Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+](C1C=C[C:8]([O:11][C:12](=[O:33])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)[CH:15]=2)=[CH:7]C=1)([O-])=O.[CH3:34][N:35](C)[CH2:36]CO.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[ClH:30].[CH3:34][N:35]([CH3:36])[CH2:7][CH2:8][O:11][C:12](=[O:33])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)[CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Reactant: CN(C)CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C)CCOC(=O)Nc1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Yield: 73.9 %

Procedure:
Under stirring and argon atmosphere [3(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester—hydrochloride salt (15 mg, example 151, intermediate 1) was suspended in dichloromethane (1.5 ml) and 2-dimethylamino-ethanol (3 mg) dissolved in dichloromethane (0.5 ml) was added. After stirring for 6 h and standing over night dichloromethane, water and saturated potassium carbonate solution were added. The organic layer was separated, washed three times with saturated potassium carbonate solution, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC. The product containing fractions were combined and the acetonitrile was removed in vaccuo. After addition of sodium bicarbonate the aqueous phase was extracted with ethyl acetate. The organic layer was separated, dried (magnesium sulphate), filtered and concentrated in vaccuo. The residue was dissolved in water/2N hydrochloric acid and freeze dried to give 5 mg of the title compound.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11](F)=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[N:7]=[C:6]2[N:19]([CH3:22])[N:20]=[CH:21][C:5]=12>C(O)CCC>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:12]3[C:11]=2[NH:2][N:1]=[C:13]3[NH2:14])[N:7]=[C:6]2[N:19]([CH3:22])[N:20]=[CH:21][C:5]=12
Reactant: Cn1ncc2c(Cl)cc(-c3cccc(C#N)c3F)nc21
Reactant: NN
Solvent: CCCCO
Product: Cn1ncc2c(Cl)cc(-c3cccc4c(N)n[nH]c34)nc21
Temperature: 90 °C

Procedure:
Hydrazine (0.34 mL, 1.04 mmol) was added to a solution of 3-(4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorobenzonitrile 15 (0.030 g, 0.1046 mmol) in n-butanol and the reaction mixture was heated at 90° C. for 1 hour. The solvent was removed and diluted with ethylacetate, washed with saturated bicarbonate solution followed by brine. Drying and concentration gave 16.
Reaction SMILES: CS[C:3]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=O)=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].C(O)(=O)C.C(Cl)Cl>[Zn].S([O-])([O-])(=O)=O.[Cu+2].O>[O:24]=[C:22]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][N:14]1[C:11]1[CH:12]=[CH:13][C:8]([CH:3]([CH3:7])[C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1
Reactant: CSC(C)(C(=O)O)c1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 84.5 %

Procedure:
α-Methylthio-α-[p-(o-carboxybenzoylamino)phenyl]propionic acid (130 mg), 300 mg of zinc powder and 20 mg of of anhydrous copper sulfate were added to 1.5 ml of acetic acid and the resulting mixture was heated under reflux for 5 hours with stirring. After cooling, 30 ml of methylene chloride and 20 ml of water were added. The insoluble precipitate was separated by filtration. The filtrate was acidified to a pH of 1 with conc. hydrochloric acid, and extracted three times with 20 ml of methylene chloride. The organic layer was washed with 20 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford 86 mg of α-[p-(1-oxo-2-isoindolinyl)phenyl]propionic acid in a yield of 85%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:14]=[CH:15][C:16](Cl)=[N:17][CH:18]=1>O1CCOCC1.[Cl-].[Na+].O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:17][CH:18]=1
Reactant: Clc1ccc(Br)cn1
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCCOc1ccc(Br)cn1
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
2-Methoxyethanol (5.12 mL, 85.0 mmol) was dissolved in 1,4-dioxane (125 ml). Potassium tert-butoxide (7.00 g, 62.4 mmol) was added under N2. The mixture was stirred for 10 minutes. 5-Bromo-2-chloropyridine (10.0 g, 52.0 mmol) was added and the resulting mixture was refluxed for 2 hours. The mixture was poured into brine and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated to dryness. Purification by flash chromatography (silica, heptanes/EtOAc 4:1) gave the title compound as a colorless oil (8.74 g, 73%) sufficiently pure for the next step.
Reaction SMILES: [CH3:1][NH+:2]1[CH2:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH2:4][CH2:3]1.[Cl-]>O.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][CH:6]([C:8]([OH:10])=[O:9])[CH2:7]1
Reactant: C[NH+]1CCC=C(C(=O)O)C1
Agent: [Pd]
Agent: [Cl-]
Solvent: O
Product: CN1CCCC(C(=O)O)C1
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
Arecaidine hydrochloride (4 grams) (22.6 mmoles) was hydrogenated in water (100 ml) using 10% Pd-C at 40 psi at 25° C. for 24 hours. The catalyst was filtered off and washed with water. The aqueous solution was shaken with BioRad AG1X8 resin (OH- form) (23 ml bed) and after 5 minutes the resin was filtered off and washed with water. The aqueous solution was evaporated to give the title compound (Yield: 2.95 grams, 92%).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]3[S:10][C:11]4[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=4[N:13]=3)=[O:7])=[CH:4][N:3]=2)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(N4CCN(C(C)=O)CC4)nc3)nc12
Temperature: 120 °C
Yield: 31.6 %

