Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14](Br)[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]([C:37]1[CH:38]=[CH:39][C:40]([O:46][CH3:47])=[C:41](B(O)O)[CH:42]=1)([CH3:36])[CH3:35].C(O)C.C([O-])(O)=O.[Na+]>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>[CH2:1]([O:8][C:9]([C:10]1[CH:15]=[C:14]([C:41]2[CH:42]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:38]=[CH:39][C:40]=2[O:46][CH3:47])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COc1ccc(C(C)C)cc1B(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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 84 %

Procedure:
A mixture of 2,4-bis-benzyloxy-5-bromo-benzoic acid benzyl ester (503 mg, 1 mmol) and 5-isopropyl-2-methoxy-phenylboronic acid (388 mg, 2 mmol) was heated in a mixture of toluene (5 ml), ethanol (5 ml) and saturated NaHCO3 (5 ml) under nitrogen in the presence of a catalytic amount of Pd(PPh3)4 (60 mg, 0.052 mmol) at 80° C. for 2-3 h. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (25 ml×3), and the combined organics were washed with water and brine and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to provide 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid benzyl ester (481 mg, 84%). M.p.: 139-141° C.; 400 MHz 1H NMR (CDCl3) δ: 7.44-7.22 (m, 16H), 7.17 (dd, J=8.0, 2.4 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.58 (s, 1H), 5.32 (s, 2H), 5.11 (s, 2H), 5.04 (s, 2H), 3.71 (s, 3H), 2.87 (hept, J=7.2 Hz, 1H), 1.23 (d, J=7.6 Hz, 6H); LCMS: 573 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[C:13](OC)(=[O:16])[CH:14]=[CH2:15].C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:11][C:10]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1ccc(C2CCC(=O)CC2=O)cc1

Procedure:
A mixture of 4-methoxyphenylacetone (50 g) and methyl acrylate (26.2 g) was added dropwise to a stirred suspension of sodium methoxide (from 7.5 g sodium in 50 ml methanol) in dry xylene (160 ml) at ambient temperature. The resulting solution was then refluxed for 3 hours. The xylene was evaporated in vacuo and the residue partitioned between water and diethyl ether. The aqueous phase was further extracted with diethyl ether. The aqueous layer was finally acidified with concentrated hydrochloric acid to precipitate 4-(4-methoxyphenyl)cyclohexane-1,3-dione (37 g) as a white solid (after an ether washing) of m.p. 150°-151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([C:9]#[N:10])[S:8][C:4]=2[C:3]=1[C:13]#[N:14].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:9]([C:7]1[S:8][C:4]2[C:3]([C:13]#[N:14])=[C:2](/[N:1]=[CH:17]/[N:18]([CH3:20])[CH3:19])[CH:12]=[CH:11][C:5]=2[N:6]=1)#[N:10]
Reactant: N#Cc1nc2ccc(N)c(C#N)c2s1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N

Procedure:
The thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib were prepared following scheme 1: N-Boc Protection of 2-amino-5-nitrobenzonitrile using di-tert-butyl dicarbonate in a suitable solvent, such as dichloromethane, in presence of suitable bases such as triethylamine and 4-(dimethylamino)pyridine and preferably at room temperature, provides tert-butyl (2-cyano-4-nitrophenyl)carbamate I in high yield. Reduction of the nitro intermediate I, for example by treatment with ammonium formate and a catalytic amount of 10% palladium charcoal preferably in ethanol under microwave irradiation for preferably 30 min at 600 W, provides tert-butyl 4-amino-2-cyanophenylcarbamate II in high yield. Treatment of intermediate II by a solution of bromine in dichloromethane in a suitable solvent, such as acetic acid, preferably at room temperature provides tert-butyl 4-amino-3-bromo-2-cyanophenylcarbamate III in a quantitative yield. Intermediate III is reacted with Appel's salt (4,5-dichloro-1,2,3-dithiazolium chloride) (Appel, R. et al., Chem. Ber., 1985, 118, 1632) preferably in dichloromethane at room temperature to afford (Z)-tert-butyl-3-bromo-4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-cyanophenylcarbamate IV. N-Boc deprotection of intermediate IV using di-tert-butyl dicarbonate in a suitable solvent, such acetic acid, preferably under microwave irradiation at 118° C. provides (Z)-6-amino-2-bromo-3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzonitrile V in a quantitative yield. Cyclization of intermediate V may be accomplished by treatment with copper iodide in a suitable solvent, such as pyridine, preferably under microwave irradiation at 400 W at 130° C. for 20 min to obtain 6-aminobenzo[d]thiazole-2,7-dicarbonitrile VI in good yield (Besson, T. et al., J. Chem. Soc., Perkin Trans. 1, 1998, 3925). Treatment of intermediate VI in a suitable solvent, such as dimethylformamide dimethylacetal, preferably under microwave irradiation at 70° C. (600 W) gives (E)-N′-(2,7-dicyanobenzo[d]thiazol-6-yl)-N,N-dimethylformimidamide VII in good yield. Cyclization of intermediate VII in thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib may be accomplished by a Dimroth rearrangement using the appropriate aniline or primary amine R3NH2 (preferably 1.5 equivalent) in a suitable solvent, such acetic acid and preferably under microwave irradiation at 118° C. (600 W) (Foucourt, A. et al., Tetrahedron, 2010, 66, 4495).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][N:12]=[CH:13]3)=[CH:8][CH:7]=2)=[CH:2]1.Cl.[H][H]>ClCCl.C(O)C.[Pt]=O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][NH:12][CH2:13]3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: c1cc2ccc(-c3ccsc3)cc2cn1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: c1cc(-c2ccc3c(c2)CNCC3)cs1
Yield: 63.5 %

