Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]([O:36][CH3:37])=[O:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[CH3:37][O:36][C:34](=[O:35])[C:23]1[CH:22]=[C:21]([C:19]2[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:16]=[N:17][C:18]=2[CH2:38][CH2:39][CH2:40][CH3:41])[CH:26]=[CH:25][C:24]=1[O:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Reaction time: 1 h

Procedure:
To a solution of 4-[6-butyl-5-(4-cyclohexyloxy-3-methoxycarbonyl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.754 mmol, 428 mg) in DCM (6 mL) was added 4 N HCl in dioxane (2 mL) and the reaction mixture was stirred for 1 h. The organic solvents were removed in vacuo and 5-[3-Butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester dihydrochloride was obtained as yellow solid, which was used for next reaction directly
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:15])OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCc1cccnc1
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 5 h
Yield: 95.2 %

Procedure:
4.22 g (0.02 mole) of ethyl N-(4-nitrophenyl)carbamate, 1.80 g (0.0167 mole) of 3-aminomethyl-pyridine and 3.18 g (0.0173 mole) of tributylamine are dissolved in 25 ml of dry toluene, and the mixture is boiled for 5 hours. The separated product is filtered off, washed twice with 10 ml of acetone, each, and dried. 4.33 g (85.1%) of N-(4-nitrophenyl)-N'-(3-pyridylmethyl)-urea are obtained; m.p.: 222°-224° C. (the authentic sample melts at 223°-225° C.).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11](=[N:17]O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)C(C)C)(C)C.O>ClCCl>[C:2]1([C:1]2[O:8][N:17]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.219 mL; 1.89 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (18 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried and concentrated under reduced pressure. The residue was refluxed in a sealed tube with pyridine (6 mL) for 20 hours and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.239 (60%) of ethyl 5-phenyl-1,2,4-oxadiazole-3-carboxylate as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:25])([CH3:24])[C:11](=[O:23])[CH:12]([CH2:18][CH2:19][CH2:20][CH2:21]I)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:26])[C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH3:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:25])([CH3:24])[C:11]([C:12]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:23])[C:6](=[O:26])[C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(CCCCI)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)C(C)(C)N2COC(C)=C(c3ccccc3)C2=O)CCCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
Sodium hydride (40 mg of 60% oil dispersion) was added at 0° C. to a solution of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-(4'-iodobutyl)-4-methyl-3-oxo-pentanoate (0.25 g) in N,N-dimethylformamide, and stirred at 20° C. for 2 hours. The mixture was diluted (ether),washed (brine), dried (MgSO4) and evaporated. The residue was purified by column chromatography (ethyl acetate/hexane 1:3) to give ethyl 1-[2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionyl]cyclopentylcarboxylate (Compound 1, 0.14 g), NMR 1.21(3H, t), 1.4-1.6(8H, m), 1.7-1.8(2H, m), 1.91(3H, s), 2.1-2.2(2H, m), 2.4-2.5(2H, m), 3.60(2H, s), 4.14(2H, q), 5.16(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](/[CH:27]=[CH:28]/B(O)O)([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](/[CH:28]=[CH:27]/[C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: CC(C)(C)/C=C/B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(/C=C/C(C)(C)C)c3O2)cc1
Yield: 81.1 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.0 g, 20.87 mmol) with [E]-2-tert-butylvinylboronic acid (4.01 g, 31.31 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.82 g, 1.04 mmol), and potassium carbonate (7.21 g, 52.19 mmol) generally according to the procedure described for Intermediate 37 provided 6.54 g (81%) of (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 85-88° C.; Anal. calcd. for C22H26O4S: C, 68.37; H, 6.78. Found: C, 68.27; H, 6.86.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[OH-].[Na+]>>[CH2:17]([N:14]1[CH2:15][CH2:16][C:11]2([CH2:10][C:9](=[O:28])[C:8]3[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=3)[O:24]2)[CH2:12][CH2:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2
