Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][C:10]([Si:13]([CH3:24])([CH3:23])[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>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].C1(C)C=CC=CC=1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][O:14][Si:13]([C:10]([CH3:12])([CH3:11])[CH3:9])([CH3:23])[CH3:24])[CH2:22][CH2:21]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccc(Cl)nc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
5-Bromo-2-chloropyridine (3.15 g, 16.4 mmol), compound 246 (4.00 g, 16.4 mmol), Pd2(dba)3 (0.749 g, 0.818 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.947 g, 1.64 mmol) and sodium tert-butoxide (1.82 g, 19.0 mmol) were combined in a screw cap vial and solvated under argon atmosphere with degassed toluene (44 mL). The reaction was briefly sparged with argon, then sealed and stirred at 100° C. After 3 h, the reaction contents were poured into saturated sodium bicarbonate (100 mL) and extracted with 10% methanol in dichloromethane (3×200 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 100% ethyl acetate in hexanes switching to 3% methanol in DCM) afforded compound 247 (5.40 g, 92.7% yield). 1H NMR (500 MHz, CDCl3) δ 0.08 (s, 6 H) 0.91 (s, 9 H) 2.60 (t, J=5.87 Hz, 2 H) 2.70 (br. s., 4 H) 3.20 (d, J=4.40 Hz, 4 H) 3.80 (t, J=6.11 Hz, 2 H) 7.17 (d, J=1.71 Hz, 2 H) 8.02 (s, 1 H) ppm.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][C:28](=[O:30])[CH3:29])[CH2:25][CH3:26])[C:5]1=[O:31])[CH:2]=[CH2:3].[CH3:33][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][C:28]([OH:30])([CH3:33])[CH3:29])[CH2:25][CH3:26])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(C)=O)C1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-5-oxohexan-3-yl)piperidin-2-one (90 mg, 0.19 mmol; Example 131, Step A) in THF (1.9 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (408 μL, 0.571 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 4 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure and purification of the residue by chromatography on silica gel (12 g SiO2, 30% and 35% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].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:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:27]2[CH:26]=[C:25]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=2[F:21])[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(C(=O)O)c1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cc(C(C)(C)C(=O)O)ccc2F)n1
Yield: 29 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichlorophenyl)-ethyl]amine (0.24 g), 2-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methyl-propionic acid (0.4 g), Cs2CO3 (1.01 g) and tetrakis(triphenylphosphine)palladium (0) (100 mg) in water (20 mL)/DME (80 mL) is heated at 90° C. for 16 h. The solution is poured into water and extracted with EtOAc (2×200 mL). The organic layer is dried over sodium sulfate, filtered, evaporated in vacuo. The residue is chromatographed on silica gel eluting with EtOAc to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-4-fluoro-phenyl)-2-methyl-propionic acid (100 mg), which is dissolved in THF (4 mL) and treated with 4 N HCl in 1,4-dioxane (1 mL). The mixture is concentrated in vacuo and the residue is suspended in ether (25 mL). The solid is formed and filtered under nitrogen to afford 2-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-4-fluoro-phenyl)-2-methyl-propionic acid hydrochloride (67 mg, Example 99). MS: 478 (M+H); 1H NMR (300 MHz, NMR, CD3OD) □7.8, (d, 1H, J=0.3 Hz); 7.4 (m, 2H); 7.35 (s, 1H); 7-7.15 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 3.6 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H). IC50=0.5 nM
Reaction SMILES: O[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16].S(=O)(=O)(O)O>>[CH:2](=[C:3]([CH2:8][O:18][C:15](=[O:17])[CH3:16])[C:4]([O:6][CH3:7])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(C(=O)OC)C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)C(=Cc1ccccc1)COC(C)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 110.8 %

