Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[NH2:43][C@@H:44]1[CH2:49][CH2:48][C@H:47]([OH:50])[CH2:46][CH2:45]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:43][C@H:44]5[CH2:49][CH2:48][C@@H:47]([OH:50])[CH2:46][CH2:45]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@@H](O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.08 g (0.18 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.13 mL (0.72 mmole) of ethyldiisopropyl amine and 0.030 g (0.20 mmole) of cis-4-amino-cyclohexanol hydrochloride in 2.0 mL of dimethylformamide was added 0.085 g (0.2 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.066 g of cis-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-hydroxy-cyclohexyl)-3-methoxy-benzamide (I-68) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:32][C:33]2[C:34]([CH3:42])=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][CH:37]=[CH:36]3)=[C:5]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:14][C:12]=3[CH:13]=2)[CH:6]=[N:7][CH:8]=1)#[N:2]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:42][C:34]1[C:33]([NH:32][C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[CH:6][C:5]=2[C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:14][C:12]=3[CH:13]=2)=[CH:41][CH:40]=[C:39]2[C:35]=1[CH:36]=[CH:37][NH:38]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)ccc3o2)ccc2[nH]ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCNCC4)ccc3o2)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A mixture of tert-butyl 4-[(2-{5-cyano-4-[(4-methyl-1H-indol-5-yl)amino]pyridin-3-yl}-1-benzofuran-5-yl)methyl]piperazine-1-carboxylate (63 mg, 0.11 mmol) in 10% trifluoroacetic acid/CH2Cl2 was stirred at room temperature for 4 h, concentrated in vacuo, and the residue was purified by preparative HPLC (column: Prodigy ODS3, 4.6×150 mm, from Phenomenex (Torrance, Calif.); mobile phase A: 0.02% trifluoroacetic acid (TFA) in water; mobile phase B: 0.02% TFA in CH3CN, 10-95% B in 25 minutes (min.); flow rate: 1.0 mL/min; column temperature: 40° C.; detection wavelength: 254 and 215 nm) to provide 46 mg (50%) of the trifluoroacetic salt of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[5-(piperazin-1-ylmethyl)-1-benzofuran-2-yl]nicotinonitrile 540 as an orange solid. HPLC retention time: 5.8 min.(g); MS: 463.3 (M+H); melting point: 113-115° C.; and HRMS: 463.2234.
Reaction SMILES: ClC1N=C(Cl)C(Cl)=C(Cl)C=1Cl.[F:12][C:13]1[C:18]([Cl:19])=[C:17]([F:20])[C:16]([Cl:21])=[C:15](Cl)[N:14]=1.[F:23]C1C(Cl)=C(Cl)C(Cl)=C(F)N=1>>[Cl:21][C:16]1[C:15]([F:23])=[N:14][C:13]([F:12])=[C:18]([Cl:19])[C:17]=1[F:20]
Reactant: Fc1nc(Cl)c(Cl)c(F)c1Cl
Reactant: Fc1nc(F)c(Cl)c(Cl)c1Cl
Agent: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Product: Fc1nc(F)c(Cl)c(F)c1Cl
Yield: 54.2 %

Procedure:
The method for this Example was similar to Example 1 except as follows. The reaction mixture contained 251.3 g (1.0 mole) pentachloropyridine and 236.9 g (4.0 mole KF) of the KF/FeCl3 mixture, and the reaction temperature was 350° C. and the pressure was 340 psig. There was obtained, 4.3 percent yield of a mixture of 2,4-difluoro-3,5,6-trichloropyridine and 2,6-difluoro-3,4,5-trichloropyridine and 54.2 percent yield of 3,5-dichloro-2,4,6-trifluoropyridine and a 24.9 percent yield of 3-chloro-2,4,5,6-tetrafluoropyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22](OCC)=[O:23])=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=[O:23])=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C)cc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(C=O)cc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of ethyl 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazole-3-carboxylate (700 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/L solution (3.8 mL) of diisobutylaluminum hydride in toluene was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in acetonitrile (15 mL) were added tetra-n-propylammonium perruthenate (66 mg), N-methylmorpholine N-oxide (442 mg) and molecular sieves 4A powder (1.0 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow solid (yield 224 mg, 36%).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C([O-])=O.[Na+]>O>[CH:14]1[C:8]2[C:7](=[O:15])[NH:6][C:5]3[CH:16]=[CH:17][CH:2]=[CH:3][C:4]=3[NH:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1Nc2ccc(Cl)cc2Nc2ccccc21