Yield: 95 %

Procedure:
(E)-3-{1′-Benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (414 mg, 1.06 mmol) was hydrolyzed with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (380 mg) as a white solid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn]([C:48]#[N:49])(CCCC)CCCC)CCC.Cl[C:51]1[CH:52]=[CH:53][CH:54]=[C:55]2[C:60]=1[N:59]=[C:58]([C:61]1[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=1)[C:57]([CH3:68])=[C:56]2[NH:69][C:70]1[CH:71]=[N:72][CH:73]=[C:74]([N:76]2[CH2:81][CH2:80][O:79][CH2:78][CH2:77]2)[CH:75]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:68][C:57]1[C:58]([C:61]2[CH:66]=[C:65]([CH3:67])[CH:64]=[CH:63][N:62]=2)=[N:59][C:60]2[C:55]([C:56]=1[NH:69][C:70]1[CH:71]=[N:72][CH:73]=[C:74]([N:76]3[CH2:81][CH2:80][O:79][CH2:78][CH2:77]3)[CH:75]=1)=[CH:54][CH:53]=[CH:52][C:51]=2[C:48]#[N:49]
Reactant: Cc1ccnc(-c2nc3c(Cl)cccc3c(Nc3cncc(N4CCOCC4)c3)c2C)c1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3c(C#N)cccc3c(Nc3cncc(N4CCOCC4)c3)c2C)c1
Temperature: 100 °C

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), tri-n-butyltin cyanide (0.104 g, 0.33 mmol), 8-chloro-3-methyl-2-(4-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (0.15 g, 0.33 mmol) and Pd2dba3 (0.012 g, 0.013 mmol) in toluene (3.30 mL) was added sodium tert-butoxide (0.079 g, 0.82 mmol). The reaction mixture was heated to 100° C. for 66 h. After which, the reaction mixture was filtered through a plug of alumina eluting with (EtOAc), the filtrate was cond in vacuo. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes) to give the desired product. The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 3-methyl-2-(4-methylpyridin-2-yl)-4-(5-morpholinopyridin-3-ylamino)quinoline-8-carbonitrile. 1H NMR (400 MHz, CD2Cl2) δ ppm 8.59 (1H, d, J=5.5 Hz), 8.06 (2H, ddd, J=14.8, 7.9, 1.4 Hz), 7.86 (1H, d, J=2.5 Hz), 7.78-7.83 (1H, m), 7.67 (1H, d, J=2.3 Hz), 7.48 (1H, dd, J=8.5, 7.1 Hz), 7.27 (1H, m), 6.60 (1H, s), 6.43 (1H, t, J=2.3 Hz), 3.75 (4H, m), 3.05 (4H, m), 2.51 (3H, s), 2.36 (3H, s). Mass Spectrum (ESI) m/e=437.1 (M+1).
Reaction SMILES: [OH2:1].OO.[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1>O1CCCC1.O>[F:11][C:10]1[CH:9]=[C:8]([OH:1])[CH:7]=[N:6][C:5]=1[F:4]
Reactant: CC1(C)OB(c2cnc(F)c(F)c2)OC1(C)C
Reactant: O
Agent: OO
Solvent: C1CCOC1
Product: Oc1cnc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
A mixture of hydrogen peroxide water (1.50 mL, 13.2 mmol) and 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.8 g) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 h, then diluted with water and extracted with ethyl acetate. Combined organic portions were washed with aqueous 5% sodium thiosulfate solution and saturated saline water, dried over anhydrous sodium sulfate and concentrated. Purification via Biotage Spla HPFC system (C18, mobile phase: 0.01% NH4HCO3, CH3CN/water, 10˜95%) afforded the title product as a white solid (450 mg).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])([O-:8])=[O:7].[CH3:25]O>>[CH3:25][O:17][C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[C:10]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[CH:11]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (50 mL) was added slowly to a solution of 2-(4-nitro-3-(2,2,2-trifluoro-ethoxy)phenyl)acetic acid (180 g, 0.64 mol) in MeOH (500 mL). The reaction mixture was stirred at room temperature overnight. The methanol was evaporated and EtOAc (500 mL) was added. The solution was washed with water (2×200 mL) and brine and dried over MgSO4. The solvent was evaporated, the solid residue was stirred with heptane (200 mL), and the solid was filtered. Yield 182.2 g (96%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.82 (d, J=8.7 Hz, 1H), 7.07-7.05 (m, 2H), 4.47 (q, J=8.0 Hz, 2H), 3.68 (s, 3H), 3.67 (s, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 170.1, 150.4, 141.2, 139.4, 125.9, 123.9, 122.6 (d, 1JCF=277.6 Hz), 117.5, 67.6 (q, 1JCF=36.7 Hz), 52.4, 41.0.