Procedure:
A stirred suspension of 200 mg (0.49 mmol) 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide, 2.53 g (19.8 mmol) 1-acetylpiperazine and 290 mg (0.89 mmol) cesium carbonate in 4 ml NMP in a thick-walled glass pressure tube fitted with a teflon cap was heated at 120° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (0/99-4/96 methanol/dichlormoethane) followed by trituration in ether afforded 77 mg (31%) 6-(4-acetyl-piperazin-1-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide as a white crystalline solid. ES-MS m/e (%): 519 (M+Na+, 26), 417 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:44][C@@H:45]1[CH2:50][NH:49][CH2:48][CH2:47][N:46]1C(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C(O)(C(F)(F)F)=O>CS(C)=O.ClCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:49]5[CH2:48][CH2:47][NH:46][C@H:45]([CH3:44])[CH2:50]5)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CCN[C@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (50 mg, 0.086 mmol) was added 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (34.4 mg, 0.172 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 mL). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified using a Gilson HPLC (acidic condition). Product fractions were combined and solvent evaporated using a GeneVac EZ-2 evaporator. To the obtained residue was added TFA (0.198 mL, 2.57 mmol) in dichloromethane (0.2 mL) and that mixture was placed in a Glas-Col evaporator overnight and then the residue was redissolved in MeOH/DMSO and purified using a Gilson HPLC (acidic condition). Product fractions were combined and solvent was evaporated using a GeneVac EZ-2 evaporator That residue was basified by cartridge to afford the title compound 5.7 mg (9.4%). LC-MS m/z 667 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:30]/[CH:31]=[CH:32]/[CH2:33][C:2]([CH3:7])([CH3:3])[CH3:1])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: C1CCOC1
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)C/C=C/CC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (3.15 g, 13.1 mmol) in tetrahydrofuran (25 mL) at −78° C. was treated dropwise with a lithium hexamethyldisilazide solution (14.4 mL, IM in tetrahydrofuran, 14.4 mmol) and stirred for 30 minutes at −78° C. Example 35B (3.26 g, 17.0 mmol) was added to the solution and the reaction was allowed to warm to 25° C. and stirred for an additional 4 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, washed with a saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 5% ethyl acetate in hexane, and 10% ethyl acetate in hexane to give the title compound (3.32 g, 72%). 1H NMR (300 MHz, CDCl3): δ ppm 0.80 (m, 9 H) 1.53 (m, 3 H) 1.79 (m, 2H) 2.63 (m, 1 H) 2.82 (m, 1 H) 5.10 (m, 2 H) 5.18 (m, 1 H) 5.47 (m, 1 H) 7.27 (m, 10 H). MS (ESI+) m/z 368 (M+NH4)+.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5][CH2:4][NH:3]1.[C:18]1(=O)N(C2CCCNC2=O)C(=O)C2=CC=CC=C12>>[CH3:18][O:1][C:2]1[CH:6]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5][CH2:4][N:3]=1
Reactant: O=C1NCCC1N1C(=O)c2ccccc2C1=O
Reactant: O=C1NCCCC1N1C(=O)c2ccccc2C1=O
Product: COC1=NCCC1N1C(=O)c2ccccc2C1=O

Procedure:
By analogy with the method described in example 1 (step 1.1), using 2-(2-Oxo-pyrrolidin-3-yl)-isoindole-1,3-dione (prepared by analogy to the method described in (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin -2-one, the compound was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:28])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([CH3:40])=[C:34]2[C:39]=1[O:38][CH2:37][CH2:36][CH2:35]2.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:28])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH:20]=2)[C:16]=1[C:32]1[C:33]([CH3:40])=[C:34]2[C:39](=[C:30]([F:29])[CH:31]=1)[O:38][CH2:37][CH2:36][CH2:35]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
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: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 125 °C
Yield: 37.1 %

