), 2.00 (d, 2H, J=12.8), 1.38 (m, 2H); 13C NMR (DMSO) δ 167.5, 157.9, 156.3, 151.6, 146.6, 131.2, 129.6, 123.9, 116.7, 113.8, 111.2, 105.6, 104.0, 55.9, 55.6, 48.8, 42.7, 31.2; HRMS (FAB) m/z 409.1878 (M+H)+ (C22H24N4O4 requires 409.1876); Anal. (C22H24N4O4 ·3CF3COOH·11/4H2O·1CH3OH) C, H, N.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:22]1[CH:21]=[C:20]([N:13]2[C:14]3[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1cccc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(-n2ccc3ccccc32)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) 1H-indole (3, 2.43 g, 10 mmol), and 3-bromofluorobenzene (1.09 mL, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 1.88 g (88%) of the product 4-(3-fluoro-phenyl)-1H-indole as a colorless syrup.
Reaction SMILES: [F:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:4][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10]=2[CH:11]=1.[CH2:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5](=[N:4][C:3]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:22]=3[CH2:21][CH2:20][CH2:19]4)[CH2:33][CH2:32]1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9]2
Reactant: c1cc2c(c(N3CCNCC3)c1)CCC2
Reactant: O=CCCCOc1nc2c(cc1F)CCC(=O)N2
Product: O=C1CCc2cc(F)c(OCCCCN3CCN(c4cccc5c4CCC5)CC3)nc2N1

Procedure:
The title compound was prepared by reductive amination of 4-(3-fluoro-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-indan-4-yl-piperazine according to the above procedure. MS: APCI: M+1: 439.2 (Exact Mass: 438.24).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:9]=2)[CH:7]=1.C(OC(=O)[N:34]([S:40]([C:43]1[CH:48]=[C:47]([Cl:49])[C:46](F)=[CH:45][C:44]=1[F:51])(=[O:42])=[O:41])[C:35]1[N:36]=[CH:37][S:38][CH:39]=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>CS(C)=O.O>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[Cl:49][C:47]1[C:46]([O:27][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[N:9]=2)=[CH:45][C:44]([F:51])=[C:43]([S:40]([NH:34][C:35]2[N:36]=[CH:37][S:38][CH:39]=2)(=[O:41])=[O:42])[CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3O)n2)CC1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N3CCNCC3)n2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
tert-Butyl 4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate (Preparation 2, 48.6 mg, 0.11 mmol), tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 43.6 mg, 0.11 mmol) and potassium carbonate (21.9 mg, 0.16 mmol) were mixed in dimethylsulfoxide (1 mL) and shaken at ambient temperature for 18 hours. The reaction mixture was diluted with water and the precipitate collected by filtration. The solid was dissolved in dichloromethane (2.0 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered and trifluoroacetic acid (0.060 mL, 0.78 mmol) was added to the filtrate. After 2 hours the reaction mixture was concentrated in vacuo to a residue and purified by reverse phase HPLC to afford the title compound as a tan glass (55 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:4].Cl.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[C:19]([CH2:18][CH2:17][CH2:16][C:15]#[C:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([NH:5][CH:3]([CH3:4])[CH2:2][OH:1])=[O:7])=[O:21]
Reactant: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)O)c1
Reactant: CNC
Agent: Cl
Product: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)N(C)C)c1
Yield: 96 %

Procedure:
6-[3-(2-Hydroxy-1-methyl-ethylcarbamoyl)phenyl]-hex-5-ynoic acid (4) (0.109 g, 0.377 mmol) was reacted using method C with dimethylamine hydrochloride to obtain 8 (0.115 g, 0.363 mmol; 96% yield).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([C@H:11]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[NH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])C.C1COCC1>O>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([C@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:5]([C:4]([OH:29])=[O:3])[C:6]([OH:8])=[O:7])=[CH:19][NH:20]2
Reactant: CCOC(=O)C(C(=O)OCC)[C@@H](c1ccccc1)c1c[nH]c2cccc(OC)c12
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2[nH]cc([C@H](c3ccccc3)C(C(=O)O)C(=O)O)c12