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccccc2Nc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A suspension of title compound 85 (1.75 g, 7.15 mmol) in a solution of sodium formate (2.43 g, 35.8 mmol) in water (32 mL) was stirred at 50° C. for 8 hours and then at room temperature. The reaction mixture was filtered and the resulting solid was dissolved in THF (20 mL), diluted with ethyl acetate (200 mL) then filtered through Celite® and concentrated. The crude residue was triturated in 30% ethyl acetate in hexanes to afford title compound 86 (1.17 g, 78%) as a yellow solid. LRMS (ESI): (calc) 210.08. (found) 211.2 (MH)+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.84 (s, 1H), 7.84 (s, 1H), 7.67 (dd, J=7.9, 1.7 Hz, 1H), 7.33 (ddd, J=8.1, 7.2, 1.8 Hz, 1H), 7.00-6.86 (m, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH3:20][O:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[S:35][CH3:36]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:20][O:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][C:25]([C:26]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:27])=[CH:24][C:23]=1[S:35][CH3:36]
Reactant: COc1c(SC)cc(C(=O)Cl)cc1C(F)(F)F
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(SC)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (346 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in chloroform (4 mL), and triethylamine (0.43 mL) and 4-methoxy-3-methylsulfanyl-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (g).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[N:8]=1.[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH:21]([OH:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[N:8]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Brc1cccc(C2OCCO2)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1cccc(C2OCCO2)n1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (2.0M, 12.4 ml, 24.8 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (20 ml) solution of 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (2.7 ml, 24.8 mmol) under ice cooling. The reaction mixture was stirred at room temperature for 3 hours. To the resulting brown solution was added dropwise 2,5-difluorobenzaldehyde (2.7 ml, 24.8 mmol) under ice cooling. The temperature of the reaction mixture was raised gradually to room temperature and then, stirring was conducted for 16 hours. After a saturated aqueous solution of ammonium chloride was added, the resulting mixture was extracted with ethyl acetate. The extract was washed sequentially with water and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (2.90 g, 9.89 mmol, 40%) as a colorless oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C:41]3([CH3:51])[CH3:50])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[CH3:50][C:41]1([CH3:51])[CH2:42][N:43]([CH:46]2[CH2:49][O:48][CH2:47]2)[CH2:44][CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][N:15]5[C:16]6[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=6[CH:22]=[C:14]5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4(C)C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc(F)cc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3(C)C)cn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and was charged with 125f (85 mg, 1 eq., 0.11 mmol), lithium hydroxide (14 mg, 5 eq., 0.55 mmol), i-propanol (3 mL), THF (3 mL) and water (2 mL). The mixture was stirred at 30° C. for 1 h. It was then filtered and the residue was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 125 (43 mg, 57%). MS: [M+H]+ 682.4. 1H NMR (500 MHz, DMSO) δ 8.62 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.41-7.39 (m, 2H), 7.33-7.31 (m, 1H), 7.23-7.17 (m, 2H), 6.52 (s, 1H), 4.86 (brs, 1H), 4.54 (t, J=6.5 Hz, 2H), 4.42 (t, J=6.0 Hz, 2H), 4.30 (s, 2H), 4.17-4.11 (m, 3H), 3.89-3.86 (m, 1H), 3.58 (m, 3H), 3.39-3.36 (m, 1H), 3.08-2.98 (m, 2H), 2.63-2.56 (m, 2H), 2.46 (t, J=6.0 Hz, 2H), 2.33-2.12 (m, 4H), 1.80-1.67 (m, 4H), 0.96 (s, 6H).
