Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1(Br)[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:4]=[C:3]1[CH3:18].[NH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH2:21].Cl>O>[CH3:18][C:3]1[CH:2]([N:21]=[N:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:4]=1
Reactant: CC1=NN(c2ccc(S(=O)(=O)O)cc2)C(=O)C1(Br)Br
Reactant: NNc1ccccn1
Agent: Cl
Solvent: O
Product: CC1=NN(c2ccc(S(=O)(=O)O)cc2)C(=O)C1N=Nc1ccccn1

Procedure:
41.0 g (0.10 mole) of 4,4-dibromo-3-methyl-1-(4-sulfophenyl)-2-pyrazolin-5-one, which can be prepared according to the method of Machiele, U.S. Pat. No. 3,952,009 (Example 1), and 16.0 g (0.15 mole) of 2-hydrazinopyridine were combined in 180 ml of water. The mixture was heated on the steam bath a total of six hours. After a few minutes of heating, the solution goes to a very thick slurry. The mixture was cooled somewhat, 10 ml of concentrated HCl were added, and the orange solid was isolated by suction filtration. After washing once with tetrahydrofuran, twice with ether, and drying, the yield of dye was 17.8 g (50 percent).
Reaction SMILES: C([N:8]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=3[F:25])[CH2:13]2)[CH2:9]1)C1C=CC=CC=1.C1COCC1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:12]2[CH2:11][C@@H:10]3[C@@H:14]([CH2:15][NH:8][CH2:9]3)[CH2:13]2)=[C:17]([F:25])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(N2C[C@H]3CN(Cc4ccccc4)C[C@H]3C2)c(F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2C[C@H]3CNC[C@H]3C2)c(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
cis-3-Benzyl-7-(2-fluoro-4-nitrophenyl)-3,7-diazabicyclo[3.3.0]octane (9.11 g, 26.71 mmol), THF (100 mL), and methanol (50 mL) are combined with 10% palladium on carbon (6.67 g) and ammonium formate (16.83 g, 266.90 mmol) under nitrogen, heated to reflux for 2.5 hours, cooled to ambient temperature, stirred 15 hours, filtered through celite and concentrated in vacuo to give crude cis-3-(4-amino-2-fluorophenyl]-3,7-diazabicyclo[3.3.0]octane. cis-3-(4-Amino-2-fluorophenyl]-3,7-diazabicyclo[3.3.0]octane, water (100 mL), acetone (100 mL), and potassium carbonate (7.75 g, 56.07 mmol) are combined, cooled to 0° C., and benzyl chloroformate is added slowly. The reaction is warmed to ambient temperature, stirred 15 hours, concentrated in vacuo, and diluted with ethyl acetate. The organic phase is washed with water (2×150 mL) and saline (150 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with hexane/ethyl acetate (80/20). The appropriate fractions are combined (Rf =0.41, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 121-122° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([OH:22])[CH2:20][OH:21].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:21][CH2:20][CH2:19][OH:22])[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step ii) 5 g) and ethylene glycol (1.517 g) in THF (100 ml) was added NaH (1.3 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between EtOAc (200 ml) and H2O (200 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by column chromatography on silica gel 10% EtOAc/90% iso-Hex to give the subtitle compound as a clear oil. Yield: 2.4 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[O:12][N:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: COc1ccccc1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccccc2OC)n1
Yield: 34.9 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2-methoxyphenyl)acetic acid (0.629 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.346 g (12%) of ethyl 5-(2-methoxybenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][C:11]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(F)c(-c2ccc(C(=O)O)cc2N2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2N2CCCCC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a cooled solution of 67.20C (0.2929 g, 0.8893 mmol) in dry THF (10 mL) at 0° C. was added LAH (1M in THF) (1.8 mL, 1.8 mmol). Upon complete addition, the reaction was maintained at 0° C. and was monitored by TLC and LCMS. After 2 hours, 1N NaOH was added to quench the reaction (gas