Procedure:
To a 2-5 ml microwave tube was added (S)-methyl 2-(tert-butoxy)-2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (420 mg, 0.995 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.099 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 mg, 1.094 mmol), DMF (4 mL), followed by 2M K2CO3 solution (400 μl). The reaction mixture was heated in a microwave reactor at 125° C. for 45 min. The reaction mixture was filtered and the filtrate was purified by silica gel chromatography to afford (204 mg, 37.2%) of the title compound. Enantiomeric Excess was determined by Chiral SFC method: Chiralpak AD-H analytical column, 4.6×250 mm, 5 μm. Mobile Phase: 15% MeOH in CO2. Temp: 35° C. Flow rate: 2.0 mL/min. for 10 min. UV monitored @ 266 nm. Injection: 5 uL of ˜2.0 mg/mL solution in 50:50 MeOH:CHCl3. The enantiomeric Excess is 93.0%. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.83-7.78 (m, 1H), 7.69 (dt, J=6.7, 1.8 Hz, 1H), 7.35-7.28 (m, 2H), 6.87 (d, J=10.7 Hz, 1H), 6.84 (s, 1H), 5.00 (s, 1H), 4.48-4.26 (m, 2H), 3.64 (s, 3H), 2.85-2.67 (m, 5H), 2.30-2.13 (m, 2H), 1.84 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C@@H:11]1[C@@H:15]2[O:16]C(C)(C)[O:18][C@H:19]([CH:20]=[CH2:21])[C@@H:14]2[O:13][C:12]1=[O:24])[CH3:9]>O>[CH2:8]([O:10][C@@H:11]1[C@H:15]([OH:16])[C@H:14]([C@H:19]([OH:18])[CH:20]=[CH2:21])[O:13][C:12]1=[O:24])[CH3:9]
Reactant: C=C[C@H]1OC(C)(C)O[C@@H]2[C@H]1OC(=O)[C@@H]2OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OCC)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
2.8 ml of TFA are added to a 25 mL round-bottomed flask containing 13 mL of water and 800 mg of 50 (3.30 mmol). The medium is stirred for 2 h at RT and then the medium is diluted with 200 mL of water, frozen and freeze-dried. 550 mg of expected product 51 (flaky white solid) are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][C:10]1[N:9]([CH2:8][C:4]2[CH:3]=[C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=3)[CH:7]=[CH:6][CH:5]=2)[C:17]2[C:12]([CH:11]=1)=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(Br)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
Synthesized as described in Example 310D using 1-[(3-bromophenyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 318A) and [3-(trifluoromethyl)phenyl]boronic acid: 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.65-7.35 (m, 8H), 6.81 (d, J=7.6 Hz, 1H), 6.68 (s, 1H), 5.44 (s, 2H), 2.48 (s, 3H): MS (ES) m/z 459 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]([O-])(=O)=O.[K+]>S(=O)(=O)(O)O.O>[Br:14][C:5]1[CH:4]=[C:3]([N+:11]([O-:13])=[O:12])[C:2]([CH3:1])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a mixture of 2-methyl-1,3-dinitro-benzene (10 g) and 1:1 concentrated sulfuric acid-water (100 mL) at 80° C. was added potassium bromate (10.1 g) portionwise over 2-21/2 hr. The mixture was stirred at 80° C. for an additional 2 hr and cooled to room temperature. The mixture was poured into 500 g ice and then extracted with diethyl ether (300 mL). The ether layer was washed with 10% sodium bicarbonate solution (250 mL), brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (4:96) to afford 5-bromo-2-methyl-1,3-dinitro-benzene (5.3 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C@@H:17]([C:21]([OH:23])=[O:22])[C@@H:18]([CH3:20])[OH:19]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([NH:16][C@@H:17]([C:21]([OH:23])=[O:22])[C@@H:18]([CH3:20])[OH:19])=[O:15])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(CC(=O)O)cc1
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Product: CCCCOc1ccc(CC(=O)N[C@@H](C(=O)O)[C@@H](C)O)cc1

