Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:32])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[F:20][CH:18]([F:19])[O:17][C:10]1[C:9]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)=[C:8]([CH3:32])[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:33])=[O:2])[N:11]=1
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of [2-difluoromethoxy-8-fluoro-3-(4-methanesulfonylbenzyl)-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.57 g), methanol (24 mL), 5.0 M aqueous lithium hydroxide solution (0.5 mL) and water (1.0 mL) was stirred at room temperature for 90 minutes. The pH of the mixture was adjusted to 4 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration, washed with water and dried to afford to title compound as a white solid, 0.53 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:30][CH2:31]O.CN(C(/N=N/C(N(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:30][CH2:31][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:7][CH2:8]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: Cc1ccc(-c2nc(CCO)c(C)o2)cc1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)cc4)oc3C)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
A suspension of the ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate prepared in Example 135 (507.5 mg, 2.30 mmol), and 2-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethanol prepared in Example 10 (500 mg, 2.30 mmol), TMAD (792.6 mg, 4.60 mmol), and Ph3P (1.21 g, 4.60 mmol) in 15 mL anhydrous DCM was stirred at rt under Ar for 12 hours. DCM was removed under reduced pressure. Flash chromatograph of the residue over silica gel using 1% CH3CN/CH2Cl2 gave ethyl 2-((1S)-5-{2-[5-methyl-2-(4-methylphenyl)(1,3-oxazol-4-yl)]ethoxy}indanyl)acetate (776.3 mg, 1.85 mmol, 80.5%). HPLC/MS (M+H)+ m/z 420.5.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:12]=[CH:13][N:14](C)C)=[N:5][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:7][N:8]=1)#[N:2].N[C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[S:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)(=O)C>[CH2:25]([O:24][C:22]1[CH:21]=[CH:20][C:19]([S:32][C:33]2[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=2)=[C:18]([NH:2][C:1]2[C:3]3[C:4](=[N:5][C:6]([CH:9]([CH3:10])[CH3:11])=[CH:7][N:8]=3)[N:12]=[CH:13][N:14]=2)[CH:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CC(C)c1cnc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CC(C)c1cnc2c(Nc3cc(OCc4ccccc4)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of the product from Example 244C (56.2 mg, 0.259 mmol) and the product from Example 27A in acetic acid (1 mL) was heated under reflux for 2 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The resulting residue was triturated with methanol to provide the title compound (55.5 mg, 53% yield) as a beige solid. 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.37 (s, 1H), 9.65 (s, 1H), 9.03 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 7.38 (d, J=8.09 Hz, 1H), 7.21 (d, J=8.82 Hz, 2H), 7.03 (dd, J=8.09, 1.47 Hz, 1H), 6.68 (d, J=8.82 Hz, 2H), 3.35-3.46 (m, 1H), 2.37 (s, 3H), 1.38 (d, J=6.62 Hz, 6H). MS (ESI+) m/z 404.2 (M+H)+ (ESI−) m/z 402.3 (M−H)−.
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)[CH2:2][CH3:3].[OH-].[Na+]>CO.O>[CH2:26]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[C:6]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:27][CH3:28]
Reactant: CCCN(CCC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a solution of methyl 3-(dipropylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (50 mg, 0.13 mmol) in methanol (15 mL) was added a solution of sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3N). The resulting solution was extracted with dichloromethane (4×20 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 3-(dipropylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (22.4 mg, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].I[C:17]1[C:25]2[C:20](=[N:21][CH:22]=[N:23][C:24]=2[NH2:26])[N:19]([CH:27]([CH3:29])[CH3:28])[N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:27]([N:19]1[C:20]2=[N:21][CH:22]=[N:23][C:24]([NH2:26])=[C:25]2[C:17]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[N:18]1)([CH3:29])[CH3:28]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)cc(OC)c1OC
Temperature: 80 °C
Yield: 89 %

Procedure:
A solution of 3,4,5-trimethoxyphenylboronic acid (123 mg, 0.58 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.23 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA64 (70 mg, 89% yield). ESI-MS (M+H)+ m/z calcd 344.1, found 344.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=C[O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[O:4].Cl>CO>[ClH:16].[CH3:1][O:2][C:3](=[O:4])[CH:5]([NH2:6])[C:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)=[O:8]
Reactant: COC(=O)c1ncoc1-c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 121.6 %

