Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.[F:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:25]1[CH2:26][CH2:27][CH:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:29][CH:28]=2)[CH2:24]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: Fc1ccc(CC2CCNC2)cc1
Agent: Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(Cc2ccc(F)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-fluorobenzyl)pyrrolidine hydrochloride (12.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (10.1 mg). Calcd for C21H18ClFN2O2: 384.1041, found 384.1042.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl.C(N(CC)CC)C.[O:18]1[CH:22]=[CH:21][CH2:20][CH2:19]1>CN(C)C=O>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F

Procedure:
In 15 ml of dimethylformamide were dissolved 1.3 g of 5-fluorouracil and 0.41 g of triethylamine hydrochloride. To this solution were added 3 ml of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 16 hours at 150° C. After the reaction, dimethylformamide was removed from the reaction liquid by distillation and the residue was treated in the same manner as described in Example 7 to obtain 0.8 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. From the chloroform insoluble matter 0.6 g of the starting 5-fluorouracil was recovered. The yield of the end product was 74% based on the consumed 5-fluorouracil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:37])[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:22]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:37])[C:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1NC(=O)c1ccc(Cl)nc1
Temperature: 100 °C
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 100° C. for 2 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of isohexane and diethyl ether. There was thus obtained the title compound in 63% yield; NMR Spectrum: (DMSOd6): 2.2 (s, 3H), 3.3 (m, 4H) 3.75 (t, 4H), 7.25 (d, 1H), 7.35 (s, 1H), 755-7.65 (m, 1H), 7.65 (s, 1H), 7.7-7.75 (m, 2H), 7.8 (d, 1H), 8.35-8.4 (m, 1H), 8.95 (d, 1H), 10.15 (s, 1H), 10.33 (s, 1H); Mass Spectrum M+H+ 519 and 521.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]#[N:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].Cl>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:15]#[N:16])([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[C:18]([F:17])([F:28])[F:29])[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: COC(=O)C(C#N)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C#N)(C(=O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
0.10 g (2.6 mmols) of sodium hydride was suspended in 20 ml of tetrahydrofuran. To the suspension was added dropwise, while stirring and cooling, 5 ml of a tetrahydrofuran solution in which 0.42 g (2.0 mmols) of methyl 2-(4-chlorophenyl)cyanoacetate and 0.41 g (2.6 mmols) of 2-trifluoromethylbenzoyl chloride had been dissolved. The mixture was stirred at room temperature over night. The reaction mixture was poured into ice water. The water phase thereof was acidified by diluted hydrochloric acid and twice extracted with 30 ml of ethyl acetate. The ethyl acetate extraction solutions were mixed, washed with a saturated brine solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thus-obtained was purified by silica gel column chromatography (n-hexane:benzene=1:1), giving 0.45 g of the desired product (yield 59%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:35][N:36]([CH3:47])[CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>C(O)(C)C.Cl>[CH3:35][N:36]([CH3:47])[CH2:37][CH2:38][O:39][C:40]1[CH:41]=[C:42]([NH:43][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:34])[C:26]5[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=5[F:33])[CH:21]=[CH:22][CH:23]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: O=C(Nc1cccc(-c2nn3cccc(F)c3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4cccc(F)c34)n2)c1
Yield: 69.2 %

Procedure:
To the solution of N-{3-[3-(2-chloro-4-pyrimidinyl)-4-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (0.10 g) in isopropanol (6 mL) was added 3-{[2-(dimethylamino)ethyl]oxy}aniline (0.06 g) and 3 drops of concentrated hydrochloric acid. The reaction was microwaved in a sealed tube at 180° C. for 10 min. The isopropanol was removed by rotovaporation and the residue was treated with sat. NaHCO3 (5 mL), extracted with EtOAc (2×5 mL), and dried (Na2SO4). Concentration and purification with column chromatography afforded the title compound as a white solid (0.09 g, 70% yield). 1H NMR (400 MHz, CDCl3) 8 ppm 2.22 (s, 6H), 2.63 (t, J=5.6 Hz, 2H), 391 (t, J=5.6 Hz, 2H), 6.48 (dd, J=8.0, 1.7 Hz, 1H), 6.77 (td, J=7.2, 4.9 Hz, 1H), 6.82-6.85 (m, 1H), 6.86 (s, 1H), 6.89-6.94 (m, 3H), 7.00-7.07 (m, 1H), 7.21-7.32 (m, 4H), 7.43 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.90 (s, 1H), 8.33 (d, J=6.8 Hz, 1H), 8.35-8.38 (m, 1H), 8.45 (s, 1H); ESIMS (M+H)+=624.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[CH2:19]([NH2:22])[C:20]#[CH:21]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:22][C:19]#[C:20][CH3:21])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccccn1
Reactant: C#CCN
Solvent: CC#N
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1ccccn1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of the product of Step A (2.0 g; 7.03 mmoles and propargylamine (3.44 g; 62.5 mmoles) in acetonitrile (30 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 1.5 hours then stirred at ambient temperature for 42 hours. The reaction mixture was filtered and the product collected. Recrystallization from acetonitrile gave the title compound; mp 147°-148°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CC(N(C)C)=O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)ccn1
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccnc(N)c2)CC1
Temperature: 200 °C

Procedure:
A mixture of 4-chloropyridin-2-amine (400 mg, 3.1 mmol) and N-methylpiperizine (2 mL) in DMA (2 mL) was heated at 200° C. for 5 min in a microwave reactor. LCMS analysis indicated completion of the reaction. The reaction mixture was partitioned between EtOAc and brine, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude 4-(4-methylpiperazin-1-yl)pyridin-2-amine as a brown solid (350 mg). LCMS (ESI) m/z 193 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[CH:6][C:5]=1[OH:17])([CH3:3])[CH3:2].Br[CH2:19][C:20]#[N:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[N:13]=[CH:14][S:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH2:19][C:20]#[N:21])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(O)cc1-c1cscn1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)C)c(OCC#N)cc1-c1cscn1
Yield: 72 %

