Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[N:11]=[C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([O:21]C)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[N:11]=[C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]([OH:21])=[CH:8][CH:7]=1
Reactant: COc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
BBr3 (0.4 mL, 0.39 mmol) was added to the solution of 2-(6-chloro-3-methoxypyridin-2-yl)-1H-indole (50 mg, 0.19 mmol) in CH2Cl2 (0.5 mL) at −78° C. under N2. The mixture was allowed to stir at room temperature for 3 hours. The mixture was then quenched with CH3OH (10 mL) at −78° C. After being concentrated in vacuo, the resulting resulting residue was purified using prep-TLC (petroleum ether:EtOAc=2.5:1) to provide 6-chloro-2-(1H-indol-2-yl)pyridin-3-ol (40 mg, yield: 85.1%), which was also prepared from 6-chloro-2-iodopyridin-3-ol and (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid using similar procedure of step 3 of Example 1. 1H-NMR (CDCl3, 400 MHz) δ 10.09 (s, 1H), 9.72 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.17˜7.32 (m, 3H), 7.08˜7.14 (m, 1H), 6.87˜6.96 (m, 2H). MS (M+H)+: 245/247.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:31])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Cl:29][C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([Cl:30])[CH:26]=1)[O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1Oc1cc(Cl)cc(Cl)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[2-(3,5-Dichloro-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (HVB01036, HVB01039 HVB01042, 1.09 g, 2.3 mmol) was dissolved in HCl/dioxane (4M, 18 ml), and stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness, diluted with DCM (20 ml) and neutralised with sodium hydroxide (1M). Extracted with DCM, organic layers dried over anhydrous magnesium sulphate, and evaporated in-vacuo, 183 mg, 21%. m.p. 138-139° C., Rf. 0.3 (10% Methanol/DCM), 1HNMR (CDCl3, 270 MHz) δ 1.65 (3H, m, CH2 and NH), 1.86 (2H, m, CH2), 2.36 (1H, m, CH), 2.65 (2H, td, J=2.7, 9.6 Hz, NCH2), 3.16 (2H, m, NCH2), 6.89 (2H, d, J=1.7 Hz, ArHE, ArHG), 6.90 (1H, m, ArHD), 7.06 (1H, td, J=1.5, 7.4 Hz, ArHB), 7.12 (1H, t, J=1.7 Hz, ArHF), 7.18 (1H, td, J=8.2, 1.46 Hz, ArHC), 7.55 (1H, s, NH), 8.43 (1H, dd, J=8.2 Hz, ArHA).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].C[C:12]1(C)[CH2:14][CH:13]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1(P([Pd-4](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)C=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:12]2[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: CC1(C)CC1B(O)O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(N)cccc1C1CC1
Temperature: 25 °C
Yield: 40578.6 %