Procedure:
Methyl 3-hydroxy-2-methylene-3-phenylpropionate (100.6 g, 523 mmols) obtained in Example 5 was dissolved in 113 ml (1.20 mols) of acetic anhydride, and 0.2 ml of sulfuric acid were added thereto. The mixture was stirred at 100° C. for 4 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 135.7 g of a crude product of the above title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[N:11]2)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][O:16][C:12]1[CH:13]=[CH:14][C:15]2[N:10]([N:9]=[CH:8][C:7]=2[C:5]2[CH:4]=[CH:3][N:35]=[C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[CH:31][CH:30]=3)[N:34]=2)[N:11]=1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Reactant: COc1ccc2c(C(=O)/C=C/N(C)C)cnn2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccnc(Nc4ccc(N5CCN(C)CC5)cc4)n3)cnn2n1
Temperature: 130 °C
Yield: 18 %

Procedure:
To a solution (2E)-3-(dimethylamino)-1-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one (40 mg, 0.16 mmol) in DMF (2.0 mL) was added N-[4-(4-methyl-1-piperazinyl)phenyl]guanidine.HCl (99 mg, 0.32 mmol) and potassium carbonate (112 mg, 0.80 mmol). The reaction was heated at an oil bath temperature of 130° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was concentrated in vacuo then disolved in CH2Cl2 and triturated with diethylether to give the title compound as a yellow solid (12 mg, 18%). 1H-NMR (400 MHz, CDCl3) δ 8.67 (d, 1H, J=9.5 Hz), 8.35 (d, 1H, J=5.2 Hz), 8.29 (s, 1H), 7.46 (d, 2H, J=8.9 Hz), 6.98 (m, 3H), 6.90 (s, 1H), 6.75 (d, 1H, J=9.5 Hz), 4.09 (s, 3H), 3.23 (m, 4H), 2.64 (m, 4H), 2.39 (s, 3H); MS (ESI) (M+H)+ 417.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([S:27][CH3:28])[C:3]=1[C:4]#[N:5].O.[NH2:30][NH2:31]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:30][NH:31]3)=[C:6]([S:27][CH3:28])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH:22]([CH3:23])[CH3:24])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCOC[C@H]2C(C)C)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2cc(SC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-6-(methylthio)benzonitrile (350 mg, 0.87 mmol) in ethanol (10 mL) was added hydrazine monohydrate (2.5 mL) in one portion. The resulting suspension was heated in an oil bath to 100° C. under a reflux condenser for 20 hours. LCMS showed complete conversion. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was taken up in water (30 mL) and sonicated briefly. The resulting suspension was filtered. The collected solids underwent purification by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 100% A (where A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3). After removal of eluant solvents, the residue was redissolved in CHCl3, filtered, and concentrated in vacuo. The residue was taken up in water (15 mL) as a suspension. The solids formed were collected by filtration and dryed under vacuum at room temperature over P2O5 for 20 hours. These solids were washed with hexane (3×3 mL). Further drying under vacuum at 65° C. for 20 hours gave the title compound (282 mg) as a cream-colored solid. LC-MS (ES) m/z=414 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 0.89 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H), 2.45-2.55 (m, 1H), 2.65 (s, 3H), 2.96 (s, 3H), 3.25-3.35 (m, 1H), 3.53-3.61 (m, 2H), 3.94 (dd, J=11.2, 3.4 Hz, 1H), 4.11 (d, J=11.9 Hz, 1H), 6.40 (s, 1H), 7.40 (s, 1H), 7.62 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH3:23])=[N:6][CH:7]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[CH2:31])=[CH:28][CH:27]=1.Cl.CN(C)CC(O)=O.C([O-])(=O)C.[Na+]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C.CN1CCCC1=O>[CH3:23][O:22][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[CH:3][C:2](/[CH:31]=[CH:30]/[C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=2)=[CH:7][N:6]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(Br)cn2)c(OC)c1
Reactant: C=Cc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)CC(=O)O
Solvent: N#Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(Oc2ccc(/C=C/c3ccc(C(F)(F)F)cc3)cn2)c(OC)c1
Temperature: 130 °C
Reaction time: 17 h

