Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19](=[O:24])C(F)(F)F)=[CH:7][N:8]2[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:4][CH:3]=1.[OH-:25].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]([OH:24])=[O:25])=[CH:7][N:8]2[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1cn(-c2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1cn(-c2cc(F)cc(F)c2)c2cc(Cl)ccc12
Temperature: 70 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
A suspension of 1-[6-chloro-1-(3,5-difluoro-phenyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone in 3N aqueous NaOH was stirred at 70° C. for 48 h. After washing with CH2Cl2, the aqueous phase was acidified to pH 1 and extracted with CH2Cl2. Concentration in vacuo gave the title compound in 70% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+]>C(O)C>[CH3:12][S:13]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
164 a) A suspension of o-Nitrobenzylbromide (5.71 g, 26.4 mmol) and sodium methanesulfinate (4.0 g, 40.0 mmol) in ethanol (70 mL) was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. To the residue was added water (50 mL) and stirred for 30 minutes. The suspension was filtered, rinsed with water and air dried. 1-Methanesulfonylmethyl-2-nitro-benzene was isolated as a yellow solid (5.36 g, 94%). MP=115-117° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=8.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.62-7.58 (m, 1H), 4.80 (s, 2H), 2.91 (s, 3H). 164 b) 2-Methanesulfonylmethyl-phenylamine was prepared from 1-methanesulfonylmethyl-2-nitro-benzene (1.0 g, 4.6 mmol) in a manner analogous to Example 111a. Product isolated as an off-white solid (0.84 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.20 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.86-6.76 (m, 2H), 4.30 (s, 2H), 4.28 (br s, 2H), 2.87 (s, 3H). MS=186 (MH)+. 164 c) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 2-methanesulfonylmethyl-phenylamine (440.0 mg, 2.375 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.62 g, 51%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=5.9 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.47-7.41 (m, 3H), 6.89-6.81 (m, 2H), 4.41 (s, 2H), 2.93 (s, 3H). MS=337, 339 (MH)+. 164 d) N(8)-(2-Methanesulfonylmethyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepare from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonylmethyl-phenyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.013 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.8 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.43-7.37 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.67 (t, J=7.1 Hz, 1H), 4.45 (s, 2H), 3.18-3.13 (m, 4H), 2.94 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:2]1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=C(C=Cc1c[nH]c2ccccc12)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from commercial 3-indolecarbaldehyde and acetophenone, 3-(1H-indol-3-yl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@@H:15]([CH3:18])[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].[NH2:33][C@@H](C)CO>>[NH2:33][C:16]([C@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH3:18])=[O:17]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Product: Cc1ccc(C(=O)N[C@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 2 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting D-alanine amide HCl for (S)-(+)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.62 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.5.9 (m, 2H), 4.54 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/z 521.0593 (M+H calculated for C22H20BrF2N4O4 requires 521.0630).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C>O.Cl>[NH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1cc(C(=O)O)c(NC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: COc1cc(C(=O)O)c(N)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 36.6 %

Procedure:
A solution of 2-acetamido-5-methoxy-4-nitrobenzoic acid (21.6 g, 85 mmol) in water (76 ml) and concentrated hydrochloric acid (30.5 ml) was heated at reflux for 3 hours. The reaction mixture was cooled to 0° C., the resulting solid was collected by filtration, washed with water and dried under vacuum to give 2-amino-5-methoxy-4-nitrobenzoic acid (I 6.6 g, 92%).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[CH3:7][C:8]1([CH3:19])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]1[C:17]#[N:18].OO>CS(C)=O.[Cl-].[Na+].O>[CH3:7][C:8]1([CH3:19])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]1[C:17]([NH2:18])=[O:2]
Reactant: CC1(C)C(C#N)C1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C(C(N)=O)C1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (467 mg) was added to a solution of 2,2-dimethyl-3-phenyl-cyclopropanecarbonitrile (3/1 cis/trans mixture, 4 g, 23.4 mmol) in DMSO (7 mL). The resulting mixture was cooled to 0° C. and an aqueous solution of hydrogen peroxide (30%, 2.8 mL) was added. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. A second aliquot of aqueous solution of hydrogen peroxide (30%, 2.8 mL) was added and the resulting mixture was stirred for 24 hours. A third aliquot of aqueous solution of hydrogen peroxide (30%, 3.0 mL) was added and the resulting mixture was stirred for 3 days. The reaction mixture was poured into brine and extracted with ethyl ether. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (0% to 65% of EtOAc in hexane) to give 2.66 of 2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid amide (2/1 trans/cis mixture), together with 1.125 g of starting material.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]([C:15]23[CH2:22][CH:21]4[CH2:23][CH:17]([CH2:18][CH:19]2[CH2:20]4)[CH2:16]3)=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:18]1[CH:19]2[C:15]3([C:13]([NH:12][C:11]4[C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=[CH:9][CH:10]=4)=[O:14])[CH2:22][CH:21]([CH2:23][CH:17]1[CH2:16]3)[CH2:20]2
Reactant: CCOC(=O)c1ncccc1NC(=O)C12CC3CC(CC1C3)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ncccc1NC(=O)C12CC3CC(CC1C3)C2