Procedure:
To a degazed solution of 2-amino-6-bromobenzonitrile (851 mmol, 168 mg), 2,2-dimethylcyclopropylboronic acid (1.106 μmol, 126 mg) (Example 270b), and Cs2CO3 (2.979 mmol, 970 mg) in DME (3.4 mL) and water (850 μL) was added tetrakis(triphenylphosphino)palladium(0) (43 μmol, 50 mg) under nitrogen and the reaction mixture microwaved for 2 hours at 160° C. The reaction mixture was cooled to room temperature and extracted with EtOAc (3×5 mL). The combined organic layers was washed once with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified on silica gel (EtOAc/hexanes 10%-40%) to give the desired product (71 mg, 45%) as a waxy, yellow solid. 1H NMR (400 MHz, CDCl3) δ 0.82 (m, 1H), 0.82 (s, 3H), 0.85 (m, 1H), 1.33 (s, 3H), 1.92 (m, 1H), 4.36 (br. s, 2H), 6.47 (d, J=8 Hz, 1H), 6.56 (d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:23][CH2:22]2)=[CH:17][C:16]=1[F:24])=[O:4].[OH-].[Na+].[Cl-].[NH4+].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.ClCCl>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:6]3[C:7]4[N:8]([CH:11]=[N:12][CH:13]=4)[CH:9]=[CH:10][C:5]=3[C:3]([NH2:30])=[O:4])=[C:16]([F:24])[CH:17]=2)[CH2:22][CH2:23]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 65 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
To a solution of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (23 mg, 0.07 mmol) in IMS (1.0 mL) was added a 1.0 M aqueous solution of sodium hydroxide (0.10 mL, 0.10 mmol). The reaction mixture was heated to 65° C. for 1 hour and then cooled to room temperature and concentrated in vacuo. The resulting residue was azeotroped with toluene, and then dissolved in DMF (1 mL). Ammonium chloride (7 mg, 0.13 mmol), N-N-diisopropylethylamine (47 uL, 0.27 mmol) and HATU (51 mg, 0.13 mmol) were added sequentially, before the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was then diluted with methanol and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluent was collected and concentrated to give a residue. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 5%, methanol in dichloromethane) to afford the title compound as a pale yellow solid (5 mg, 23%). LCMS (method A): RT=6.64 min, [M+H]+=311. 1H NMR (CD3OD) 8.18 (1H, d, J=0.88 Hz), 7.64 (1H, dd, J=7.40, 0.97 Hz), 7.13 (1H, t, J=8.28 Hz), 6.93-6.86 (3 H, m), 6.35 (1H, s), 1.98-1.90 (1 H, m), 1.05-0.97 (2 H, m), 0.73-0.68 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([OH:22])=O)=[CH:11]2)[C:4]=1[CH3:23].[F:24][CH2:25][CH2:26][NH2:27]>>[F:24][CH2:25][CH2:26][NH:27][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:22]
Reactant: NCCF
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Product: COc1ncnc(Cn2cc(C(=O)NCCF)c3ncc(C)cc32)c1C
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
See FIG. 17(d). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.190 gm, 0.61 mmol) and 2-fluoroethanamine (0.077 g. 1.22 mmol), TEA (0.254 mL, 1.83 mmol) was added. After 3 min1-Propanephosphonic acid cyclic anhydride (0.484 g, 1.52 mmol) was added. The resulting reaction mixture was stirred at rt for 50 min. LCMS analysis confirmed the formation of required product. Reaction was diluted with DCM and water.DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was performed on Waters RP system to get product N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.090 g, 41.4%). ES+MS m/z: 358.36. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.17-2.30 (3, 3 H) 2.40 (s, 3 H ) 3.59-3.73 (m, 1 H ) 3.73-3.83 (m, 1 H ) 3.94 (s, 3 H ) 4.50 (t, J=4.99 Hz, 1 H ) 4.66 (t, J=4.99 Hz, 1 H ) 5.64 (s, 2 H ) 7.76 (s, 1 H ) 8.15 (s, 1 H ) 8.35 (s, 1 H ) 8.42 (s, 1 H ) 8.87 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.CN(C)C=O.[Br-:28].[Li+]>O>[Br:28][CH2:10][CH2:9][CH2:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:22])([CH3:1])[O:6]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC2COC(C)(C)O2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(CCCCBr)O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred solution of 220 g. of 2,2-dimethyl-4-(4-p-toluenesulfonyloxybutyl)-1,3-dioxolane in 800 ml. of dimethylformamide at 0° C. is added 115 g. of anhydrous lithium bromide in portions during 5 minutes. The resulting mixture is stirred at ambient temperature for 22 hours, diluted with water, and extracted with ether. The extract is washed with sodium bicarbonate solution, water, and brine; dried over magnesium sulfate; and concentrated. The residue is distilled to give a colorless liquid, b.p. 71°-74° C. (0.2 mm).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[C:3](OCC)=[O:4].C[O-].[Na+]>CO>[NH2:1][CH:2]1[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:3]1=[O:4]
Reactant: CCOC(=O)C(N)CCc1ccccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC1CCc2ccccc2NC1=O

Procedure:
A solution of ethyl 2-amino-4-(2-aminophenyl)butyrate (35.0 g) in methanol (100 ml) was added to a solution of sodium methoxide in methanol [prepared from sodium (1.0 g) and methanol (400 ml)] with stirring, under a nitrogen atmosphere. The reaction mixture was refluxed for 65 hours and evaporated under reduced pressure. The residue was distributed between water (100 ml) and dichloromethane (400 ml). The aqueous solution was extracted with dichloromethane (400 ml), and the combined organic solutions washed with water (100 ml) and dried over magnesium sulfate. Evaporation to dryness and trituration with ether (250 ml) gave 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 161°-162° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[N:25]1([C:32](=[O:34])[CH3:33])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[C:32]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[CH:3]=2)[CH2:27][CH2:26]1)(=[O:34])[CH3:33]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC(=O)N1CCCNCC1
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CO
Product: CC(=O)N1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 200 mg, 0.604 mmol) and 1-(1,4-diazepan-1-yl)ethanone (130 mg, 0.906 mmol) in Dioxane (6 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (182.5 mg, 70%). 1H NMR (METHANOL-d4) δ: 7.89-7.99 (m, 6H), 7.62-7.68 (m, 4H), 7.34 (d, J=8.6 Hz, 2H), 6.26 (t, J=2.3 Hz, 2H), 4.47 (t, J=5.7 Hz, 2H), 4.18-4.30 (m, 2H), 4.05 (dt, J=16.2, 6.0 Hz, 4H), 3.82 (dt, J=11.6, 5.8 Hz, 4H), 3.67 (dt, J=8.7, 6.0 Hz, 4H), 2.19 (t, J=5.9 Hz, 2H), 2.13 (s, 3H), 2.03-2.11 (m, 2H), 1.90 (s, 3H), 1.56 (s, 12H). ESI-MS: m/z 437.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.Cl.[CH3:13][O:14][C:15]1[C:19]([NH2:20])=[CH:18][N:17]([CH3:21])[N:16]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:20][C:19]2[C:15]([O:14][CH3:13])=[N:16][N:17]([CH3:21])[CH:18]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Reactant: COc1nn(C)cc1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 86.7 %