Reaction SMILES: OC1C=CC=C2C=1[NH+]=CC=C2.[O:12]=[C:13]1[C@@H:16]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:15]([CH3:28])[N:14]1S([O-])(=O)=O>C(O)C>[C:22]1([CH2:21][O:20][C:18]([NH:17][C@H:16]2[C@H:15]([CH3:28])[NH:14][C:13]2=[O:12])=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: Oc1cccc2ccc[nH+]c12
Solvent: CCO
Product: C[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Yield: 83.7 %

Procedure:
(3S-trans)-2-Oxo-3-[[(phenylmethoxy)carbonyl]amino]-4-methyl-1-azetidinesulfonic acid, 8-hydroxyquinolinium salt (230 mg, 0.5 mmol; see Method IA) was dissolved in absolute ethanol (10 ml) and refluxed for 4 hours. Ethanol was removed in vacuo yielding a residue which was triturated with ethyl acetate (5×10 ml). From the combined extract, solvent was removed in vacuo affording a residue which was chromatographed on silica gel (Mallinckrodt CC-7). Elution with ethyl acetate yielded (3S-trans)-3-[[(phenylmethoxy)carbonyl]amino]-4-methyl-2-azetidinone (98 mg).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.C([OH:23])C>[OH-].[Na+]>[CH2:14]([O:13][CH2:12][C:4]1[NH:3][C:2](=[O:23])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc(COCc2ccccc2)nc2nccnc12
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(COCc2ccccc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 10.0 g (0.037 mole) of crude 4-amino-2-(benzyloxymethyl)pteridine in 300 ml of 5% aqueous sodium hydroxide. Heating time: 2 hours at 80° C. Yld: 8.2 g (83%), m.p. 157°-159° C. (ethanol).
Reaction SMILES: C[O-].[Na+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][SH:10].Br[CH2:12][CH2:13][CH2:14][Cl:15]>CO.C(#N)C.C(OCC)(=O)C>[Cl:15][CH2:14][CH2:13][CH2:12][S:10][CH2:9][C:5]1[O:4][CH:8]=[CH:7][CH:6]=1
Reactant: SCc1ccco1
Reactant: ClCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: ClCCCSCc1ccco1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3.3 ml of a 30% sodium methylate solution in methanol is added in drops to 1.77 ml of furan-2-yl-methanethiol in 18 ml of anhydrous acetonitrile at 0° C. After 5 minutes, the drop-by-drop addition of 2.6 ml of 1-bromo-3-chloropropane is carried out. Then, the reaction solution is allowed to stir for 5 hours at room temperature. For working-up, the batch is diluted with ethyl acetate, washed with water and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient yields 1.1 g of 2-(3-chloropropylthiomethyl)-furan as an oil.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(Cl)Cl>[OH:8][CH2:7][CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10](=[O:11])[O:12][CH2:13][CH3:14]
Reactant: CCCCNCCO
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCCCN(CCO)C(=O)OCC
Reaction time: 2 h

Procedure:
117.2 g of 2-(n-butylamino)-ethanol are placed in 300 ml of methylene chloride. Then 54.3 g of ethyl chloroformate are allowed to drop in during 1 hour at 30°-35° C. with ice-cooling. After stirring for an additional 2 hours, the methylene chloride is evaporated and the residue is distilled to yield pure ethyl (2-hydroxyethyl)-n-butylcarbamate; b.p. 112° C./0.1 Torr.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:18]=1[C:19](OC)=[O:20].[H-].[Na+]>O1CCOCC1>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:19](=[O:20])[C:18]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:17]=1[O:16][CH3:15])=[O:3]
Reactant: COC(=O)c1cc(C)ccc1OC
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)c2cc(C)ccc2OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
A solution of methyl 3-acetyl-4-hydroxy-benzoate (6 g) and methyl 2-methoxy-5-methyl-benzoate (12 g) in dioxane (40 ml) was slowly added under stirring at room temperature to a suspension of sodium hydride 50% (4.5 g) in dioxane (40 ml). The mixture was kept under stirring for 3 hours at 80° C., cooled, then diluted with petroleum ether (100 ml), and filtered. The collected precipitate was dissolved in water, acidified with acetic acid and extracted with ethyl-acetate. The organic phase was washed with potassium carbonate 5% and water, then evaporated to dryness and crystallized from ethanol to give (2-hydroxy-5-carbomethoxy-benzoyl)-(2-methoxy-5-methyl-benzoyl)-methane (7.9 g; m.p.