Procedure:
To ethyl 3-[4-(5-bromopyridin-2-yloxy)-3-methoxyphenyl]propionate (610 mg, 1.6 mmol) were added 4-trifluoromethylstyrene (0.332 mL, 2.2 mmol), dichlorobis(benzonitrile)palladium(II) (33 mg, 0.082 mmol), N,N-dimethylglycine hydrochloride (17 mg, 0.16 mmol), sodium acetate (263 mg, 3.2 mmol) and N-methylpyrrolidone (5 mL) under an argon atmosphere. The resulting solution was stirred under an argon atmosphere for 17 hours at 130° C. To the reaction solution was added ethyl acetate and filtered. The filtrate was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 500 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.C1C(=O)N([Br:30])C(=O)C1.O>C(#N)C>[Br:30][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[C:10]3[C:2]([CH3:22])([CH3:1])[C:3]4[C:8]([C:9]3=[CH:21][C:20]2=1)=[CH:7][CH:6]=[CH:5][CH:4]=4
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Solvent: CC#N
Solvent: O
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Reaction time: 4 h

Procedure:
66.5 g (234.6 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are initially introduced in 1000 ml of acetonitrile. A solution of 41.7 g (234.6 mmol) of NBS in 500 ml of CH3CN is subsequently added dropwise at −15° C. with exclusion of light, allowed to come to RT and stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction. Yield: 47.5 g (131 mmol), 55.9% of theory, purity according to 1H-NMR approx. 97%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:35])[NH:12][C:13]1[C:14]([CH3:34])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](=[NH:33])[NH2:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:9].C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:35])[NH:12][C:13]1[C:14]([CH3:34])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([NH:32][C:45](=[O:47])[CH3:46])=[NH:33])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: CC(=O)Cl
Reactant: Cc1noc(-c2ccc(-c3ccc(CC(=N)N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(=N)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3F)cc2)cc1
Temperature: 25 °C

Procedure:
To [5-(4′-carbamimidoylmethyl-biphenyl-4-yl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-fluoro-phenyl)-ethyl ester (0.055 g, 0.12 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (0.052 mL, 0.3 mmol), followed by acetyl chloride (0.009 mL, 0.126 mmol), and the reaction was stirred at room temperature. Additional acetyl chloride (0.009 mL, 0.126 mmol) was added, and the reaction was stirred at room temperature. The mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried, filterd, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: COC1C=C(C=CC=1C1SC=CC=1)[NH2:6].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.O>C(O)(=O)C>[C:18]1(=[O:19])[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:20])[NH:6]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cc(N)ccc1-c1cccs1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)c2ccccc21

Procedure:
A stirred mixture of 5.1 g (0.025 mole) of 3-methoxy-4-(thien-2-yl)aniline (prepared in Example 4) and 4.1 g (0.03 mole) of phthalic anhydride in 20 ml of glacial acetic acid was heated at reflux for approximately 18 hours. The hot reaction mixture was poured into 700 ml of distilled water forming a precipitate. The precipitate was collected by filtration and the filter cake dissolved in methylene chloride. The methylene chloride solution was washed first with a 10% aqueous potassium carbonate solution and then with an aqueous sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by evaporation under reduced pressure to yield 8.2 g of 2-[4-thien-2-yl)-3-methoxyphenyl]-1H-isoindol-1,3-(2H)-dione as a solid (mp 153°-155° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH:25](O)[C:24]3[C:19](=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=[CH:22][CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=[CH:22][CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(C(=O)OCc3ccccc3)c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1NC(c1cccc(C(=O)OCc3ccccc3)c1)C(C)(C)C2
Temperature: 25 °C
Yield: 17 %

