Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6]2[C:10](=[C:11]3[C:23]4=[CH:24][N:25]([CH3:28])[C:26](=[O:27])[C:22]4=[C:21]4[C:13]([NH:14][C:15]5[CH:16]=[CH:17][C:18](=[O:29])[CH2:19][C:20]=54)=[C:12]3[CH:30]=1)[N:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>CN(C=O)C.CCOC(C)=O>[Br:51][CH2:2][CH2:3][CH2:4][C:5]1[C:6]2[C:10](=[C:11]3[C:23]4=[CH:24][N:25]([CH3:28])[C:26](=[O:27])[C:22]4=[C:21]4[C:13]([NH:14][C:15]5[CH:16]=[CH:17][C:18](=[O:29])[CH2:19][C:20]=54)=[C:12]3[CH:30]=1)[N:9]=[CH:8][CH:7]=2
Reactant: CN1C=c2c(c3c4c([nH]c3c3cc(CCCO)c5c(c23)N=CC=5)C=CC(=O)C4)C1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C=c2c(c3c4c([nH]c3c3cc(CCCBr)c5c(c23)N=CC=5)C=CC(=O)C4)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 13-(3-hydroxypropyl)-5-methyl-7H-indolo[6,7-a]pyrrolo[3,4-c]-carbazole-6,8-dione (1.18 g, 2.97 mmol) in DMF (45 mL) was added triphenylphosphine (1.17 g, 4.45 mmol) followed by carbon tetrabromide (1.48 g, 4.45 mmol). The resulting solution was allowed to stir at room temperature for 30 min. The solution was diluted with EtOAc (200 mL) and washed with water (2×200 mL) and brine (200 mL). The combined aqueous layers were washed with EtOAc (100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to a red-orange solid. Flash chromatography (SiO2, 20% EtOAc/hexanes) gave the title compound (1.05 g, 77%) as an orange solid, mp 238 C. 1H NMR (DMSO-d6)11.15 (s, 1H), 9.16 (d, J=7.5 Hz, 1H), 8.36 (d, J=9 Hz, 1H), 8.04 (d, J=9 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.60–7.67 (m, 2H), 7.44 (dd, J=7.5, 7.5 Hz, 1H), 6.85 (d, J=3 Hz, 2H), 5.03 (t, J=7 Hz, 2H), 3.85 (s, 3H), 3.72 (t, J=7 Hz, 2H), 2.50 (m, 2H, partially buried under DMSO signal). MS (atmospheric pressure chemical ionization, m/z) 460, 462 [C24H18BrN3O2+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(Cn2cncn2)cc1
Reaction time: 20 h

Procedure:
A mixture of 1 g of 4-bromobenzyl bromide, 0.41 g of 1,2,4-triazole, 0.55 g of potassium carbonate and 33 mg of potassium iodide in 30 ml of acetone is stirred at 50° for 20 hours. The solid is removed by filtration and the solution is concentrated by evaporation. The resulting crude precursor (1) is purified by column chromatography (SiO2, hexane/ethyl acetate 1:1) and crystallised from ether; m.p. 77°-79°; 1H-NMR (CDCl3): δ=5.3 (2H,s), 7.15 and 7.5 (4H,m), 7.95 (1H,s), 8.08 (1H,m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:20][C:21](O)=[O:22])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:21](=[O:22])[CH2:20][C:14]1[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([F:11])[CH:13]=1
Reactant: COc1ccc(OC)cc1
Reactant: COc1cc(F)cc(CC(=O)O)c1
Solvent: O
Product: COc1cc(F)cc(CC(=O)c2cc(OC)ccc2OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a solution of 1,4-dimethoxybenzene (2.62 g, 19 mmol) in PPA (10 mL) at room temperature, 2-(3-fluoro-5-methoxyphenyl)acetic acid (2.33 g, 12.6 mmol) was added. The mixture was stirred at 80° C. for 3 h, cooled to room temperature, and then H2O (100 mL) was added. After extraction with ethyl acetate (3×50 mL), the organic phase was dried over Na2SO4, concentrated, and the crude was purified by silica-gel column chromatography (ethyl acetate/petroleum ether=1/4) to give 1.0 g of 1-(2,5-dimethoxyphenyl)-2-(3-fluoro-5-methoxyphenyl)ethanone. LCMS: 305.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][CH2:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(CCc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CCc3ccc(C(=O)O)cc3)s2)c1
Temperature: 100 °C
Yield: 95.4 %