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A 200 L reactor under N2 atmosphere was loaded with 2-[(S)-(4-methoxy-1H-indol-3-yl)-phenyl-methyl]-malonic acid diethyl ester (12 kg) and THF (53 kg). A solution of EDTA tetrasodium decahydrate (8 kg) in 20 L of cold tap water was separately prepared with shaking to dissolve the solid. One half of the EDTA tetrasodium decahydrate solution was added to the reactor, and the mixture was agitated for 10 minutes. The layers were allowed to separate over 20 minutes, and the aqueous phase was drained. The remaining EDTA tetrasodium decahydrate solution was added to the reactor and the mixture was agitated for 10 minutes before allowing the phases to separate over 20 minutes. The aqueous phase was drained, and saturated aqueous NaCl solution (14.4 kg) was added to the reactor. The mixture was agitated for five minutes, after which the phases were allowed to separate over 20 minutes. The aqueous phase was drained from the reactor, and cold tap water (55 L) was added to the reactor and agitation. KOH (50 wt %, 27.2 kg) was added, and the reactor was configured for reflux. The mixture was heated at 60-65 degrees C. (jacket temperature) overnight. A 10 mL aliquot of the reaction mixture was taken, and HPLC showed the amount of starting material and monoester were <2%. The reaction mixture was then cooled to 22 degrees C. and toluene (52 kg) was added, the contents were agitated for five minutes and then the layers were allowed to separate. The aqueous product layer was separated, combined with isopropanol (37.9 kg), and then acidified with concentrated HCl (41.4 kg). Cooling and stirring were applied during addition to maintain the internal reactor temperature below 30 degrees C. The product slowly precipitated out of solution. Once a thick slurry was formed, cold tap water (72 L) was added, the reactor jacket temperature was set at 5 degrees C., and the slurry was aged one hour. The mixture was filtered on a Rosenmund filter and collected solid was washed twice with cold tap water (50 L). The product was dried in a vacuum oven at 70 degrees C. with N2 bleed to afford 2-[(S)-(4-Methoxy-1H-indol-3-yl)-phenyl-methyl]-malonic acid as an off-white crystalline solid (8.772 kg, 86% yield). 1H mm (CDCl3): 3.80 (s, 3H), 4.28 (d, 2H, J=12.4 Hz), 5.43 (d, 2H, J=12.4 Hz), 6.35 (dd, 1H, J=1.08 Hz, J=7.41), 6.86-6.96 (m, 2H), 7.07 (m, 1H), 7.17 (m, 3H), 7.37 (m, 2H). Mp=155-157° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]#[N:29])[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1.[OH:30][NH:31][C:32](=N)[CH:33]([CH3:35])[CH3:34]>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[O:30][N:31]=[C:32]([CH:33]([CH3:35])[CH3:34])[N:29]=4)[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)c(F)c1
Product: CC(C)c1noc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5F)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.53 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@@H:13](O)[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[C:5]([F:17])=[CH:4][N:3]=1.[F:18]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1.O.CCOC(C)=O.CCCCCCC>[F:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([F:18])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[C:5]([F:17])=[CH:4][N:3]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[C@H](O)[C@H]1COC(=O)N1c1nc(F)ncc1F
Agent: F
Solvent: O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](F)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
To a round bottom flask containing a solution of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (0.47 g, 1.917 mmol) in THF (6.4 mL) was added perfluorobutanesulfonyl fluoride (1.03 mL, 5.75 mmol) followed by the addition of triethylamine trihydrofluoride (0.94 mL, 5.75 mmol) and triethylamine (2.40 mL, 17.3 mmol) resulting reaction mixture allowed to stir at room temperature for 6 hr. The reaction mixture was diluted with water and the aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 60%) provided a white crystalline of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((R)-1-fluoroethyl)oxazolidin-2-one (150 mg, 0.61 mmol, 32% yield). 1H NMR (400 MHz, CDCl3) δ 1.37 (dd, J=24.26, 6.26 Hz, 3H) 4.48 (dd, J=9.39, 4.70 Hz, 1H) 4.63 (t, J=8.80 Hz, 1H) 4.90-5.02 (m, 1H) 5.02-5.25 (m, 1H) 8.50 (s, 1H). LCMS m/z 248.0 (M+H)+, Rt 0.59 min.