Reaction SMILES: FC1C=C(C=CC=1)C(NC1C=C2C(C(Cl)=C(OCCC)OC2=O)=CC=1)=O.COC1C=CC(C(NC2C=C3C(C(Cl)=C(OCCC)OC3=O)=CC=2)=O)=CC=1.[F:54][C:55]([F:81])([C:77]([F:80])([F:79])[F:78])[C:56]([F:76])([F:75])[C:57]([NH:59][C:60]1[CH:70]=[C:69]2[C:63]([C:64]([Cl:74])=[C:65]([O:71][CH2:72]C)[O:66][C:67]2=[O:68])=[CH:62][CH:61]=1)=[O:58].FC(F)(C(F)(F)F)C(F)(F)C(NC1C=C2C(C(Cl)=C(OCCBr)OC2=O)=CC=1)=O.FC1C=C(C=CC=1)C(NC1C=C2C(C(Cl)=C(OCCBr)OC2=O)=CC=1)=O.[N+](C1C=C(C=CC=1)C(NC1C=C2C(C(Cl)=C(OCCBr)OC2=O)=CC=1)=O)([O-])=O.C1(CS(NC2C=C3C(C(Cl)=C(OCCBr)OC3=O)=CC=2)(=O)=O)C=CC=CC=1>>[F:81][C:55]([F:54])([C:77]([F:78])([F:79])[F:80])[C:56]([F:75])([F:76])[C:57]([NH:59][C:60]1[CH:70]=[C:69]2[C:63]([C:64]([Cl:74])=[C:65]([O:71][CH3:72])[O:66][C:67]2=[O:68])=[CH:62][CH:61]=1)=[O:58]
Reactant: CCOc1oc(=O)c2cc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)ccc2c1Cl
Agent: CCCOc1oc(=O)c2cc(NC(=O)c3ccc(OC)cc3)ccc2c1Cl
Agent: CCCOc1oc(=O)c2cc(NC(=O)c3cccc(F)c3)ccc2c1Cl
Agent: O=C(Nc1ccc2c(Cl)c(OCCBr)oc(=O)c2c1)C(F)(F)C(F)(F)C(F)(F)F
Product: COc1oc(=O)c2cc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)ccc2c1Cl

Procedure:
7-(3-fluorobenzoyl)amino-4-chloro-3-propoxyisocoumarin, 7-(4-methoxybenzoyl)amino-4-chloro-3-propoxyisocoumarin, 7-heptafluorobutyroylamino-4-chloro-3-ethoxyisocoumarin, 7-heptafluorobutyroylamino-4-chloro-3-(2-bromoethoxy)isocoumarin, 7-(3-fluorobenzoyl)amino-4-chloro-3-(2-bromoethoxy)isocoumarin, 7-(3-nitrobenzoyl)amino-4-chloro-3-(2-bromoethoxy)isocoumarin, 7-(α-toluenesulfonyl)amino-4-chloro-3-(2-bromoethoxy)isocoumarin can be prepared by the same procedure.