Procedure:
4-Butoxyphenylacetic acid (288 mg, 1.38 mmol) is converted to the acid chloride and added to D-allo-Thr (150 mg, 1.26 mmol) to get 2c-9, following the procedure described in Example 6. The crude product is purified by chromatography (2.5×18 cm column, gradient 4% CH3OH and 0.3% HOAc in CH2Cl2): NMR δ0.96 (t, J=7.4, 3H), 1.14 (d, J=5.8, 3H), 1.47 (m, 2H), 1.74 (m, 2H), 3.53 (br s, 2H), 3.91 (t, J≈6.5, 2H), 4.10 (br s, 1H), 4.53 (br s, 1H), 4.90 (br s, >2H), 6.76 (br d, J=6.0, 1H), 6.84 (d, J=8.4, 2H), 7.13 (d, J=8.4, 2 H); MS (HR-EI) m/z 309.1567 (M calcd. for C16H23NO5, 309.1576); [α]D26 -26±2 (CHCl3); m.p. 90°-94° C.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=[O:6].FC(F)(F)C1C=CC(C(O)=O)=CC=1.CSSC>>[CH3:17][S:16][C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Agent: O=C(O)c1ccc(C(F)(F)F)cc1
Solvent: CSSC
Product: CSc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=235.0 [(M−H)−], was prepared in accordance with the general method of intermediate A from 4-(trifluoromethyl)benzoic acid and dimethyl disulfide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][CH2:38]O)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:61]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][CH2:38][Br:61])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCc2c(CCCBr)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
104.0 mg of 4-{2-[1-Benzhydryl-5-chloro-2-(3-hydroxy-propyl)-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (0.0002M, 1.0 eq.) was dissolved in 2.0 mL of anhydrous methylene chloride. To the solution 116.0 mg of polystyrene bound triphenylphosphine was added (1.61 mmol/g, 0.0002M, 1.0 eq.) followed by 125.0 mg of carbon tetrabromide (0.0004M, 2 eq.). The suspension was stirred for 2 hrs at room temperature at which point the reaction was filtered and the filtrate evaporated to an orange oil. The oil was purified via column chromatography with ethyl acetate/hexanes (2:98) to give 100 mg (86%) of 4-{2-[1-Benzhydryl-2-(3-bromo-propyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester title as a yellow foam.
Reaction SMILES: S([O-])(O)=O.[Na+].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C(=O)C>[C:17]1([C:16]2[NH:11][C:9](=[O:10])[C:8]3[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)c1ccccc1N
Reactant: O=Cc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Sodium hydrogen sulfite (0.8 g, 7.5 mmol) was added to a solution of 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and benzaldehyde (32) (0.8 g, 7.3 mmol) in N,N-dimethylacetamide (DMAC) (20 ml). The mixture was heated with stirring at 150° C. for 2 h and then poured into ice water (200 ml). The precipitate was collected, washed with water, and then dried in vacuo. After recrystallization from EtOH, 41 was obtained (1.5 g, 92.6%) as pale yellow needles. Yield, mp, and spectral data are given in Table 1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC([O-])=O.[Na+].[Br:16]Br.[OH-].[Na+]>CC(O)=O.C(Cl)Cl.O>[Br:16][C:8]1[CH:9]=[C:10]2[C:2]([CH3:1])=[N:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: Cc1n[nH]c2ncccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.4 %

Procedure:
To a solution of 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) (12.7 Kg, 95.4 mol) in HOAc (57 L) was added NaOAc (20.4 Kg, 248 mol), water (13.3 L), and Br2 (40 L, 780 mol). The reaction was stirred at room temperature for 5 hours and then at 115° C. for 6 hours. The reaction was cooled to room temperature and diluted with DCM (686 L). To this solution was added water (508 L) and cooled to 0° C. followed by dropwise addition of aqueous 30% NaOH while maintaining the temperature <20° C. under pH=9. The mixture was filtered through diatomaceous earth (14 Kg) followed by washing the diatomaceous earth with 3×DCM (50 L). The organic layer was separated, washed with aqueous 25% NaCl (200 L) and concentrated under vacuum to a volume of 70 L. The product was crystallized by charging the solution with 3×n-heptane (88 L) while concentrating the volume to 70 L after each addition of n-heptane. The solid was filtered and washed 3×n-heptane (22 L). The solid was dried under vacuum at 45° C. to yield 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (XXI) (9.8 Kg, 46.2 mol, 92.6% purity, 48.4% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.48 (s, 3H), 8.50-8.55 (m, 2H), 13.42 (brs, 1H); ESIMS found C7H6BrN3 m/z 213.7 (M+H).