evolution occurred). The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified by flash chromatography (SiO2 gel 60, eluted with 0%-50% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to afford 67.20D as a colorless oil (231.8 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.25 (1H, d, J=9.0 Hz), 7.11 (4H, m), 6.82 (1H, dt, J=9.0, 3.5 Hz), 4.71 (2H, d, J=5.5 Hz), 3.81 (3H, s), 2.81 (4H, m), 1.69 (1H, s), 1.43 (6H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41]2[CH2:45][C:44]([C:50]3[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[CH:51]=3)([C:46]([F:49])([F:48])[F:47])[O:43][N:42]=2)=[CH:33][CH:32]=1>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([C:41]3[CH2:45][C:44]([C:50]4[CH:51]=[C:52]([Cl:57])[CH:53]=[C:54]([Cl:56])[CH:55]=4)([C:46]([F:49])([F:47])[F:48])[O:43][N:42]=3)=[CH:33][CH:32]=2)[CH:10]=[N:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3ccccc23)=NO1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(-c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3ccccc23)cn1
Temperature: 75 °C

Procedure:
1-Tert-butoxycarbonyl-4-1H-pyrazoleboronic acid pinacol ester (126 mg), Tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3 (7 mg)], K3PO4 (185 mg) and 2-dicyclohexylphosphinno-2′,6′-dimethoxybiphenyl (12 mg) are added to a solution of 3-(4-bromo-naphthalen-1-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (140 mg) in dry toluene (2.4 ml). After 16 hours at 75° C. the reaction is cooled down to room temperature and filtrated. The filtrate is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 4-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-pyrazole-1-carboxylic acid tert-butyl ester (compound 1.10, Table 1) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([F:44])=[C:39](B(O)O)[CH:40]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:37]3[CH:36]=[C:35]([Br:34])[CH:40]=[CH:39][C:38]=3[F:44])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: OB(O)c1cc(Br)ccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(Br)ccc1F
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (500 mg, 0.837 mmol) was mixed with (5-bromo-2-fluorophenyl)boronic acid (211 mg, 0.963 mmol), toluene (5 mL), ethanol (278 μL) and sodium carbonate aqueous solution (2M, 0.89 mL, 1.78 mmol). The resulting mixture was stirred at 20° C. for 30 min followed by addition of tetrakis (triphenylphosphine) palladium(0) (43.5 mg, 0.0376 mmol, 4.5 mol %). The reaction mixture was heated in a 90° C. oil bath for 40 hours to complete the reaction. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 40+M cartridge). The column was eluted by an Ethyl acetate/hexanes mixture. Related fractions were pooled and concentrated in vacuo to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-bromo-2′-fluoro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=645.02; found=645.94 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:9]2=[N:10]C(C#N)=[CH:12][CH:13]=[C:8]2[N:7](C(OCC)=O)[C:6]=1[CH3:21].[H-].[Na+].[C:29]([OH:32])(=[O:31])[CH3:30]>Cl>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][C:8]2[C:9]=1[NH:10][C:30]([C:29]([OH:32])=[O:31])=[CH:12][CH:13]=2
Reactant: CCOC(=O)n1c(C)c(Cc2ccc(Cl)cc2Cl)c2nc(C#N)ccc21
Reactant: CC(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2ccc(C(=O)O)[nH]c-2c1Cc1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
A solution of ethyl 3-(2,4-dichlorobenzyl)-5-cyano-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate (180 mg) in acetic acid (1 ml) and concentrated hydrochloric acid (1 ml) was refluxed under heating. The mixture was allowed to react overnight, and concentrated hydrochloric acid (1 ml) was added, which was followed by reflux under heating for 10 hr. The reaction mixture was cooled and adjusted to pH 7 with a 30% aqueous solution of sodium hydride. After stirring for 2 hr, crystals were collected by filtration to give the object compound (135 mg) as yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1>CN(C=O)C>[CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([N:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1)=[O:10])=[O:2]