Procedure:
To a solution of Example 332A (0.23 g, 0.73 mmol) in ethanol/water (10/2) was added potassium hydroxide (0.2 g, 3.66 mmol). The solution was warmed to 65 degrees for 12 hours, cooled and diluted with ethyl acetate (50 mL). The solution was acidified with 0.5M HCl (10 mL), then washed with brine, dried over MgSO4, filtered, and concentrated to afford the title compound. MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[C@@:11]([CH3:24])([NH:17][S@@](C(C)(C)C)=O)[C:12]([F:16])([F:15])[CH2:13][OH:14])=[O:7])(C)(C)[CH3:2].S(Cl)(Cl)=O>C(O)C>[CH2:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[C@:11]([NH2:17])([CH3:24])[C:12]([F:16])([F:15])[CH2:13][OH:14])=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H]1[C@@](C)(N[S@](=O)C(C)(C)C)C(F)(F)CO
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1C[C@@H]1[C@@](C)(N)C(F)(F)CO
Temperature: 85 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of (1S,2S)-rel-2-[(R)-2,2-difluoro-3-hydroxy-1-methyl-1-((R)-2-methyl-propane-2-sulfinylamino)-propyl]-cyclopropanecarboxylic acid tert-butyl ester (1.16 g, 3.14 mmol) in ethanol (22.5 ml) was treated dropwise at 0° C. with thionyl chloride (1.89 g, 1.15 ml, 15.7 mmol). The yellow mixture was then stirred at 85° C. for 2 hours. For the workup, the solvent was evaporated at reduced pressure, then water and diethyl ether were added. The aqueous layer was treated with carbonate, thereafter extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The light yellow oil (708 mg) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (1S,2S)-rel-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (566 mg, 76% yield) was obtained as a light yellow oil. MS (ISP): m/z=238.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:30]=[CH:31]/[C:32]([O:34]CC)=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].CO.[OH-].[Na+].Cl>CCOC(C)=O.C1COCC1.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@@H](Oc1ccc(/C=C/C(=O)OCC)cc1Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: O=[Pt]=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[C@@H](Oc1ccc(CCC(=O)O)cc1Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reaction time: 5 h
Yield: 61 %