Procedure:
A solution of 7-(3-thienyl)isoquinoline (0.15 g, 3 mmol) in dichloromethane was treated with an excess of HCl gas. The mixture was evaporated under reduced pressure to give a colourless solid. The solid was dissolved in ethanol, platinum oxide (100 mg) added, the reaction mixture hydrogenated at 50 psi on a Parr apparatus until uptake of hydrogen ceased. The catalyst was collected by filtration and the filtrate was hydrogenated again using fresh catalyst until the starting material had been consumed. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), washed with sodium carbonate solution (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give crude 7-(3-thienyl)-1,2,3,4-tetrahydroisoquinoline as an oil (0.41 g, 62%). A mixture of this oil (0.40 g, 1.85 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.325 g, 1.85 mmol) in toluene (3 ml) was heated at reflux under nitrogen for 6 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from toluene afforded the title compound (0.17 g, 28%), m.p. 228°-230° C.; (Found: C, 72.82; H, 5.46; N, 12.05. C21H19N3S requires C, 73.01; H, 5.54; N, 12.16%); δH (DMSO-d6) 2.72 (2H, t, J 5.4 Hz, CH2), 2.80 (2H, t, J 5 Hz, CH2), 3.59 (2H, s, CH2), 3.82 (2H, s, CH2), 7.02 (1H, dd, J 7.7, 4.7 Hz, 5-H), 7.11 (1H, d, J 8.0 Hz, ArH), 7.35 (1H, s, ArH), 7.42-7.50 (3H, m, ArH), 7.57 (1H, dd, J 5.1, 3 Hz, ArH), 7.76 (1H, s, ArH), 8.04 (1H, dd, J 7.7, 1 Hz, 4-H), 8.20 (1H, dd, J 4.6, 1 Hz, 6-H), and 11.49 (1H, br s, NH); m/z (CI+, NH3) 345 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CI.[C:12]([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH3CN (700 mL) was added CH3I (110 g, 0.78 mol) and K2CO3 (180 g, 1.3 mol). The mixture was stirred at 25° C. overnight. The solid was filtered off and the filtrate was evaporated under vacuum to give 1-chloro-2-methoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=7.8 Hz, 1 H), 6.74-6.69 (m, 2 H), 3.88 (s, 3 H), 2.33 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-])=O)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[NH2:23])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](CCc1ccccc1)Nc1cc(C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C[C@H](CCc1ccccc1)Nc1cc(C)ccc1N
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a solution of (S)-3-(5-Methyl-2-nitro-phenylamino)-5-phenyl-pentanoic acid ethyl ester (0.9 g, 2.5 mmol) in MeOH (20 mL) was added slurry of Pd/C (0.2 g) in MeOH. The reaction mixture was de-gassed using house vacuum. The reaction mixture was stirred under H2 balloon for 3 h. When the reaction color changed from orange to colorless, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated to afford 0.84 g the desired product. This product was used for the next reaction without further purification.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>CN(C=O)C>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:11]=2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(Br)cc1
Reactant: c1ccc(CCCC(OC2CCCCO2)c2ccc(OCC3CO3)cc2)cc1
Solvent: CN(C)C=O
Product: OC(COc1ccc(Br)cc1)COc1ccc(C(CCCc2ccccc2)OC2CCCCO2)cc1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A mixture of the crude product (5.5 g) of Step 2, 4-bromophenol (5.2 g) and 2 drops of Triton B in 30 mL of DMF was heated for 8 hrs. in a 160° C. oil bath. The mixture was then cooled to r.t., quenched with 100 mL of 2N NaOH, and extracted with 200 mL of Et2O. The extract was dried over NaSO4 and concentrated. The crude product was purified by flash chromatography eluted with 2.5:1 Hexane/EtOAc to give 5.2 g of the title compound.
Reaction SMILES: C(OC1C=C([CH:15]([N:30]([CH3:44])[C:31](=[O:43])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]2)C=CC=1)C1C=CC=CC=1.[CH2:45]([OH:47])[CH3:46]>[OH-].[Pd+2].[OH-]>[C:26]([Si:23]([CH3:25])([CH3:24])[O:22][CH:19]1[CH2:20][CH2:21][CH:17]([CH:16]([C:18]2[CH:17]=[CH:16][CH:15]=[C:45]([OH:47])[CH:46]=2)[CH2:15][N:30]([CH3:44])[C:31](=[O:43])[CH2:32][C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)[CH2:18]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CCO
Reactant: CN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)C(CC1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Product: CN(CC(c1cccc(O)c1)C1CCC(O[Si](C)(C)C(C)(C)C)C1)C(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 16 h

Procedure:
To a solution of Example 39 (2.41 g, 3.8 mmol) in ethanol (220 mL) was added palladium hydroxide (20% on carbon) (0.15 g). This was hydrogenated at 30° C. for 16 hours, filtered through Celite, and the solvent removed in vacuo to give a white foam, 3.7 mmol, 97%. This was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.FC1C=C(OC)C=C(F)C=1CN1[C:39]2[N:40]=[CH:41][CH:42]=[CH:43][C:38]=2[S:37](=[O:45])(=[O:44])[N:36]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[C:48]([O:54][CH3:55])[CH:47]=2)[C:35]1=[O:56]>>[F:1][C:2]1[C:3]([CH2:9][N:10]2[C:39]3[N:40]=[CH:41][CH:42]=[CH:43][C:38]=3[S:37](=[O:45])(=[O:44])[N:36]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[C:48]([O:54][CH3:55])[CH:47]=3)[C:35]2=[O:56])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NCc1ncc(F)cc1F
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)N(Cc3ncc(F)cc3F)c3ncccc3S2(=O)=O)cc1OC

Procedure:
The title compound (16 mg, 0.03 mmol) was prepared in two steps from (IntC1) (82 mg, 0.25 mmol) and (3,5-difluoropyridin-2-yl)methanamine (108 mg, 0.75 mmol); followed by 1,1′-carbonyldiimidazole (65 mg, 0.4 mmol) and triethylamine (28 uL, 0.2 mmol) using the methods of (95).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:32]([N:35]1[CH:39]=[CH:38][CH:37]=[N:36]1)[C:33]#[CH:34]>O1CCCC1.C(N(CC)CC)C.[Cu]I.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>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:34]#[C:33][CH2:32][N:35]3[CH:39]=[CH:38][CH:37]=[N:36]3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#CCn1cccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#CCn3cccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10) was dissolved in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous triethylamine (20 mL). The solution was degassed and a solution of 1-propargylpyrazol (160 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) was added under inert atmosphere. The resulting solution was degassed and copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added and the mixture was degassed again. The reaction mixture was stirred at ambient temperature overnight; the resulting suspension was filtered through a paddle of silica gel. Silica gel was thoroughly washed with ethyl acetate; the filtrate was evaporated and the residue was dissolved in dichloromethane (30 mL). The solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 80:20) yielding methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]-allyloxy]-2-methylphenoxy]acetate as orange oil.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17]S(C)(=O)=O)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][NH:29][C:28]1=[O:33].[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][CH2:17][N:29]3[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]3=[O:33])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: CN1C(=O)CNC1=O
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCS(C)(=O)=O)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(CC[C@@H]2C[C@H]2c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1-(2,2-Dimethylpropyl)-3-methyl-5-{(1R,2S)-2-[2-(methylsulfonyl)ethyl]-cyclopropyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-5, 39 mg, 0.10 mmol, 1.0 equiv) was added to anhydrous DMF (0.50 mL) and cooled to 0° C. 3-Methylimidazolidine-2,4-dione (31-6, 58 mg, 0.51 mmol, 5.0 equiv) and NaH (20 mg, 0.51 mmol, 5.0 equiv, 60% dispersion in oil) were added sequentially and the resulting mixture was warmed to RT. After 18 h, LCMS showed complete consumption of 32-5. Purification by reverse-phase HPLC (10-100% 0.1% TFA in H2O:CH3CN) afforded 32-6 as a colorless oil. MS m/z (M+H): calculated=400.2343; observed=400.2342.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[OH:23][C@H:24]([CH2:27][OH:28])[CH2:25][NH2:26]>CC(O)C>[OH:23][C@H:24]([CH2:27][OH:28])[CH2:25][NH:26][C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1
Reactant: NC[C@H](O)CO
Reactant: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Solvent: CC(C)O