Procedure:
A suspension of 5-(3,4-dichloro-phenyl)-oxazole-4-carboxylic acid methyl ester (1.5 g, 5.51 mmol), 3 N HCl (10 mL), and MeOH (15 mL) was heated at 50° C. for 4 h. The mixture was concentrated, diluted with water, and washed with Et2O. The aqueous layer was concentrated and Et2O was added, causing precipitation of a white solid. The precipitate was collected by filtration to provide 1.0 g (63%) of the desired product as an apparent 10:1 mixture of keto-enol tautomers. MS (ESI+): mass calcd. for C10H9Cl2NO3, 261.00; m/z found, 262/264 [M+H]+. Major tautomer: 1H NMR (500 MHz, CDCl3): 8.32 (d, J=2.1, 1H), 8.09 (dd, J=8.4, 2.1, 1H), 7.79 (d, J=8.5, 1H), 3.80 (s, 3H). Minor tautomer: 1H NMR (500 MHz, CDCl3): 8.19 (d, J=2.0, 1H), 7.96 (dd, J=8.4, 2.1, 1H), 7.76 (d, J=8.4, 1H), 6.18 (s, 1H).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][C:11]1[N:16]=[C:15](/[C:17](=[N:19]/[S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH3:18])[C:14]([F:26])=[C:13]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:12]=1.[Cl-].[NH4+]>C1COCC1.C[Si](C)(C)Cl.C(OCC)(=O)C.[Zn].[Cu]Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[C@@:17]([C:15]1[C:14]([F:26])=[C:13]([Si:27]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:32][CH3:33])[CH:12]=[C:11]([Br:10])[N:16]=1)([NH:19][S@@:20]([C:22]([CH3:23])([CH3:24])[CH3:25])=[O:21])[CH3:18])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(/C(C)=N/[S@](=O)C(C)(C)C)c1F
Agent: Cl[Cu]
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1nc(Br)cc([Si](CC)(CC)CC)c1F
Reaction time: 0.75 h
Yield: 77 %

Procedure:
To a suspension of zinc (466 mg, 7.12 mmol) and copper(I) chloride (34 mg, 0.344 mmol) in dry THF (20 ml) were added 3 drops of trimethylchlorosilane under nitrogen to activate the zinc. After 10 minutes ethyl 2-bromo-2,2-difluoroacetate (1.398 g, 6.89 mmol) was added slowly by syringe over a period of 10 minutes at 25° C. (slightly exothermic). The reaction mixture was kept in an ultrasound bath for 45 minutes. This black fine suspension was added dropwise to a solution of (R)-2-methyl-propane-2-sulfinic acid [1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-eth-(E)-ylidene]-amide) (1 g, 2.296 mmol) in dry THF (10 ml) at it under inert atmosphere. After 4 h at it the reaction mixture was added to a cold aq. ammonium chloride solution (5%) and was diluted with ethyl acetate. The organic phase was washed with aq. citric acid (5% solution), water, sat. sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The crude brownish oil (1.5 g) was chromatographed over silica gel (cyclohexane/ethyl acetate 83:17) to give the title compound as a light yellow oil. 984 mg (77% yield).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28]>C1COCC1.[Pt](=O)=O>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28]
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(Br)c(C(F)(F)F)c4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc(Br)c(C(F)(F)F)c4)cc3)C2=N1
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A mixture of platinum(IV) oxide (30 mg) and 9-{4-[4-bromo-3-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (192 mg) in THF (20 mL) was stirred under a hydrogen atmosphere overnight. To the reaction mixture was added activated carbon, and the mixture was filtered through basic silica gel and celite. To the filtrate was added silica gel and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and concentrated under reduced pressure. The residue was separated by HPLC (C18, mobile phase: water/acetonitrile (0.1% TFA containing system)). To the obtained fraction was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from THF and diisopropyl ether to give the title compound (30 mg) as a white solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (95 mg, 82%), MS (ISP) m/z=387.4 [(M+H)+], mp 192.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and propionic acid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]2[CH:12]([CH2:13][O:14][CH3:15])[CH:8]([CH2:9][CH2:10]2)[N:7]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O)C>ClCCl>[C:19]([O:18][C:16]([N:7]1[CH:6]([CH2:4][OH:3])[CH:11]2[CH:12]([CH2:13][O:14][CH3:15])[CH:8]1[CH2:9][CH2:10]2)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C1C2CCC(C2COC)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
Add di-isobutylalluminium hydrate (1 M in hexanes, 14.6 mL, 14.6 mmol) to a solution of 7-methoxymethyl-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (1.53 g, 4.88 mmol) in dichloromethane (20 mL) cooled in an ice bath. Stir the mixture at room temperature for 3 h. Quench with saturated aqueous sodium tartrate and stir until the solution becomes clear. Extract the mixture with ethyl acetate (3×50 mL), wash the combined extract with saturated aqueous sodium tartrate, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 ethyl acetate:hexanes) to give the title compound (0.780 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[N:13]=1.Cl>C(OCCO)C>[ClH:19].[NH2:11][C:12]1[N:13]=[C:14]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:15]=[C:16]([CH3:18])[N:17]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(Nc2ccc(C(=O)O)cc2)nc(N)n1
Temperature: 20 °C
Yield: 95.3 %