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][O:12]C)(=O)C.B(Br)(Br)Br.O>C(Cl)Cl>[OH:12][CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1
Reactant: COCCC1=C(OC(C)=O)CCC1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1CCC=C1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The enol acetate of Example 896 is brominated and dehydrobrominated by the method described in Example 13. The crude product is then dissolved in methylene chloride and is added at -78° C. to a methylene chloride solution containing about seven molar equivalents of boron tribromide. After one hour at -78° C. the solution is allowed to warm to room temperature and is then kept at ambient temperatures for a total of 18 hours. The mixture is poured into water and extracted with ether. The organic phase is washed with saturated saline solution, then water and is dried. Evaporation of solvents leaves subject product, which is purified by distillation. The combined organic phases are washed with ice cold 5% sodium hydroxide solution, ice cold 5% hydrochloric acid, and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives a pale yellow oil; λ max 5.85 μ (carbonyl group).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]>C(O)C>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccccc2[N+](=O)[O-])c1
Solvent: CCO
Product: CS(=O)(=O)c1cccc(-c2ccccc2N)c1

Procedure:
3'-Methanesulphonyl-2-nitrobiphenyl (14 g) was heated at 90°-95° C. for 10 hours with hydrated sodium sulphide (51 g) and ethanol (400 ml) to give 2-amino-3'-methanesulphonylbiphenyl (m.p. 114°-115° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[NH:8][C:7]2=[O:16].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:26][C:27](O)=[O:28].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([F:30])([F:31])[F:17])[CH2:13][CH2:14]1)[NH:8][C:7]2=[O:16]
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Reactant: O=C1NC2(CCNCC2)c2c(Br)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
A mixture of 7-bromospiro[isoindoline-1,4′-piperidin]-3-one (194 mg, 0.69 mmol), 3-(2-(trifluoromethyl)phenyl)acrylic acid (100 mg, 0.46 mmol), EDCI (181 mg, 0.92 mmol), HOBt (124 mg, 0.92 mmol) and i-Pr2NEt (1 mL) was stirred at rt overnight. The mixture was washed with 5% aq HCl, and the organic layer was concentrated to give a residue which was purified by preparative HPLC to afford (E)-7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[isoindoline-1,4′-piperidin]-3-one (5 mg, 2%). 1H NMR (400 MHz, CDCl3): δ=1.53 (m, 2H), 2.98 (m, 3H), 3.42 (m, 1H), 4.23 (m, 1H), 4.50 (m, 1H), 4.93 (m, 1H), 6.80 (m, 1H), 7.33 (m, 1H), 7.40 (m, 1H), 7.50 (m, 1H), 7.65 (m, 3H), 7.77 (m, 1H), 7.95 (m, 1H), 8.50 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6](N)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[FH:21].N1C=CC=CC=1>>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([F:21])[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: F
Reactant: Nc1nccc2c(Br)csc12
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1nccc2c(Br)csc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of 3-bromothieno[2,3-c]pyridin-7-amine (51 mg, 0.22 mmol) in pyridine hydrofluoride (1.2 mL) was added sodium nitrite (23.1 mg, 0.334 mmol). The reaction stirred at room temperature for 18 h. The reaction was then neutralized by addition of saturated aqueous sodium bicarbonate (40 mL). The mixture was extracted with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (1×20 mL), dried over sodium sulfate, filtered, and concentrated to afford 33 mg (59%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.20 (dd, J=5.6, 1.3 Hz, 1 H), 7.76 (s, 1 H), 7.62 (dd, J=5.6, 2.8 Hz, 1 H); MS (ESI): 232.04, 234.04 [M+H]+; HPLC tR=3.49 min (ZQ3, polar—4 min).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1([NH:7][C:8]2[C:13]([CH:14]([OH:16])[CH3:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=[CH:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
1-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (13 mg, 0.034 mmol) in methanol (1 mL) was stirred with sodium borohydride (30 mg, 0.79 mmol) at room temperature for 1 hour and at 60° C. for another 5 hours. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→3/1 (v/v)) to give the title compound as a colorless oil (9.1 mg, yield 70%).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:32]>C(O)C>[Na+:32].[CH:1]1([C:5]2[N:6]=[C:7]([CH:10]=[CH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([O-:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cc1ccccc1C(=O)[O-])Nc1cccc(C=Cc2nc(C3CCC3)cs2)c1

Procedure:
A solution of 0.418 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid in 10 ml of ethyl alcohol was mixed at room temperature with 5.0 ml of 0.2N sodium hydroxide solution. This mixture was warmed on a steam bath until all the solids had solubilized. After cooling the reaction mixture was condensed in vacuo at 40° C. to constant weight to yield E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid sodium salt as a white solid.