Procedure:
To a solution of methyl 2-(3-(benzyloxycarbonyl)phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-carboxylate (0.66 g, 1.49 mmol), triethylsilane (0.5 g, 4.3 mmol) in dichloro methane (10 mL) was added a solution of trifluoroacetic acid (0.69 g, 6.1 mmol), which was placed in a drop funnel, under nitrogen with ice cooling. Upon completion of addition, the resulting mixture was allowed to warm back to room temperature naturally overnight. Thin layer chromatography (petroleum ether:ethyl acetate=20:1) showed the reaction was complete. The reaction mixture was basified with solid sodium carbonate to pH=6 and filtered. The filtrate was concentrated in vacuo and the residual was purified by column chromatography (petroleum ether:ethyl acetate=25:1) to give 109 mg of methyl 2-(3-(benzyloxycarbonyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-8-carboxylate as a off-yellow solid, yield: 39.6%.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][O:26][CH2:27][CH:28]([OH:44])[CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:33]5[CH:32]=[N:31][N:30]([CH2:29][CH:28]([OH:44])[CH2:27][O:26][CH3:25])[CH:34]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Reactant: COCC(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCC(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
Similar to as described in General Procedure C, 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 1-methoxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 404. LCMS: 481.2.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]1[CH:21]2[CH:12]([CH2:13][C:14]3[C:19]([CH:20]2[N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25](N)[N:24]=[CH:23]2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]1.O>CN(C)C=O>[CH2:8]1[CH:21]2[CH:12]([CH2:13][C:14]3[C:19]([CH:20]2[N:22]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=[CH:23]2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1c(N)ncn1C1c2ccccc2CC2CCCCC21
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cncn1C1c2ccccc2CC2CCCCC21
Yield: 38 %

Procedure:
4.3 Parts of 1,1-dimethylethyl nitrite were dissolved in 40 ml N,N-dimethylformamide and heated to +60° C. A solution of 8 parts of methyl 1-(1,2,3,4,4a,9,9a,10-octahydroanthracen-9-yl)-4-amino-1H-imidazole-5-carboxylate in 50 ml N,N-dimethylformamide was dropwise added at +60° C. After 1.5 hour the solution was poured into water and extracted with ethyl acetate. The organic phase was dried with Na2SO4, filtered and concentrated. The resulting 8.5 parts of crude material were chromatographed on a silica gel column with an ethyl acetate/hexane mixture (1:1). 2.9 Parts (38%) of methyl 1-(1,2,3,4,4a,9,9a,10-octahydroanthracen-9-yl)-imidazole-5-carboxylate, mp. 151°-152° C. (compound 2.2), were obtained. According to 1H-NMR the product consists of an epimeric mixture of 2 isomers.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:15]([C:16](=[O:19])[NH:17][CH3:18])=[C:9]2[CH:8]=1)(=O)=O.B([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:14]2[C:15]([C:16](=[O:19])[NH:17][CH3:18])=[C:9]3[CH:8]=[C:7]([C:32]4[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=4)[C:35]([OH:37])=[O:36])[CH:12]=[CH:11][N:10]3[N:13]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Temperature: 95 °C

Procedure:
To a degassed solution containing 2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.19 g, 0.44 mmol), 3-boronobenzoic acid (0.11 g, 0.67 mmol), cesium carbonate (0.22 g, 0.67 mmol), dioxane (3.7 mL) and water (0.74 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.0090 g, 0.010 mmol). The solution was maintained at 95° C. for 7 h. The solution was cooled to room temperature, concentrated and dissolved in a solution containing water and methanol (1.8/1, 14 mL). The solution was filtered to remove fine particulates and washed with dichloromethane (3×5 mL). The aqueous portion was concentrated to dryness to afford 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid as a pale grey solid which was used without further purification. LCMS: retention time: 1.830 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 390 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:27])[C@H:22]([CH:24]([CH3:26])[CH3:25])[NH2:23]>>[CH3:19][O:20][C:21](=[O:27])[C@H:22]([CH:24]([CH3:26])[CH3:25])[NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(C)C

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-valine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid.