Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[CH:30]=[CH:29][N:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([CH2:42][CH:43]3[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[CH2:49]([N:46]1[CH2:45][CH2:44][CH:43]([CH2:42][C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:32](=[O:33])[N:31]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[CH:30]=[CH:29][N:28]=4)=[O:26])=[CH:20][C:19]=3[F:41])[NH:8][N:9]=2)[CH2:48][CH2:47]1)[CH3:50]
Reactant: CCN1CCC(Cc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCC(Cc2n[nH]c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
N-(4-(1-(4-methoxybenzyl)-3-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide (18 mg, 0.025 mmol) was added to a small round bottom flask and dissolved in excess TFA (d 1.48) (0.2 ml, 2.550 mmol). The mixture was stirred at 70° C. overnight. The solvent was evaporated, and the crude was chromatographed on Si (preparative TLC) 0.5 mm thickness, eluting with 10% MeOH/DCM w/1% NH4OH. Product isolated and determined to by mono-TFA salt by 19F-NMR. Yield 1.4 mg, 8%. 1H NMR (400 MHz, MeOD) δ 8.29 (d, 1H), 8.08 (d, 1H), 7.93 (d, 1H), 7.79 (d, 2H), 7.60 (m, 2H), 7.54 (br d, 1H), 7.41 (t, 1H), 7.35 (t, 2H), 6.33 (d, 1H), 3.10 (d, 2H), 2.75 (br s, 2H), 2.43 (br s, 2H), 2.11 (br m, 1H), 1.88 (d, 2H), 1.55 (m, 2H), 1.19 (t, 3H). LRMS (APCI pos) m/e 586.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:7][C:8]([OH:10])=[O:9]>C(O)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(C=CC(=O)O)cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCC(=O)O)cc1OC
Yield: 89.1 %

Procedure:
To a suspension of 3-methoxy-4-methoxycarbonylcinnamic acid (8.35 g) in acetic acid (200 ml) is added 10% palladium-carbon (1.0 g), and the mixture is subjected to hydrogenation at room temperature. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is crystallized from diethyl ether-n-hexane to give 3-(3-methoxy-4-methoxycarbonylphenyl)propionic acid (7.5 g).
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[C:18]3[N:19]=[CH:20][N:21]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]=3[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=2)C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)=O>[C:23]1([CH2:22][N:21]2[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[N:10]=[C:9]([NH2:8])[C:18]=3[N:19]=[CH:20]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3c(c4c2ncn4Cc2ccccc2)CCCC3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Product: Nc1nc2c(c3c1ncn3Cc1ccccc1)CCCC2
Yield: 91.6 %

Procedure:
N,N,1-Tris(phenylmethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (4.49 g, 9.8 mmole), palladium hydroxide on carbon (1.0 g, Pearlman's catalyst) and formic acid (20 mL) were combined and heated at reflux for 4 days. During the course of the reaction the formic acid evaporated out of the reaction vessel. The residue was diluted with formic acid (15 mL) and water (20 mL) then filtered through a layer of celite. The filtrate was basified with 28% ammonium hydroxide then extracted with methylene chloride (3×100 mL). The methylene chloride extracts were combined, dried over magnesium sulfate and concentrated to provide 2.5 g of a yellow foam. The foam was loaded onto a 3 cm by 15 cm column of silica gel and eluted with methylene chloride:methanol 90:10. The early fractions were combined and evaporated to provide 0.54 g of N,2-bis(phenylmethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, m.p. 199°-200° C. The later fractions were combined and evaporated to provide 1.58 g of a mixture of 6,7,8,9-tetrahydro-N-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine and 6,7,8,9-tetrahydro-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid. This mixture was loaded onto a 3 cm by 20 cm column of silica gel and eluted with methylene chloride:methanol 90:10. 80 fractions, 6 mL each, were collected. Fractions 18-27 were combined and evaporated to provide 0.48 g of 6,7,8,9-tetrahydro-N-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 168°-170° C. Fractions 40-57 were combined and evaporated to provide 180 mg of the desired product, 6,7,8,9-tetrahydro-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine, as a white solid, m.p. 231°-233° C. (dec). Analysis: Calculated for: C18H19N4 +1/5 CH2Cl2 : %C, 69.95; %H, 6.28; %N, 18.97; Found: %C, 70.44; %H, 6.16; %N, 18.93.
Reaction SMILES: [C:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:14])[CH:5]1[CH2:15][C:16]([O:18]C)=O)(=[O:3])[CH3:2].BrC1C=CC=C2C=1C=C[N:25]=C2.C([Si](OC(OC)=C)(C)C)(C)(C)C.Cl>C(Cl)Cl>[Br:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:25][C:16](=[O:18])[CH:15]=[C:5]12
Reactant: COC(=O)CC1c2cccc(Br)c2C=CN1C(C)=O
Reactant: Brc1cccc2cnccc12
Agent: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
methyl 2-(2-acetyl-5-bromo-1,2-dihydroisoquinolin-1-yl)acetate. To a stirred solution of 5-bromoisoquinoline (100 g, 481 mmol) in DCM (1900 mL) acetyl chloride (35.9 mL, 505 mmol) was dropped at RT and the solution was stirred for 60 min. The solution was cooled to −78° C. (yellow suspension) and then a solution of tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (95 g, 505 mmol) in DCM (500 mL) was added in one portion. The resulting yellow solution was stirred at −78° C. for 1 h and then allowed to warm to rt overnight. 2N aqueous HCl (400 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was separated and washed with brine (2×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (1000 mL), charcoal was added and the mixture was filtrated through a pad of celite. The solvent was evaporated and the crude product was dried under high vacuo overnight to yield the title compound (147 g) which was used without further purification. UPLC-MS: MS 324.0/326.0 (M+H+); UPLC rt 1.03 min.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:21])[C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)(C(C)(C)C)(C)C>C(O)C.Cl.O>[Cl:20][C:15]1[N:14]=[C:13]([N:12]([CH3:21])[CH2:11][CH2:10][CH2:9][OH:8])[C:18]([F:19])=[CH:17][N:16]=1
Reactant: CN(CCCO[Si](C)(C)C(C)(C)C)c1nc(Cl)ncc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(CCCO)c1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
A mixture of N-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-fluoro-N-methyl-4-pyrimidinamine (Example 82, 2.22 g, 6.65 mmol) in ethanol/HCl/water (95:1:4, 50 mL) was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was passed through a plug of silica gel to give the title compound (1.13 g, 77%) as a viscous yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, 1H), 3.59 (t, 2H), 3.43 (t, 2H), 3.24 (d, 3H), 1.74-1.71 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][C:5]#[N:6].[N-:8]=[N+:9]=[N-:10].[Na+].C(Cl)(Cl)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N:8]([CH2:2][CH:3]([OH:7])[CH2:4][C:5]#[N:6])=[N+:9]=[N-:10]
Reactant: N#CCC(O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#CCC(O)CN=[N+]=[N-]
Yield: 98 %

Procedure:
A mixture of 48 g (0.40 mole) of 4-chloro-3-hydroxybutyronitrile, 52 g (0.080 mole) of sodium azide, 4.8 g of tetra-n-butylammonium bromide, 250 ml of chloroform and 100 ml of water was stirred while heating under reflux for 32 hr. The organic layer was separated and set aside. The aqueous layer was saturated with 4.8 g of potassium carbonate and then extracted three times with methylene chloride. The methylene chloride extracts were combined with the above organic layer and the solution was dried over anhydrous sodium sulfate and the mixture was filtered. The filtrate was evaporated to give a brown oil weighing 49.46 g, a 98% yield based on the crude. Proton NMR showed signals for the desired product and a small amount of tetra-n-butylammonium salt: (CDCl3, ppm): 7.20 (singlet, chloroform), 4.35 to 3.90 (pentet, methine proton of product), 3.85 (singlet, hydroxyl proton of product), 3.45 (doublet, methylene protons next to the azide group of the product), 2.60 (doublet, methylene protons next to the cyano group of the product), 3.25 to 2.85 and 1.90 to 0.80 (multiplets, signals from about 4% of tetra-n-butylammonium salt).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>N1C=CC=CC=1>[CH:1]1([N:4]([CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]2[CH:6]=[CH:7][C:8]([CH2:11][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: c1cc(NC2CC2)ccc1CN1CCOCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CC1)C(=O)OCC
Temperature: 145 °C

Procedure:
To a flask containing N-cyclopropyl-4-(4-morpholinylmethyl)aniline (0.55 g) from Preparation No. 23 is added diethyl ethoxymethylenemalonate (0.45 mL) and pyridine (0.33 mL). The flask is tightly capped and heated to 145° C. for 2 hours. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3×). The residue is dissolved in dichloromethane and washed with brine, dried and concentrated under reduced pressure. The residue is chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.77 g of the title compound as an oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][NH:15][CH:14]([CH2:17][OH:18])[CH:13]=[C:12]2[CH3:19])=[CH:7][CH:6]=1)[CH3:3].C(N(CC)CC)C.[C:27]([NH:30][C:31]1[CH:40]=[CH:39][C:34]([S:35](Cl)(=[O:37])=[O:36])=[CH:33][CH:32]=1)(=[O:29])[CH3:28]>ClCCl>[C:27]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([S:35]([N:15]2[CH:14]([CH2:17][OH:18])[CH:13]=[C:12]([CH3:19])[CH:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:2][CH3:3])=[CH:10][CH:9]=3)[O:16]2)(=[O:37])=[O:36])=[CH:39][CH:40]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc(C2ONC(CO)C=C2C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(CO)C=C2C)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 3,6-dihydro-6-(4-ethoxyphenyl)-3-hydroxymethyl-5-methyl-2H-1,2-oxazine hydrochloride (1.31 g, 4.59 mmol) and triethylamine (1.34 ml, 9.63 mmol) in dichloromethane (50 ml) was added 4-N-acetylsulphanilyl chloride (1.07 g, 4.59 mmol). After 4 h at room temperature, the reaction mixture was washed twice with water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to a foam, purified on flash silica eluting with ethylacetate to give 2-(4-acetamidobenzenesulphonyl)-3,6-dihydro-6-(4-ethoxyphenyl)-3-hydroxymethyl-5-methyl-2H-1,2-oxazine as a white foam. 1H NMR (CDCl3)δ 1.39(3H, t), 2.21(3H, s), 3.85(2H, m), 4.00(2H, q), 4.54(1H, m), 5.32(1H, s), 5.70(1H, m), 6.80(2H, d), 7.09(2H, d), 7.54(1H, bs) 7.63(2H, d), 7.85(2H, d).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](=[NH:9])[NH2:8])[CH2:3][CH2:2]1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21]>C1(C)C=CC=CC=1>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[C:25]([OH:26])=[N:9][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][C:20]=1[OH:21]
Reactant: CCOC(=O)C(C(=O)OCC)c1nc2ccccc2s1
Reactant: N=C(N)C1CCOCC1
Solvent: Cc1ccccc1
Product: Oc1nc(C2CCOCC2)nc(O)c1-c1nc2ccccc2s1

Procedure:
A solution of oxane-4-carboximidamide (160 mg, 1.25 mmol, 1.00 equiv), and 1,3-diethyl 2-(1,3-benzothiazol-2-yl)propanedioate (366 mg, 1.25 mmol, 1.00 equiv) in Toluene (3 mL) was heated for 3 h at 110° C. in an oil bath. After concentrated under reducing pressure, 460 mg (crude) of the title compound was obtained as a white solid, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 330.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[NH:16][C:17]([CH:19]1[C:24](=O)[C@@:23]2(C)[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=O)=O)(C)(C)C>ClCCl>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:15]1[C:13](=[O:12])[C:19]2[C@@H:20]3[C:26]([CH3:28])([CH3:27])[C@@:23]([CH3:24])([CH2:22][CH2:21]3)[C:17]=2[NH:16]1
Reactant: CC(C)(C)OC(=O)N(NC(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
Trifluoroacetic acid (55 mL) was added slowly over 1-2 min to a solution of N-(2-chloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (23.4 g, 56 mmol) in dry dichloromethane (55 mL), and the resulting solution was stirred at room temperature for 3 h. The solvent was evaporated and dichloromethane (350 mL) was added. The solution was washed with water (3×150 mL) and brine (150 mL), dried (sodium sulfate), filtered, evaporated, and dried under high vacuum over the weekend to give (4S,7R)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (16.07 g, 95%) as a pale solid.