Procedure:
A suspension of 6-chloro-2-fluoro-9H-purine (5.49 g, 31.8 mmol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (6.60 g, 40.34 mmol, 1.26 eq), and N,N-diisopropylethylamine (16.6 mL, 95.5 mmol, 3.00 eq) in DMSO (31.8 mL) was stirred at ambient temperature for 19 hr. The reaction mixture was then concentrated in vacuo at 50° C., poured into water (250 mL), and stirred vigorously at 0° C. for 1 hr. The resulting solids were filtered off, washed with ice cold water (20 mL), and dried for 16 hr at 50° C. to give the title compound (7.26 g, 87% yield, 96% purity) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3H). m/z (APCI+) for C10H11FN7O 264.2 (M+H)+.
Reaction SMILES: [C@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][C:13]([NH2:20])=[N:14][C:15]=3N)[S:7][C@@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:23].C>O>[C@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:23])[NH:14][C:13]([NH2:20])=[N:12][C:11]2=3)[S:7][C@@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn([C@H]3S[C@@H](CO)[C@@H](O)[C@@H]3O)c2n1
Solvent: O
Product: Nc1nc2c(ncn2[C@H]2S[C@@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reaction time: 72 h

Procedure:
To a solution of 12β (50 mg, 0.17 mmol) in 20 mL of water was added 100 units of adenosine deaminase type VIII (40 μL). The reaction was stirred for 72 hours, the solution was boiled for 3 min to deactivate the enzyme, and the suspension was treated with charcoal and filtered through Celite. The filtrate was concentrated to give gelatinous 13 which was dissolved in hot water (4 mL) and filtered through 0.45 μm filter (25 mm, Gelman Acrodisc GHP-GF). The clear filtrate was lyophilized to provide 13 as a fluffy white solid which was crystallized from water (20 mg, 40%): TLC,3:1:0.1 CHCl3—MeOH—NH4OH, Rf 0.40; m.p. 260; MS 300 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[CH3:5][C:6]1[C:7](=O)[O:8][C:9](=[O:12])[C:10]=1[CH3:11]>O>[CH3:5][C:6]1[C:7](=[O:8])[NH:3][NH:4][C:9](=[O:12])[C:10]=1[CH3:11]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: NN
Agent: Cl
Solvent: O
Product: Cc1c(C)c(=O)[nH][nH]c1=O
Temperature: 100 °C
Yield: 62.5 %

Procedure:
Hydrazine dihydrochloride (83.6 g) was dissolved in water (20 ml) and heated to 100° C., and 3,4-dimethylfuran-2,5-dione (100.4 g) was introduced while stirring. Then the mixture was heated to reflux for 3 h. Subsequently, the precipitate formed was filtered off with suction, washed with water and dried. The residue was suspended in EA (2 l), filtered off with suction and dried. 69.7 g of the title compound were obtained. LC-MS rt: 0.19 min[M+H]+: 141.1 (met. b)
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH2:13][CH2:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH:19]=1.B([O-])([O-])O[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH2:32]([O:31][CH2:30][CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:5]2[CH:6]=[CH:7][C:8]3[NH:14][CH2:13][CH2:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=3[CH:19]=2)=[CH:27][CH:26]=1)[CH2:33][CH2:34][CH3:35]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
In toluene (200 ml) and ethanol (35 ml) were suspended methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (5.0 g), 4-butoxyethoxyphenyl borate (4.6 g) and 1M potassium carbonate solution (35 ml), and the mixture was stirred for 30 minutes under argon atmosphere. Then, to the mixture was added tetrakistriphenylphosphinepalladium (1 g), and the mixture was heated at 100° C. overnight under argon atmosphere. After allowing to cool, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed a with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=4:1) to give the solid, which was washed with hexane to give methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (5.7 g) as yellow crystals.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=34)=[CH:15][N:16]=[C:11]2[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=34)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3ncn4cc(Cl)ccc34)nc12
Temperature: 25 °C
Yield: 29.6 %