Procedure:
To a stirring solution of ethyl (2E)-3-{3-chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate (54 mg, 0.10 mmol) in EtOAc (4 mL) under nitrogen at ambient temperature was added PtO2 (20 wt %, 11 mg) and the mixture stirred under an atmosphere of hydrogen for 5 h. The resulting mixture was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with EtOAc. The filtrate was then reduced and purified further by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 20:1) to give an inseparable mixture containing the desired material and some de -chlorinated compound (51 mg). This material was then dissolved in THF (2 mL) and MeOH (2 mL) at ambient temperature and treated with NaOH (2N, 2 mL). The resulting mixture was then stirred for 2 h and then left to stand overnight. HCl (2N, 2 mL) was then added and the mixture reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 20:1 to 0:1) to give a residue which was purified further by mass directed autoprep HPLC to give the title compound (30 mg).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].CCOCC>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[C:9]2([CH2:11][CH2:12][CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7][CH2:8]2)[O:10][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
This compound was prepared from ethyl cyclohexanone-4-carboxylate by following the procedure of Pearson et al. (J. Org. Chem., 1997, 62, 5284). A mixture of ethylene glycol (131 mL, 2350 mmol), ethyl 4-oxocyclohexanecarboxylate (100 g, 588 mmol), and p-toluene sulfonic acid monohydrate (2.012 g, 10.58 mmol) in benzene (125 mL) was stirred overnight at room temperature, under N2. The solution was poured into Et2O (1 L) and the mixture washed with water (3×300 mL), sat. NaHCO3 (100 mL) followed by brine (100 mL). The organic layer was then dried (MgSO4), filtered, and concentrated to yield the title compound (125.5 g, 586 mmol, 100% yield) as a clear oil: LCMS m/z 215.13 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]\[O:6][CH3:7].Cl>CO>[CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: CO/N=C(\C(=O)OC)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: CO
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccccc1

Procedure:
To Z-α-methoxyimino-2-phenoxyphenylacetic acid methyl ester VI'(0.29 g, 1.0 mmole) were added dried methanol (3 ml) and 10% hydrochloric acid solution in methanol (0.36 g, 1.0 mmole) and the mixture was heated under reflux for 6 hours to conduct isomerization.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].Cl.CCOC(C)=O>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:10][C:6]1[CH:5]=[C:4]([C:3](=[O:11])[C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(Br)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 20 h
Yield: 63.7 %

Procedure:
In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution to −78° C., TBAF (232 μL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to rt overnight. After stirring for 20 hr, 2N HCl (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc. The combined organic fractions were dried (MgSO4), concentrated in vacuo, and resulting crude oil was purified using SiO2 flash chromatography (elution: 5–20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz) δ 8.18 (br s, 1H), 7.98–8.00 (m, 1H), 7.82–7.85 (m, 1H), 7.42–7.46 (m, 1H). 19F-NMR (CDCl3; 400 MHz) δ −72.06 (s).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:24][OH:25])=[CH:9][CH:8]=1)[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[CH2:26]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH:24]=[O:25])=[CH:9][CH:8]=1)[CH3:27]
Reactant: CCN(CC)CCNc1ccc(CO)c2sc3ccc(OC)cc3c(=O)c12
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCNc1ccc(C=O)c2sc3ccc(OC)cc3c(=O)c12
Yield: 79.7 %

Procedure:
A solution of 1-[[2-(diethylamino)ethyl]amino]-4-(hydroxymethyl)-7-methoxythioxanthen-9-one (8.8 g, 0.023 mol) in toluene (268 mL) was heated to 60° C. under nitrogen and then MnO2 (13.2 g) was added. The mixture was heated overnight, filtered, and the filtrate was concentrated in vacuo to afford 7.05 g (81%) of 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-carboxaldehyde (Formula II: R1 =R2 =Et; R8 =7-OCH3 ; n=2).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[C:14](F)[C:13]([F:17])=[CH:12][C:11]=3[N+:18]([O-:20])=[O:19])[CH:5]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]([F:17])=[C:14]([NH:30][C@H:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[CH3:29])[CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c([N+](=O)[O-])cc1F)c1ccc(F)cc1
Temperature: 160 °C
Yield: 84.2 %

Procedure:
A mixture of 5-cyclopropyl-N-(4,5-difluoro-2-nitrophenyl)-1H-pyrazol-3-amine (Method 86; 0.300 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.164 g, 1.18 mmol), and DIEA (0.280 ml, 1.61 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 160° C. for 16 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=3:1) to give the title compound as an orange solid (0.360 g, 84%). NMR (400 MHz) 12.29 (s, 1H), 10.14 (s, 1H), 7.75 (d, J=12.8 Hz, 1H), 7.63 (d, J=6.4 Hz, 1H), 7.41 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 7.00 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 4.55 (m, 1H), 1.90 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.98 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 399; Found: [M+H]+ 400.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]2=[O:13].Cl.[N:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([NH:21][C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Reactant: NNc1ccncc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(=O)N(Nc1ccncc1)C2=O
Yield: 33.9 %