=145°-147° C.), which was then refluxed for 15 minutes with 99% formic acid (28 ml). After cooling and dilution in water and filtration, the collected precipitate was crystallized from acetone to obtain 6-carbomethoxy-2'-methoxy-5'-methyl-flavone (6 g), m.p.=154°-156° C., which was hydrolyzed with a 1% solution of potassium hydroxide (100 ml) in 95% ethanol at reflux temperature for 30 minutes. The mixture was cooled, acidified with 23% HCl to pH=3, and the precipitate was filtered, washed with ethanol 95% and water so obtaining, after crystallization from ethanol, 6-carboxy-2'-methoxy-5'-methyl-flavone (5.3 g), m.p.=246°-247° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[BH4-].[Na+].II.CO>C1COCC1>[CH3:1][NH:2][CH2:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=1
Reactant: CNC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.3 %

Procedure:
At 0° C. a solution of 4′-(trifluoromethyl)biphenyl-2-carboxylic acid methylamide (8.50 g, 36.44 mmol) in THF (100 ml) was added to a suspension of sodium borohydride (2.8 g, 73.05 mmol) in THF (50 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of iodine (7.70 g, 36.44 mmol) in THF (100 ml) was added dropwise. The reaction mixture was heated to reflux for 16 hours. It was cooled to 0° C. Methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in tert-butyl methyl ether (150 ml) and a 20% aqueous solution of sodium hydroxide (150 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×80 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g) using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 2.35 g of N-methyl-N-((4′-(trifluoromethyl)biphenyl-2-yl)methyl)amine.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([B:15]3[NH:26][C:25]4[C:27]5[C:21]([CH:22]=[CH:23][CH:24]=4)=[CH:20][CH:19]=[CH:18][C:17]=5[NH:16]3)[CH:12]=[CH:13][CH:14]=2)O1.Cl[C:30]1[C:31]2[N:38]=[CH:37][N:36]([CH2:39][CH3:40])[C:32]=2[N:33]=[N:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:39]([N:36]1[C:32]2[N:33]=[N:34][CH:35]=[C:30]([C:9]3[CH:10]=[C:11]([B:15]4[NH:26][C:25]5[C:27]6[C:21]([CH:22]=[CH:23][CH:24]=5)=[CH:20][CH:19]=[CH:18][C:17]=6[NH:16]4)[CH:12]=[CH:13][CH:14]=3)[C:31]=2[N:38]=[CH:37]1)[CH3:40]
Reactant: CC1(C)OB(c2cccc(B3Nc4cccc5cccc(c45)N3)c2)OC1(C)C
Reactant: CCn1cnc2c(Cl)cnnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCn1cnc2c(-c3cccc(B4Nc5cccc6cccc(c56)N4)c3)cnnc21
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A room temperature solution of 2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-2,3-dihydro-1H-1,3-diaza-2-boraphenalene (Preparation 61, 7.8 g, 21.1 mmol), 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8, 2.6 g, 14.1 mmol) and cesium carbonate (13.8 g, 42.3 mmol) in dioxane (160 mL) and water (13 mL) was degassed. 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride (0.91 g, 1.4 mmol) was then added in one portion and the reaction mixture was again purged with nitrogen gas three times. The resultant solution was then stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH, 50:1 to afford the title compound as a yellow solid in 83.6% yield.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:23])[N:14]([CH3:22])[CH:15]([C:18]([O:20][CH3:21])=[O:19])[C:16](=N)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=[O:27])C.OS(O)(=O)=O>CO>[CH2:1]([N:8]1[C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([OH:27])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1C(=N)c2ccn(Cc3ccccc3)c2C(=O)N1C
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(O)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of methyl 1-benzyl-4-imino-6-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (9.0 g, 28.9 mmol) in Methanol (100 mL) was treated with Water (40 mL) and Acetic Acid (50 mL), followed by H2SO4 (1.575 mL, 29.6 mmol), and the resultant was stirred at 90° C. overnight. The mixture was concentrated, diluted with water and then adjusted to pH>6 with saturated sodium bicarbonate. The mixture was extracted with Ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl 1-benzyl-4-hydroxy-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.0 g, 22.4 mmol, 76% yield) as a pale yellow solid which was used in the next step without any further purification. 1H NMR (400 MHz, CHLOROFORM-d) ppm 11.23 (s, 1H) 7.20-7.36 (m, 5H) 7.04-7.11 (m, 1H) 6.62-6.70 (m, 1H) 5.86 (s, 2H) 3.98 (s, 3H) 3.67 (s, 3H); LCMS (m/z) ES+=313 (M+1).