Procedure:
The product of Step 1 (65 mg, 0.130 mmol) was taken up in MeOH (2.0 ml) in a microwave vial, and 1.0M sodium hydroxide (0.261 ml, 0.261 mmol) was added. The reaction was heated to 100° C. for 10 min in the microwave. The colorless solution was adjusted to a pH of 3-4 with 1 N HCl, diluted with water, and extracted with 15% IPA/CHCl3 (2×). The combined organic layers were dried (MgSO4) and evaporated to afford the title compound (60 mg, 0.124 mmol, 95% yield) as a colorless solid. MS ESI: [M+H]+ m/z 485.0 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.24 (s, 1H), 8.81 (d, J=4.9, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=8.1, 2H), 7.43 (s, 1H), 7.39 (d, J=8.1, 2H), 7.27 (d, J=4.9, 1H), 7.12 (s, 1H), 3.41-3.20 (m, 2H), 3.13 (t, J=7.6, 2H), 2.29 (s, 3H). rhSYK activity=+++
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25]([CH2:26][C@@H:27]([OH:37])[CH2:28][CH2:29]2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[CH:16][CH3:17]>CC(C)=O>[CH3:14][C:15]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH2:28][CH2:29]2)[C:24](=[O:3])[CH2:23]3)[CH2:20][CH2:19]1)=[CH:16][CH3:17]
Reactant: CC(C)=O
Reactant: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC=C(C)[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h
Yield: 29 %

Procedure:
Jones reagent (2.67 M, 2.0 ml. 5.3 mmol) was added to a solution of 20,21-dimethylpregna-5,20-dien-3β-ol (6, 460.1 mg, 1.400 mmol) in 50 ml of acetone and the reaction was stirred 45 min. After quenching with 2-propanol (1.0 ml) the mixture was poured into 100 ml of water and extracted three times with 50 ml of ethyl acetate. The combined organic extracts were washed with 50 ml of saturated sodium bicarbonate+50 ml of brine, dried over magnesium sulfate, and filtered through Celite. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Flash chromatography (25% ethyl acetate/hexanes on silica gel) and recrystallization of the residue from 95% ethanol gave yellow needles (138.2 mg, 0.4059 mmol, 29%), m.p. 172-178° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:29])C>C(Cl)(Cl)Cl.O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[S:11][CH:12]=[C:13]([CH:15]=[O:29])[N:14]=1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc(CCl)cs1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nc(C=O)cs1

Procedure:
2-(1-methyl-5-nitroimidazol-2-yl)-4-chloromethylthiazole (0.2 mole) and hexamine (0.3 mole) in chloroform (400 ml.) were stirred and boiled under reflux for 20 hours. The solid product was collected, washed in chloroform and dried to yield 2-(1-methyl-5-nitroimidazol-2-yl)-4-thiazolylmethyl hexaminium chloride. The latter (0.078 mole) was dissolved in water (150 ml.) and glacial acetic acid (150 ml.). Hexamine (10 g.) was added and the solution refluxed for 11/2 hours. The solution was evaporated to 50 ml. and water (200 ml.) added. The precipitate was collected and dried to give 2-(1-methyl-5-nitro-imidazol-2-yl)thiazole-4-carboxaldehyde, m.p. 180°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH3:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C(Cl)Cl>[CH3:24][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:12]([O:11][CH3:10])[C:13]=1[C:14]([NH:16][C:17]([NH:4][C:3]1[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[F:9])=[O:18])=[O:15]
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Reactant: Nc1c(F)cccc1F
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 60 g. portion of 2,6-difluoroaniline was dissolved in 1500 ml. methylene chloride and cooled to 10° C. Under a nitrogen atmosphere, 90 g. of 2,6-dimethoxybenzoylisocyanate in 200 ml. methylene chloride was added dropwise. The mixture was allowed to stir at 25° C. for three hours. The solid was collected and washed with water. The filtrate was evaporated to dryness, and 150 ml. diethyl ether and 150 ml. ethanol were added. The solid was again collected. Yield 89.0 g. (60%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[CH:27][C:22]2=[C:21]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[N:20]=1)([CH3:3])[CH3:2].Cl.[CH3:42][N:43]([CH3:48])[CH2:44][C:45](Cl)=[O:46].C(N(CC)CC)C>ClCCl>[CH3:42][N:43]([CH3:48])[CH2:44][C:45]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]2[CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([NH:18][C:19]3[N:24]=[C:23]4[NH:25][N:26]=[CH:27][C:22]4=[C:21]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])[N:20]=3)=[CH:7][C:8]=2[CH3:17])[CH2:12][CH2:13]1)=[O:46]
Reactant: CN(C)CC(=O)Cl
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CN(C)C)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (56 mg) was dissolved in 3 mL of dichloromethane. The solution was cooled to 5° C. and 2-(dimethylamino)acetyl chloride hydrochloride (24 mg) was added to the solution followed by triethylamine (15 mg). The solution was stirred at room temperature for approximately 30 minutes. After Prep-LC-MS, the final product is obtained. MS (ES+): 649.32 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19]Br)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(CCc2ccc(OC)cc2)C1