Procedure:
A mixture of 5-methoxyisobenzofuran-1,3-dione (33.0 g), 4-pyridinylhydrazine hydrochloride (25.7 g) and glacial acetic acid (100 ml) was heated overnight, under reflux, under nitrogen, with stirring. Water (100 ml) was added, and the mixture was evaporated and dried in vacuo. The residue was triturated with acetone, the acetone decanted, and the residue was triturated with methanol to give 16.1 g of 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione. To a mixture of lithium aluminum hydride (6.00 g) and dry tetrahydrofuran (150 ml) at ambient temperature, under nitrogen, 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione hydrochloride (16.1 g) was added in portions, with stirring. The reaction mixture was stirred at room temperature, under nitrogen, 4 hrs, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter cake was washed thoroughly with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane:methanol:ammomium hydroxide. The appropriate fractions were collected and concentrated. The residue was crystallized from ethanol to give 5.8 (46%) of product, mp 166-167° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(N(CC)C(C)C)(C)C>COCCOC.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>[Cl:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1-c1ccc(C)cc1

Procedure:
methyl 2-(4,6-dichloro-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (1 eq), p-tolylboronic acid (1 eq), tetrakis(triphenylphosphine)palladium(0) (0.1 eq) are placed in a reaction tube and dissolved in a mixture of degassed DME and water (3/1 v/v; 5 mL/mmol). N,N-Diisopropylethylamine (4 eq) is added, the tube is sealed and irradiated in a microwave oven at 130° C. for 30 min. The reaction mixture is partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. Purification of the crude material is performed by flash chromatography on silica gel using a linear gradient of ethyl acetate in heptane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[SH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: Sc1ccncc1
Reactant: ClCc1cccc(Cl)c1
Solvent: CCO
Product: Clc1cccc(CSc2ccncc2)c1
Yield: 55.2 %

Procedure:
3-Chlorobenzyl chloride (1.61 g) and 4-mercaptopyridine (1.11 g) in ethanol (10 ml) were heated at reflux for 4 hours and cooled. Crystals which precipitated were removed by filtration and dried to give the title compound as the hydrochloride (1.3 g) mp 222°-4° C. (Found: C, 52.6; H, 4.3; N, 5.1. C12H10ClNS requires C, 52.95; H, 4.1; N, 5.1%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([NH2:19])[C:16]([C:20]([Si](C)(C)C)=[CH:21][C:22]#[C:23][Si](C)(C)C)=[C:15]([O:32][CH2:33][CH3:34])[N:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[NH2:19][C:17]1[C:16](/[CH:20]=[CH:21]/[C:22]#[CH:23])=[C:15]([O:32][CH2:33][CH3:34])[N:14]=[C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:35]=[CH:36][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:12])[CH:18]=1
Reactant: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C(=CC#C[Si](C)(C)C)[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#C/C=C/c1c(N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of compound from Example 274A (28 mg, 0.05 mmol) in tetrahydrofuran (5 ml) was added tetrabutyl ammonium fluoride (52 mg, 0.2 mmol). The mixture was stirred at room temperature for overnight, and then water and ethyl acetate (20 ml, 1:1) were added. The organic layer was washed with brine and dried over MgSO4. The crude product was purified by reverse phase HPLC (10 mM ammonium acetate, 5% acetonitrile in H2O/CH3CN) to give the titled compound (18.5 mg, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.02 (t, 1H), 7.87 (d, J=8.14 Hz, 2H), 7.54 (d, J=8.48 Hz, 2H), 7.08 (d, J=16.28 Hz, 1H), 7.04 (s, 1H), 6.57 (s, 2H), 6.48 (dd, J1=16.28, 2.37 Hz, 1H), 4.56 (d, J=6.44 Hz, 2H), 4.46 (q, J=7.01 Hz, 2H), 4.09 (d, J=2.37 Hz, 1H), 3.17 (s, 3H), 1.34 (t, J=7.12 Hz, 3H); MS (APCI) m/z 400 [M+H]+, 398 [M−H]−.