Reactant: Cc1cc(C)c(C(=O)O)cc1C=O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a stirred solution of 5-formyl-2,4-dimethylbenzoic acid (compound 16.3, 950 mg, 5.33 mmol, 1.10 equiv) in DMF (15 mL) was added DIEA (2.48 g, 19.19 mmol, 4.00 equiv) followed by HBTU (3.67 g, 9.68 mmol, 2.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.00 equiv). After stirring overnight at ambient temperature, the reaction was quenched by the addition of 60 mL of water. The resulting mixture was extracted with 3×150 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10-1:3) as eluent to yield 1.4 g (84%) of the title compound as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]3[C@@H:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][N:23]([C@H:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[C:33]([OH:35])=[O:34])[CH2:22]3)[CH2:16][CH2:15]2)=[CH:7][CH:6]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][C@@H:21]3[C@@H:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][N:23]([C@H:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[C:33]([OH:35])=[O:34])[CH2:22]3)[CH2:18][CH2:19]2)=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(CCCC2CCN(C[C@H]3CN([C@@H](C(=O)O)C4CCCCC4)C[C@@H]3c3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCC2CCN(C[C@H]3CN([C@@H](C(=O)O)C4CCCCC4)C[C@@H]3c3ccccc3)CC2)cc1

Procedure:
A solution of 27 mg (0.05 mmol) of 2-(R)-(3-(S)-(4-(3-(4-(carbomethoxy)phenyl)propyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-3-methylbutanoic acid (from EXAMPLE 29, Step D) in 3 mL of MeOH was treated with 0.2 mL of 5.0 N NaOH and the resulting mixture was heated at reflux for 1 h. The mixture was cooled and concentrated. The residue was partially dissolved in H2O and the solids filtered and dried to afford 11 mg (42%, 2 steps) of the title compound: ESI-MS 547 (M+H); HPLC B: 6.57 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=4[CH3:23])[C:13]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-:32].[K+].[K+].OO.O>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21](=[O:32])[NH2:22])=[CH:17][C:16]=4[CH3:23])[C:13]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCc1ccc(-c2ccc3c(c2)OCO3)n1-c1ccc(C#N)cc1C
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc2c(c1)OCO2
Yield: 87 %

Procedure:
To a mixture of ethyl 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (100 mg, 0.249 mmol) and potassium carbonate (52 mg, 0.373 mmol) in DMSO (1 mL) was added 30% aqueous H2O2 (28.2 mg, 0.249 mmol). The resultant mixture was stirred at room temperature for 2 h. TLC showed the reaction was completed. Water (7 mL) was added and white solid precipitated. The suspension was centrifuged and the aqueous phase was discarded. The resultant solid was dried in vacuum to afford the amide intermediate as a white solid (85 mg, yield 81%). To the mixture of this intermediate in H2O (0.6 mL) and THF (0.6 mL) was added LiOH H2O (10 mg, 0.238 mmol). The reaction mixture was stirred at room temperature overnight. THF was evaporated in vacuum. The residue was acidified to pH=4 with 5% hydrochloric acid, centrifuged and dried to afford 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid as a white solid (46 mg, overall yield 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:32])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:14][CH:13]2[C:33]([O:35]C)=[O:34])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:32])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:14][CH:13]2[C:33]([OH:35])=[O:34])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COC(=O)C1CN(C(=O)c2cc(F)ccc2C)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3cc(F)ccc3C)CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