Procedure:
To a solution of N-tert-butyl-2-(6-chloroimidazo[1,5-a]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (50 mg, 100 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (228 mg, 154 μL, 2.00 mmol) and the mixture stirred at room temperature. After 16 h the reaction mixture was concentrated, then the residue was redissolved in dichloromethane (2 mL), methanol (1 mL) and ammonium hydroxide (0.22 mL) and stirred at room temperature. After 2 h the reaction was concentrated in vacuo. The residue was purified by chromatography (silica, 30-100% of a 0.5:10:89.5 ammonium hydroxide:methanol:dichloromethane solution in dichloromethane). The collected material was concentrated, triturated with methanol and filtered to give N-tert-butyl-2-(6-chloroimidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (12 mg, 29.6 μmol, 30%) as a yellow solid. MS (M+H)+=369.1; 1H NMR (DMSO-d6) δ: 12.69 (s, 1H), 9.08 (s, 1H), 8.79 (s, 1H), 8.53 (s, 1H), 8.34 (d, J=9.7 Hz, 1H), 8.30 (s, 1H), 7.84 (s, 1H), 7.05 (d, J=9.7 Hz, 1H); 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:12]([C:14]([F:17])([F:16])[F:15])[OH:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:20][C:21]1[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=1>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:12]([O:13][C:24]3[N:25]=[CH:26][C:21]([F:20])=[CH:22][N:23]=3)[C:14]([F:17])([F:15])[F:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ncc(F)cn1
Reactant: OC(c1ccnc2cc(Cl)ccc12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cnc(OC(c2ccnc3cc(Cl)ccc23)C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
7-Chloro-α-(trifluoromethyl)-4-quinolinemethanol (0.25 g, 0.96 mmol) was dissolved in 5 ml of tetrahydrofuran in a oven dried, nitrogen swept 25 ml round bottomed flask and the resulting solution was cooled to 0° C. under nitrogen. With stirring, NaH (0.042 g, 1.1 mmol, 60% dispersion in mineral oil) was added all at once. After 15 minutes, 5-fluoro-2-(methylsulfonyl) pyrimidine (0.17 g, 0.96 mmol) was added dropwise via syringe as a solution in tetrahydrofuran (2.5 ml) over 5 minutes. An additional 2 ml of tetrahydrofuran was used to rinse the flask containing the sulfone and the syringe. The milky solution was allowed to warm to room temperature and stir for 15 hours by which time thin layer chromatography (hexanes:ethyl acetate/1:1) indicated complete consumption of the starting materials. The reaction mixture was partitioned between water and ethyl acetate, the layers separated and the aqueous layer extracted with an additional portion of ethyl acetate. The combined organic layers were dried (MgSO4) filtered and concentrated to dryness. Purification by flash silica gel chromatography (hexanes:ethyl acetate/2:1) provided 7-chloro-4-[2,2,2-trifluoro-1-[(5-fluoro-2-pyrimidinyl) oxy]ethyl]quinoline (0.32 g, 94%) as a white solid. An analytical sample was prepared by recrystallization from hexane. (mp 92° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([OH:31])=O)[N:28]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.Cl.C([N:37]=C=NCCCN(C)C)C.CN(C)C=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([NH2:37])=[O:31])[N:28]=3)=[CH:32][CH:33]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(Cc3nc(C(=O)O)cs3)cc2)c1-c1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(Cc3nc(C(N)=O)cs3)cc2)c1-c1ccc(F)cc1
Yield: 87.7 %

Procedure:
A mixture of 2-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxylic acid (0.24 g), a 1-hydroxy-1H-1,2,3-benzotriazole ammonia complex (0.12 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.15 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]-1,3-thiazole-4-carboxamide as colorless crystals (0.21 g, yield 88%). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:35]=[CH:36][CH:37]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]1[CH2:27][O:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:13]>>[ClH:8].[ClH:1].[Cl:8][C:9]1[C:10]([F:38])=[C:11]([C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:27][O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:13])[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cl)c2F)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1cccc(Cl)c1F)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 92 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(3-chloro-2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (70 mg, 0.16 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure, yielding 60.5 mg (92%) of the title compound. LC-MS: RT=3.80 min, [M+H]+=350.5.