Procedure:
This compound was prepared as described in Preparation 3 using ethyl piperidine-3-carboxylate and 4-methoxyphenethyl bromide as reagents. The title compound was obtained as a colourless oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH3:33])[CH:14]2[Si:19]([CH:22]1[C:30]2[C:25](=[C:26](Br)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32])([CH3:21])[CH3:20]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[C:13]([CH3:33])[CH:14]3[Si:19]([CH:22]2[C:30]3[C:25](=[C:26]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]2[CH3:32])([CH3:21])[CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C(C)=Cc2c(Br)cccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1C(C)=Cc2c(-c3ccccc3)cccc21
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF 13.0 ml of 1.0 M phenylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.37 g (5.0 mmol) of 1 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 2.27 g (97%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[C:4]2[N:9]([C:10]=1[C:11](OCC)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:35]1(C)[CH:40]=CC=C[CH:36]=1>COC(OC)(C)C.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[OH:12][C:11]1[C:10]2[N:9]3[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]3)=[C:3]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])[C:2]=2[N:1]=[C:35]([CH3:40])[CH:36]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1c(N)c(-c2c(C)cc(C)cc2C)c2ccccn12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COC(C)(C)OC
Product: Cc1cc(C)c(-c2c3nc(C)cc(O)c3n3ccccc23)c(C)c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of 2-amino-3-ethoxycarbonyl-1-(2,4,6-trimethylphenyl)-indolizine (19.2 g; 59.6 mmol) in 2,2-dimethoxypropane (100 mL) is added dl-camphorsulfonic acid (0.2 g). The mixture is stirred at reflux for 30 minutes and then distilled slowly to remove ca. 60 mL of volatiles over a 30-minute period. The solution is cooled to ambient temperature under an inert atmosphere, diluted with anhydrous toluene (50 mL), and concentrated in vacuo. The residue is dissolved in toluene (50 mL) and to the stirred solution is then added a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (250 mL; 125 mmol) dropwise over a 1-hour period. After the addition is complete, the mixture is further stirred for 2 hours at room temperature before being concentrated in vacuo to a small volume and then diluted with aqueous ammonium chloride. The resulting emulsion-like biphasic mixture is suction-filtered and washed succesively with water, methanol, and ethyl ether. Air- and vacuum drying provides 10.1 g of the title compound as a pale yellow solid (54%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[P:14]([O:21]CC)([O:18]CC)[O:15]CC.[Br-]>>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P:14](=[O:15])([OH:21])[OH:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCCCCCc1ccccc1
Reactant: CCOP(OCC)OCC
Agent: [Br-]
Product: O=P(O)(O)CCCCCCc1ccccc1

Procedure:
The 1-bromo-6-phenylhexane (˜7.304 g, ˜30 mmol) from the previous step was then added to triethyl phosphite (25 mL, 143.7 mmol) in a round bottom flask fixed with a condenser and under Argon pressure. This was allowed to reflux overnight. GCMS (PJH-I-37b) showed no starting bromide left and the reaction was stopped. A distillation was performed to remove the excess triethyl phosphate and then a column in 2:1 hexane:ethyl acetate. The desired product had an Rf=0.55. The desired product was obtained with only a trace impurity of the bisphenyl substituted hexane. The product was be purified further as it is a new compound, but some of it was used in the next step.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](O)[CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([O:9][C:16]1[CH:15]=[CH:14][C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)SCC(CC(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
2-[(Acetylthio)methyl]-4-methylpentanoic acid (5.1 g, see Example 1D) in 100 ml of ethyl acetate is cooled to 5° C. and treated with p-nitrophenol (3.5 g) followed by 5.1 g of dicyclohexylcarbodiimide, in portions. After stirring for four hours at 5° C., the dicyclohexylurea is filtered and the ethyl acetate is removed in vacuo. The resulting solid is washed with hexane to give the title compound, 8.0 g, as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([OH:16])(=[O:15])[C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9]>>[N+:1]([C:14]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:5]([OH:16])=[O:15])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccccc1C(=O)O
Product: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reaction time: 3 h