Product: COc1ccc2nc(NC[C@H](O)CO)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
A solution of 2-chloro-4-(3-fluorophenyl)-6-methoxyquinoline-3-carbonitrile (65.0 mg, 0.208 mmol) and (S)-2,3-dihydroxypropylamine (114 mg, 1.25 mmol) in 10 mL of 2-propanol was heated in a sealed tube at 120° C. for 63 hours. Another portion of (S)-2,3-dihydroxypropylamine was added (50 mg), and the reaction was stirred for another 12 hours. The solution was concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product (17 mg, 22%). Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C20H19FN3O3 (M+H+): 368.1405. Found 368.1398.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][NH:5][C:6](=[O:11])OC(C)=C.[NH2:14][C:15]1[C:16]([F:34])=[CH:17][C:18]([F:33])=[C:19]([C:21]2[CH:32]=[N:31][C:24]3[N:25]=[C:26]([NH:29][CH3:30])[N:27]=[CH:28][C:23]=3[CH:22]=2)[CH:20]=1.CN1CCCC1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[F:34][C:16]1[CH:17]=[C:18]([F:33])[C:19]([C:21]2[CH:32]=[N:31][C:24]3[N:25]=[C:26]([NH:29][CH3:30])[N:27]=[CH:28][C:23]=3[CH:22]=2)=[CH:20][C:15]=1[NH:14][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:1])([CH3:12])[CH3:13])=[O:11]
Reactant: CNc1ncc2cc(-c3cc(N)c(F)cc3F)cnc2n1
Reactant: C=C(C)OC(=O)NCCC(C)(C)C
Agent: CN1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3F)cnc2n1
Temperature: 65 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
Treat a solution of prop-1-en-2-yl (3,3-dimethylbutyl)carbamate (0.039 g, 0.209 mmol) and 6-(5-amino-2,4-difluorophenyl)-N-methylpyrido[2,3-d]pyrimidin-2-amine (0.060 g, 0.209 mmol) in dioxane (5 mL) with catalytic 1-methylpyrrolidine (1.8 mg, 0.021 mmol) and heat at 65° C. overnight. Add 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine (0.1 mL) and additional prop-1-en-2-yl (3,3-dimethylbutyl) (25 mg, 0.135 mmol) and heat the mixture at 85° C. overnight. Add additional 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine (0.1 mL) and prop-1-en-2-yl (3,3-dimethylbutyl) (25 mg, 0.135 mmol) and heat the mixture at 85° C. for another 24 h. Cool the mixture to RT, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hexane). Treat the resulting material with DCM, allow to stand at RT overnight, and collect the solid via filtration to afford 1-(2,4-difluoro-5-(2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (30 mg, 35% yield). MS (m/z): 415.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].CI.[C:17](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:17])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)N(C)C(=O)CO2
Yield: 83.9 %

Procedure:
6-Acetyl-2H-benzo[b][1,4]oxazin-3(4H)-one (1 g, 5.23 mmol), methyl iodide (1.13 g, 7.84 mmol) and cesium carbonate (2.55 g, 7.84 mmol) were dissolved in DMF (2 mL). The reaction mixture was irradiated by microwave for 30 minutes at 100° C. The solvent was removed and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 6-acetyl-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.9 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.60 (d, 1H), 7.01 (d, 1H), 4.70 (s, 2H), 3.42 (s, 3H), 2.60 (s, 3H); MS (ESI) m/z: Calculated for C11H11NO3: 205.1. found: 206.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=O)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].[Cl-].O[NH3+:26].C([O-])(=O)C.[Na+]>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:26])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (3.00 g) is dissolved in ethanol (40 ml) and thereto are added hydroxyl ammonium chloride (1.29 g) and sodium acetate (1.53 g), and the mixture is stirred under nitrogen atmosphere at 60° C. for 1 hour and a half. The reaction solution is concentrated under reduced pressure, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue (3.3 g) is dissolved in methanol (40 ml), and thereto is added Raney nickel (5 g) and the mixture is stirred under hydrogen atmosphere at room temperature overnight. Raney nickel is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (1.57 g). MS (m/z): 324 [M+H]+