Procedure:
p-Aminobenzoic acid (D1) (1.48 g, 10.8 mmol) and 4-chloro-6-methyl-2-pyrimidinamine (A8) (1.60 g, 11.9 mmol) was dissolved in warm 2-ethoxyethanol (20 mL),then two drops of c.HCl was added and refluxed for 1 h. The reaction mixture was cooled to 20° C. and the resulting precipitate was filtered washed with more 2-ethoxyethanol and EtOAc. The solid was boiled in MeOH, cooled and filtered washed with more MeOH and dried to give D2 (2.89 g, 95%); m.p. (MeOH)>300° C.; 1H NMR [(CD3)2SO] δ12.93 (br, 1 H, N+H or COOH), 12.80 (br, 1 H, N+H or COOH), 10.87 (s, 1 H, NH), 7.92 (s, 6 H, ArH &NH2)), 6.27 (s, 1 H, ArH), 2.32 (s, 3 H, CH3); mass APCI+ 245.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11]Br)=[N:10][C:5]2=[CH:4][CH:3]=1.[F:13][C:14]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]([F:24])[C:15]=1[C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:23][C:22]3[C:14]([F:13])=[C:15]([C:19]([F:24])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: BrCc1nc2ccc(Br)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 5-bromo-2-bromomethyl-thiazolo[5,4-b]pyridine (2.0 g, 6.493 mmol) in 10 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (1.01 g, 5.84 mmol) and potassium carbonate (3.09 g, 22.72 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound (1.80 g, 69%). 1H NMR (DMSO-d6, 400 MHz): δ 5.72 (s, 2H), 7.12 (t, J=7.60 Hz, 1H), 7.39 (m, 1H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 8.80 (m, 2H). MS ES+ (402.08), HPLC (method I) Rt=15.50 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7](/[C:11](/[CH3:19])=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([CH3:21])([CH3:20])[C:3]1=[O:22].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7](/[C:11](/[CH3:19])=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([CH3:21])([CH3:20])[CH:3]1[OH:22]
Reactant: C/C(=C\c1ccccc1)c1ccc2c(c1)C(C)(C)C(=O)C2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C/C(=C\c1ccccc1)c1ccc2c(c1)C(C)(C)C(O)C2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
1.4 g of 1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]2-indanone are dissolved in 100 ml of ethanol and treated at room temperature with 6 g of sodium borohydride. After stirring at room temperature for 16 hours the reaction mixture is poured on to ice and extracted repeatedly with ether. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. The residue can be recrystallized from hexane and gives 1.1 g of 1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanol in colourless crystals, melting point 63°-67°.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:21][CH2:22][CH2:23][CH3:24])=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].Br[C:26]1[C:31]2[N:32]=[C:33]([C:36]3[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=3)[N:34]=[CH:35][C:30]=2[C:29](=[O:42])[N:28]([CH3:43])[CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:21][CH2:22][CH2:23][CH3:24])=[C:10]([C:26]2[C:31]3[N:32]=[C:33]([C:36]4[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=4)[N:34]=[CH:35][C:30]=3[C:29](=[O:42])[N:28]([CH3:43])[CH:27]=2)[CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCCOc1ccc(S(=O)(=O)CC)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(-c2ncc3c(=O)n(C)cc(Br)c3n2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCOc1ccc(S(=O)(=O)CC)cc1-c1cn(C)c(=O)c2cnc(-c3cnn(C)c3)nc12
Temperature: 70 °C
Yield: 83.2 %