Procedure:
100 parts by weight and 150 parts by weight 99% by weight concentrated nitric acid are each added to a reaction vessel and brought to a temperature of 70° C. To each solution is added 10 parts by weight phthalic acid. Nitration is allowed to continue at 70° C. for three hours and produces yields of greater than 90% of theoretical yield consisting essentially of a mixture of 3- and 4- nitrophthalic acid. Table 1 shows the make-up of the reaction product mix in mole percent. The mole ratio of 4- to 3- nitrophthalic acid formed was approximately 1.1:1.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([NH:40][NH2:41])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1N=CN([C:58](N2C=NC=C2)=[O:59])C=1>C1COCC1>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]6[O:39][C:58](=[O:59])[NH:41][N:40]=6)=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:52])[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ncc(-c2ccc(C(=O)NN)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: C1CCOC1
Product: COc1ncc(-c2ccc(-c3n[nH]c(=O)o3)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzohydrazide (Step A, 108 mg, 0.147 mmol) in THF (1.5 mL) was treated with N,N-carbonyldiimidazole (71.6 mg, 0.442 mmol). The reaction was stirred at room temperature overnight. The reaction was purified directly by silica gel chromatography, eluting with a gradient of 25-100% ethyl acetate/hexanes to give the titled compound. LCMS (M+H)+: 760.5. 1H NMR (CDCl3, 500 MHz): δ 9.08 (br, 1H), 8.22 (d, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.74 (s, s, 3H), 7.49 (d, 1H), 7.36 (d, 1H), 5.68 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.73 (d, 1H), 4.47 (m, 3H), 4.31 (m, 2H), 4.01 (m, s, 4H), 2.38 (s, 3H), 0.76 (d, 3H). RTA IC50: 12 nM.
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Cl[CH2:14][C:15]([C:17](=[N:23][O:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=O>C(Cl)(Cl)Cl>[S:2]1[CH:14]=[C:15]([C:17](=[N:23][O:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: NCCS
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC)C1=CSCCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.7 %

Procedure:
To a stirred solution of 2-mercaptoethylamine hydrochloride (10.0 g.) in chloroform (100 ml.) were added triethylamine (18.7 g.) and ethyl 2-chloroacetyl-2-methoxyiminoacetate (26.2 g., purity 70%) under ice-cooling and stirred at room temperature for 1.5 hours. After the resultant solution was concentrated in vacuo, water was added to the residue and extracted with diethyl ether four times. The extract was washed with a saturated aqueous solution of sodium chloride, and extracted with 10% hydrochloric acid 4 times. The hydrochloric acid extract was washed with diethyl ether twice and adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate, and further extracted with diethyl ether 4 times. The extract was dried over magnesium sulfate and concentrated in vacuo to give ethyl 2-(2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 5.2 g.), oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]#[N:13])[CH:6]=[C:5]2[S:14][CH3:15].[OH:16]OS([O-])=O.[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]#[N:13])[CH:6]=[C:5]2[S:14]([CH3:15])=[O:16]
Reactant: O=S([O-])OO
Reactant: CSc1cn(CC#N)c2ccc(Cl)cc12
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1cn(CC#N)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of (5-chloro-3-methylsulfanyl-indol-1-yl)-acetonitrile (1.0 g, 4.22 mmole) dissolved in methanol (65 ml) cooled to ca. 0° C., was added a cold solution (ca. 7° C.) of Oxone® (1.29 g, 2.11 mmole) dissolved in water (40 ml) in portions over a 10 minute time period. The cooling bath was removed and the solution was stirred at room temperature for 4 h. Tlc analysis at this point showed some unreacted starting material and thus 0.1 g more Oxone® was added and the mixture continued stirring overnight. The reaction mixture was evaporated to dryness and the residue was taken up in methanol and the insoluble material was filtered. The methanol soluble material was isolated by evaporation of the solvent and the residue was triturated with ether which was discarded and then with toluene. The solid which remained was further purified by column chromatography (silica gel) eluting with methanol:methylene chloride (3:97). The resulting (5-chloro-3-methanesulfinyl-indol-1-yl)-acetonitrile weighed 0.851 g (80% yield) after drying.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([O:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH2:6][CH3:7])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(C)CO
Product: CCCC(C)COS(C)(=O)=O

Procedure:
The title compound was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (856 mg, 89%) from 2-methyl-1-pentanol (497 mg, 4.90 mmol) and methanesulfonyl chloride (821 mg, 7.30 mmol). 1H NMR (CDCl3, 300 MHz) δ0.89-0.93 (m, 3H), 0.98 (d, 3H, J=6.6 Hz), 1.15-1.43 (m, 4H), 1.88-1.90 (m, 1H), 3.00 (s, 3H), 3.98-4.11 (m, 2H) ppm.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:29]1([C:35]([NH:37][NH2:38])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([NH:38][NH:37][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:36])=[O:28])[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1

Procedure:
100 mg (0.25 mmol) of the compound from Example 44A and 65 mg (0.50 mmol) of benzenecarbohydrazide were reacted according to the General Method 11A.