Reaction SMILES: COCCOC.FC(F)(F)C([N:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)=O.[OH:39][CH:40]1[CH2:44][CH2:43][CH:42]([CH3:45])[O:41]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C(N(CC)CC)C>[CH2:21]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:39][CH:40]2[CH2:44][CH2:43][CH:42]([CH3:45])[O:41]2)=[O:17])=[CH:19][CH:20]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CC1CCC(O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC2CCC(C)O2)cc1
Reaction time: 4 h

Procedure:
In 50 ml. of 1,2-dimethoxyethane, 9.4 g. of N-trifluoroacetyl-4-(hexadecylamino)benzoyl chloride, 2.2 g. of triethylamine and 2.2 g. of 2-hydroxy-5-methyltetrahydrofuran are heated together at 60° C. for 24 hours. After addition at 30° C. of a small amount of aqueous potassium carbonate and standing for 4 hours, the white crystalline product is isolated by addition of water, filtration and recrystallization from acetonitrile.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([CH3:20])[C:6]2[CH:12]=[C:11](Br)[C:10](=[O:14])[N:9]([C@@H:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[C:7]=2[N:8]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[NH2:2][C:3]1[N:4]=[C:5]([CH3:20])[C:6]2[CH:12]=[C:11]([C:25]3[CH:24]=[N:23][C:22]([NH2:21])=[CH:27][CH:26]=3)[C:10](=[O:14])[N:9]([C@@H:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[C:7]=2[N:8]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@@H]1CCOC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1cc(-c1ccc(N)nc1)c(=O)n2[C@@H]1CCOC1
Temperature: 95 °C
Yield: 78.7 %

Procedure:
To a solution of (R)-2-amino-6-bromo-4-methyl-8-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one hydrobromide (2.97 g, 7.36 mmol) in 1,4-dioxane (100 mL) and water (25 mL) were added 2-aminopyridine-5-boronic acid pinacol ester (2.43 g, 11.0 mmol), K2CO3 (3.05 g, 22.1 mmol) and Pd(PPh3)4 (170 mg, 2 mol %) under a nitrogen atmosphere. The reaction mixture was heated at 95° C. for 3 h. After the reaction was complete by LC/MS, the reaction mixture was partitioned with ethyl acetate (200 mL). The precipitate in the aqueous layer was collected by filtration. Meanwhile, the aqueous layer was washed with ethyl acetate (100 mL×3) and the organic layers with brine. The organic layers were collected and dried with MgSO4, and the mixture filtered. The solvent was removed in vacuo to give a yellow solid. The combined solids were washed with ethyl acetate and water to give the desired product (1.96 g, 79% yield, >98% HPLC purity).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:10]([NH2:20])[CH:11]=[C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:13]=1.C(O)(=O)C.[CH:25](N)=[NH:26]>CC(O)CC.[OH-].[Na+]>[CH3:8][C:9]1[N:10]([NH:20][CH:25]=[NH:26])[CH:11]=[C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:13]=1
Reactant: Cc1nc(-c2cnn(C)c2)cn1N
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cnn(C)c2)cn1NC=N
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-amine, trifluoroacetate salt (103.0 g, 353.7 mmol) and formamidine acetate (98%, 131 g, 1.23 mol) were combined in 2-butanol (350 mL). The reaction was heated to 100° C. for 3 hours, at which time it was allowed to cool to room temperature and diluted with a 2:1 mixture of 10 N sodium hydroxide solution/saturated aqueous sodium chloride solution (300 mL). After vigorous stirring, the layers were separated, and the aqueous layer was extracted with 2-butanol (4×250 mL). The combined organic layers were concentrated in vacuo, and the resulting solid was slurried with acetonitrile (550 mL), stirred for 2 hours at room temperature and filtered. The collected solids were washed with dry acetonitrile (3×100 mL), then dried in vacuo at 40° C. for 2 hours to provide the product as an off-white solid. Yield: 61.5 g, 301 mmol, 85%. The mother liquor was concentrated to dryness, then dissolved in acetonitrile (200 mL) and allowed to stand for 18 hours. The resulting solid was isolated by filtration to provide additional product as an off-white solid. Combined yield: 64.8 g, 317 mmol, 90%. 1H NMR (500 MHz, CD3OD), presumed to be a mixture of rotamers or tautomers: δ 2.25 and 2.29 (2 s, 3H), 3.88 and 3.88 (2 s, 3H), 7.03 and 7.19 (2 s, 1H), 7.39 and 7.94 (2 s, 1H), 7.69 and 7.67 (2 s, 1H), 7.77 and 7.75 (2 s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[C:6](I)[CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCOCC1>[CH3:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:9]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([C:32]4[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=4)[CH:6]=[C:7]3[N:8]=2)[N:13]=[C:14]([NH2:19])[CH:15]=1