Reaction SMILES: BrC1N=CN=C2C=1NC=N2.NC[C:13]1[N:14]=[C:15]2[CH:30]=[CH:29][CH:28]=[C:27](C)[N:16]2[C:17](=[O:26])[C:18]=1C1C=CC=C(F)C=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:14]1[CH:13]=[CH:18][C:17](=[O:26])[N:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=12
Reactant: Cc1cccc2nc(CN)c(-c3cccc(F)c3)c(=O)n12
Agent: Brc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccnc2ccccn12
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 6-bromopurine (0.02040 g, 0.1025 mmol), 2-(aminomethyl)-3-(3-fluorophenyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.02420 g, 0.08542 mmol), and DIEA (0.04464 mL, 0.2563 mmol) in 1-butanol (2.000 mL) was stirred at 110° C. After 18 h, the mixture was removed from the heat and concd under reduced pressure. The crude mixture was purified by revered-phase semi-prep HPLC using 20-70% gradient of CH3CN (0.1% of TFA) in water (0.1% of TFA) over 40 min as eluent. The acetonitrile was concd under reduced pressure and to the remaining acidic aq layer was added satd NaHCO3 to neutralize the TFA salt. The resulting precipitate was collected by filtration and washed with water to give 3-(3-fluorophenyl)-6-methyl-249H-purin-6-ylamino)methyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.87 (1 H, s), 8.07-8.16 (2 H, m), 7.68 (1 H, dd, J=9.0, 7.0 Hz), 7.55 (1 H, s), 7.39-7.51 (2 H, m), 7.24-7.31 (2 H, m), 7.15-7.23 (1 H, m), 6.92-7.00 (1 H, m), 4.51 (2 H, br. s.), 2.92 (3 H, s); Mass Spectrum (ESI) m/e=402.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=1[F:42])=[O:33])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)=[O:16])[S:14][C:7]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:20][CH2:19][CH2:18][NH:17][C:15]([C:13]1[S:14][C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:28]=[CH:29][C:30]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[F:42])=[O:33])=[C:2]([F:1])[CH:3]=2)[CH:12]=1)=[O:16]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCNC(=O)OC(C)(C)C)sc34)cc2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCN)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate (488 mg, 0.82 mmol) in 10 ml of dichloromethane was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for one hour and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 400 mg, 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: COc1ccccc1B(O)O
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: O
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 87 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.062 g (87%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methoxybiphenyl-4-carboxamide.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C:38](C1C=CC=CC=1B(O)O)#[N:39]>>[NH2:37][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:38]#[N:39])=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: N#Cc1ccccc1B(O)O
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccccc2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-cyanophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=522, obsd.=522).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[O:7][C@H:8]2[CH2:14][NH:15][CH:16]=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45]>ClC(Cl)C>[C:44]([O:43][C:42](=[O:48])[NH:41][CH2:40][CH2:39][N:21]1[CH2:20][CH2:19][CH:18]([C@@H:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:13])[C:3]=3[O:2][CH3:1])[C@H:8]([CH2:14][NH:15][CH:16]=[O:17])[O:7]2)[CH2:23][CH2:22]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(CCNC(=O)OC(C)(C)C)CC1)O[C@H]2CNC=O
Reaction time: 42 h

Procedure:
Stir a solution of N-((1R,3S)-5-methoxy-6-methyl-3-(4-piperidinyl)-1-isochromanyl-methyl)formamide (4.0 g, 12.5 mmole) in dichloroethane (110 mL) and add sodium triacetoxyborohydride (4.0 g, 18.8 mmole). Dissolve t-butyl N-(2-oxoethyl)-carbamate (1.0 g, 6.3 mmole) in dichloroethane (20 mL) and add it to the reaction mixture. After 6 hours add another 6.3 mmole of t-butyl N-(2-oxoethyl)-carbamate in dichloroethane. After another 42 hours adjust the pH of the reaction mixture to about 14 with 50% NaOH and extract with dichloromethane. Wash the combined extracts with water and dry over Mg2SO4. Purify the crude product on a 33 g silica gel column (eluting with ammonium hydroxide:methanol:ethyl acetate 1:1:98). Collect the appropriate fractions and concentrate to obtain the title compound. CIMS 462, tR (min)=0.46.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:23].CO.[NH2:26][C@H:27]([C:35]([NH:37][C@H:38]([C:45]([NH:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:45]([NH:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:46])[CH2:39][O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:23]
Reactant: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CNC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
5.3 g of Z-Arg-OH (17.3 mmols) are suspended in 15 ml of dimethylformamide and after cooling with an ice-sodium chloride mixture, 5.9 ml of hydrobromic acid in methanol (3.06 N, 18 mmols) are added. After brief stirring a clear colourless solution is produced. A solution of 5.6 g of H-Phe-Ser(tBu)-Gly-OCH3 (14.4 mmols) in 15 ml of dimethylformamide is added dropwise thereto at -18°C and a further 7 ml of dimethylformamide are added. A solution of 3.85 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride is then added, the cooling mixture is replaced by ice water after 1 hour, and after a further 3 hours the reaction mixture is stirred overnight at room temperature. The precipitate of dicyclohexylurea which has separated out is then filtered off and the filtrate is concentrated in vacuo to half its volume, cooled to 0°C and stirred into 600 ml of ether. The solution is decanted from the resulting precipitate, and the precipitate is washed with ether, dissolved in about 50 ml of methanol and again precipitated with 600 ml of ether. After again dissolving in methanol, the material is evaporated and dried in a high vacuum. In a thin layer chromatogram on silica gel layers the product shows: Rf52 = 0.48; Rf100 = 0.54; on Selekta cellulose Rf45 = 0.81.