To a mixture of 1.9 g (3.71 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate in 10 ml of tetrahydrofuran was added 5 ml (4.82 mmol) of 1 N NaOH. The mixture was stirred at room temperature for 1.5 hours and the solvent removed under vacuum. To the residue was added ethyl acetate and the mixture neutralized with 1 N HCl. The organic layer was separated, washed with brine and dried with Na2SO4. The solvent was removed under vacuum to give 1.41 g of white solid. Anal. for C25H23FN2O6S: Calc'd: C,60.2; H,4.7; N,5.6; Found: C,60.2; H,4.8; N,5.4 S,6.4; F,3.6; Mass spectrum (ES) 497.5 (M-H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CN(C=O)C>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Br:30])[S:16]([C:19]2[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])(=[O:17])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCBr
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2c3ccccc3nc3ccccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(CCCCCBr)c2c3ccccc3nc3ccccc23)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of 450 mg (1.20 mmol) of N-(9-acridyl)-mesitylenesulfonamide in 20 mL of DMF was placed under an atmosphere of argon and cooled to 0° C. To the cooled solution was added 36 mg (1.42 mmol) of NaH (95%). The reaction mixture was stirred at 0° C. for 5 min and at room temperature for 1 hr. Then the reaction mixture was cooled to 0° C., and 1.65 mL (12.1 mmol) of 1,5-dibromopentane were added. The reaction mixture was stirred at 70-80° C. for 23 hr. The reaction mixture was cooled, and quenched with 20 mL of water. The mixture was partitioned between CH2Cl2 and water. The aqueous phase was washed with CH2Cl2 (2×20 mL). The CH2Cl2 washes were combined with the organic phase, dried with MgSO4, and evaporated to dryness. The material was purified by column chromatography on silica gel with CH2Cl2 to afford 382.2 mg (60%) of bromide 542 as an orange oil: 1H NMR (300 MHz, CDCl3, TMS) δ 8.25 (d, J=9 Hz, 2H), 7.94 (d, J=9 Hz, 2H), 7.76 (t, J=8 Hz, 2H), 7.45 (t, J=8 Hz, 2H), 6.87 (s, 2H), 4.0-3.9 (m, 2H), 3.27 (t, J=6.5 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 6H), 1.8-1.6 (m, 4H), 1.4-1.3 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1C=CC=CC=1.CO>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([O:8][CH3:15])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a stirred solution of 4-hydroxy-3-nitrobenzoic acid (5.18 g, 28.29 mmol) in benzene-MeOH (4:1, v/v, 140 mL) was added TMSCHN2 (14.10 mL, 28.20 mmol, 2 M solution in hexane) at room temp, and the resulting mixture was stirred overnight. The mixture was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3 as eluent to give 4.18 g (75%) methyl 3-nitro-4-hydroxybenzoate as a yellow crystalline solid. 1H-NMR (CDCl3) δ 3.95 (s, 3H), 7.22 (d, 1H, J=8.8 Hz), 8.24 (dd, 1 , J=2.0, 8.8 Hz), 8.83 (d, 1H, J=2.0 Hz), 10.89 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:59][C:57]2[S:56][C:46]3[C:47]([CH:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 6 h
Yield: 75.7 %

Procedure:
To a stirred solution of 42 mg (0.30 mmol) 4-fluoro-benzoic acid in 4 ml THF were added 126 mg (0.33 mmol) HATU and 0.066 ml (0.60 mmol) N-methylmorpholine and stirring continued at 50° C. for 6 h. 40 mg (0.15 mmol) 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 44 mg (75%) 4-fluoro-N-[7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-yl]-benzamide as a white crystalline solid. ES-MS m/e (%): 388 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:20]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].O.[C:30](=O)(O)[O-].[Na+]>C1COCC1.C[Mg]I>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:20]([CH:21]2[CH2:26][CH2:25][C:24]([OH:27])([CH3:30])[CH2:23][CH2:22]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccccn3)nc2n1C1CCC(=O)CC1
Agent: C[Mg]I
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccccn3)nc2n1C1CCC(C)(O)CC1
Yield: 4 %

Procedure:
To a solution of 7-(4-oxo-cyclohexyl)-2-(pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (25 mg, 0.066 mmol) in THF is added 20 drops of MeMgI. After reaction is completed, added 25 mL of water then 30 mL of aqueous sodium bicarbonate. Extraction with dichloromethane (3×50 mL) and concentrated to give a mixture of diastereomers. Preparative HPLC to give 7-(4-hydroxy-4-methyl-cyclohexyl)-2-(pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (2 mg, 4%). MS (ESI) m/z 395.3 (M+H)+