Reactant: Cc1cc(N)nc(CCC(=O)Nc2c(I)ccnc2N)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(C(F)(F)F)cc4)cnc3[nH]2)c1
Temperature: 110 °C
Yield: 54.1 %

Procedure:
96 mg N-(2-amino-iodo-pyridin-3-yl)-3-(6-amino-4-methyl-pyridin-2-yl)-propionamide (compound A10) is dissolved in 3.0 ml anoxic dioxane under a nitrogen atmosphere. Subsequently, 0.7 ml of an aqueous sodium bicarbonate solution (2.0 M), 52 mg 4-(trifluoromethyl)phenyl-boronic acid, and 14 mg trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 20 h. Thereafter, the volatile components are removed in vacuo and the remaining residue is re-dissolved in a mixture of water/dichloromethane (1:1). The aqueous phase is extracted several times with dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield 161 mg of a colourless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethanol 8:1) to afford 52 mg of the title compound. M.p. 170° C. ESI-MS: 398.3 (MH+). TLC: Rf=0.25 (dichloromethane/methanol 8:1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.ClC1C=CC(C(C2N(C)N=NC=2)O)=CC=1.[Li]CCCC.[CH3:27][C:28]1[S:29][C:30]([CH:34]=[O:35])=[C:31]([CH3:33])[N:32]=1>C1COCC1>[CH3:27][C:28]1[S:29][C:30]([CH:34]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][CH:5]=2)[OH:35])=[C:31]([CH3:33])[N:32]=1
Reactant: Cc1nc(C)c(C=O)s1
Reactant: Cn1ccnn1
Agent: Cn1nncc1C(O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(O)c2cnnn2C)s1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (1.60 g, 19.3 mmol, Intermediate 42, step a) was added THF (200 mL) and the solution was cooled to −40° C. To this colorless homogeneous solution was added n-BuLi (2.5 M in hexanes, 7.7 mL, 19.2 mmol) dropwise which immediately afforded a dark brown viscous mixture. The mixture was kept between −10 to −20° C. for 60 min, then 2,4-dimethylthiazole-5-carbaldehyde (3.03 g, 21.5 mmol) in THF (5 mL) was introduced and the reaction mixture began to stir much more easily, but still remained brownish. Once the aldehyde was added the reaction was placed in an ice-bath and maintained there until it warmed to room temp. After 3 hours the reaction was quenched by pouring into a saturated solution of NH4Cl at room temperature. The aqueous portion was extracted with EtOAc (5×100 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a brown oil-foam. Flash chromatography on silica gel (10-30% acetone increasing gradient to 10% MeOH-DCM) gave the title compound as a light orange foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][S:46][C:47]1[CH:48]=[C:49]([CH2:53][CH2:54]O)[CH:50]=[CH:51][CH:52]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:54][CH2:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([S:46][CH3:45])[CH:48]=3)[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: CSc1cccc(CCO)c1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(SC)c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
The compound of step 2 (0.380 g, 1.11 mmol) and triphenylphosphine (0.461 g, 1.67 mmol) were dissolved in THF. 2-(3-Methylsulfanyl-phenyl)-ethanol (0.281 g, 1.67 mmol) and DIAD (0.359 g, 1.67 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo and the residue was purified by preparative RP HPLC (water/ACN gradient) to give 0.217 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: COc1cccc(B(O)O)c1
Product: CCOC(=O)c1nc(-c2cccc(OC)c2)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 3-methoxyphenylboronic acid: MS (m/z) 441.1 (M+1).