Procedure:
The title compound of step 2 (60 mg, 0.17 mmol), the title compound of Example 224, step 4 (64 mg, 0.20 mmol), K3PO4 (108 mg, 0.51 mmol), and Pd(dppf)Cl2 (15 mg, 0.02 mmol) in dioxane (8 mL) were purged with N2 and heated at 70° C. for 18 h. CH2Cl2 extractive work up and preparative HPLC gave the title compound (66.11 mg, yield: 83.3%) as a grey solid. 1H NMR (CDCl3, 400 MHz) δ 9.64 (s, 1H), 8.19 (s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.06 (s, 1H), 7.96 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.70 (s, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.03-3.95 (m, 5H), 3.67 (s, 3H), 3.20 (q, J=7.2 Hz, 2H), 1.67-1.60 (m, 2H), 1.36 (t, J=7.2 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H). LCMS: 468.2 (M+1)+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[F:56][C:57]1[C:58]([C:64]2[CH:69]=[C:68]([NH2:70])[CH:67]=[CH:66][N:65]=2)=[N:59][C:60]([CH3:63])=[CH:61][CH:62]=1.CC([O-])(C)C.[Na+]>O1CCOCC1.O.C(#N)C.O.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]>[F:56][C:57]1[C:58]([C:64]2[CH:69]=[C:68]([NH:70][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[N:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:3]=34)[CH:67]=[CH:66][N:65]=2)=[N:59][C:60]([CH3:63])=[CH:61][CH:62]=1
Reactant: CC(C)n1ncc2nccc(I)c21
Reactant: Cc1ccc(F)c(-c2cc(N)ccn2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C(C)C)c34)ccn2)n1
Temperature: 120 °C
Yield: 23 %

Procedure:
7-Iodo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine (24 mg, 0.084 mmol), Tris(dibenzylideneacetone)dipalladium(0) (2.82 mg, 3.08 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.80 mg, 0.031 mmol), 3′-fluoro-6′-methyl-2,2′-bipyridin-4-amine (25 mg, 0.123 mmol) and sodium 2-methylpropan-2-olate (35.5 mg, 0.369 mmol) were combined in dioxane (5 mL). The mixture was heated at 120° C. for 2 hours, then cooled and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-50% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water to afford N-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine (7 mg, 15.70% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.48 (s, 6H) 2.61 (s, 3H) 5.08-5.21 (m, 1H) 7.03 (dd, J=5.81, 2.02 Hz, 1H) 7.36-7.47 (m, 2H) 7.49 (s, 1H) 7.62-7.71 (m, 1H) 8.30 (s, 1H) 8.42 (d, J=6.06 Hz, 1H) 8.51 (d, J=4.80 Hz, 1H). MS [M+H] found 363.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11]>C(Cl)(Cl)Cl.N1C=CC=CC=1.CCOCC>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH:6][S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:18][CH:17]=1)(=[O:21])=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CN
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)NCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43 %

Procedure:
To a solution of 1.00 g (7.163 mmol) of glycine ethyl ester in 10 mL of chloroform and 2.0 mL of pyridine was added 1.75 g (7.163 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride and the reaction was stirred at room temperature for 15 h. The reaction mixture was then diluted with ether and the organics were washed with 5% HCl solution and water, dried over MgSO4, filtered and concentrated in vacuo. The resulting brown solid was washed with ether to provide 0.96 g (43%) of the sulfonamide as a white solid. Electrospray Mass Spec 311.8 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:16].[Na+].Cl>CO>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[CH:1]([NH2:16])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cnccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(N)c1cnccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.5 %

Procedure:
To a solution of 2-acetylpyrazine (206.7 mg, 1.7 mmol) and ammonium acetate (1.3 g, 17 mmol) in methanol (5.0 mL) was added sodium cyanoborohydride (75 mg, 1.19 mmol) followed by 3 Å molecular sieves (0.85 g). The reaction mixture was stirred for 1 day at room temperature. It was acidified to pH 2 with concentrated HCl then filtered, and the solid was washed with methanol and H2O. The filtrate was concentrated in vacuo. The residue was dissolved in water and was made basic (pH 10-12) with 5N NaOH. The aqueous layer was extracted with CH2Cl2 several times while maintaining ˜pH 10. The combined extracts were dried over Na2SO4, filtered, and concentrated the solvent in vacuo. The crude product was purified by preparative thin layer chromatography eluting with 5% 2M NH3 in MeOH/CH2Cl2 to give 74 mg of the title compound. 1H NMR (500 MHz, CDCl3): 8.61 (s, 1H); 8.5 (d, J=1.6 Hz, 1H); 8.44 (d, J=1.6 Hz, 1H); 4.21 (q, J=6.8 Hz, 1H); 1.46 (d, J=6.8 Hz).