Procedure:
The crude 2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenol from step 4 and bromoacetonitrile (0.33 g, 2.72 mmol) together with K2CO3 (0.94 g, 6.81 mmol) in anhydrous actonitrile (30 ml) was heated at 60° C. for 3 hrs. The reaction mixture was partitioned between EtOAc and water. The combined organic extract was dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (10 to 20%% EtOAc in Hexanes) gave (2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy)-acetonitrile (0.47 g, 72%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CC(C)=O>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CC(C)=CCBr
Reactant: Sc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)=CCSc1ccc(Br)cc1

Procedure:
A mixture of 12.8 g (67.7 mmol) of 4-bromothiophenol (Compound 40) and 2.7 g (67.7 mmol) of sodium hydroxide in 50 ml acetone was heated at reflux under argon for 2.5 hours. The refluxing mixture was then treated dropwise with a solution of 10.0 g (67.1 mmol) of 4-bromo-2-methyl-2-butene (Compound 45) in 10 ml acetone and the mixture heated at reflux for a further 24 hours. The mixture was then cooled and solvent removed in-vacuo. The residue was treated with 50 ml water and extracted with 3×75 ml ether. The ether extracts were combined and washed successively with 3×30 ml of 5% NaOH, 50 ml of water and 50 ml of saturated NaCl and then dried (MgSO4). Solvent was then removed in-vacuo and the residual oil purified by kugelrohr distillation (70 degrees C., 0.1 mm) to give the title compound as a colourless oil. PMR (CDCl3 ): & 1.58 (3H, s), 1.70 (3H, s) 3.5 (2H, d, J-7.0 Hz), 5.27 (1H, t, J-7.0 Hz), 7.17 (2H, d, J-8.3 Hz), 7.36 (2H, d, J-8.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:34][CH3:35])[CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([O:34][CH3:35])[CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: COC1(c2ccc(I)cc2)CCCOCC1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(C2(OC)CCCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 85.6 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (46 mg) was reacted with 4-(4-iodophenyl)-4-methoxyoxepane (60 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxyoxepan-4-yl)phenyl]pent-4-enoic acid methyl ester (66 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:38]=[C:11]3[N:12]=[C:13]([CH3:37])[C:14]([C@H:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[C:15]([N:16]4[CH2:21][CH2:20][C:19](/[CH:23]=[CH:24]/[CH:25]=[CH2:26])([CH3:22])[CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44](B(O)O)[CH:45]=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>[CH:23](/[C:19]1([CH3:22])[CH2:18][CH2:17][N:16]([C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([C:42]5[CH:41]=[C:40]([Cl:39])[CH:45]=[CH:44][C:43]=5[OH:49])[CH:7]=[CH:6][CH:5]=4)[CH:38]=[C:11]3[N:12]=[C:13]([CH3:37])[C:14]=2[C@H:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:21][CH2:20]1)=[CH:24]\[CH:25]=[CH2:26]
Reactant: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: OB(O)c1cc(Cl)ccc1O
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: O
Solvent: C1COCCO1
Product: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5O)c4)nn23)CC1
Temperature: 90 °C
Yield: 73.9 %

Procedure:
To a microwave tube was added (S,E)-methyl 2-(2-(3-bromophenyl)-7-(4-(buta-1,3-dien-1-yl)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.172 mmol), (5-chloro-2-hydroxyphenyl)boronic acid (44.5 mg, 0.258 mmol), and 2.0 M aqueous K2CO3 (0.086 mL, 0.172 mmol) in dioxane (2 mL) and water (0.5 mL). The reaction was sparged with nitrogen for 1 minutes, treated Pd(PPh3)4 (19.87 mg, 0.017 mmol) then sparged for 1 min. The reaction tube was sealed and then heated at 90° C. in a microwave tube for 1 h. LCMS analysis showed 40% completion. Additional 10 mg of Pd(PPh3)4 added and heated at 90° C. for another 2 h. The reaction was concentrated, diluted with water (15 mL) and extracted wtih EtOAc. The EtOAc layer was washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by biotage (0%-40% EtOAc in hexanes) to isolate 80 mg (74%) of the product as off-white foam. 1H NMR (500 MHz, CDCl3) δ 8.09 (br. s., 1H), 8.06 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.50-7.45 (m, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 6.39 (dt, J=16.9, 10.2 Hz, 1H), 6.17 (dd, J=15.4, 10.4 Hz, 1H), 6.07 (s, 1H), 5.88 (d, J=15.3 Hz, 1H), 5.33 (br. s., 1H), 5.19 (d, J=17.2 Hz, 1H), 5.04 (d, J=9.6 Hz, 1H), 4.50-2.50 (m, 4 H), 3.75 (s, 3H), 2.64 (s, 3H), 1.93 (d, J=12.9 Hz, 1H), 1.87-1.73 (m, 2H), 1.67 (br. s., 1H), 1.29-1.24 (m, 12H). LCMS (M+1)=629.08.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[O:27]=[C:28]=[N:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C>C1COCC1>[C:18]1([C:17]([NH:16][CH:12]2[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:15][N:14]([C:28]([NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:27])[CH2:13]2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Reactant: COC(=O)CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg (0.19 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 2.5 ml of THF, and 22 mg (0.19 mmol) of methyl N-(oxomethylidene)glycinate and 29 μl (0.21 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 76 mg (82% of theory)
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:17][CH:16]=[N:15][CH:14]=1>ClCCl>[O:17]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[OH:6])=[CH:14][N:15]=[CH:16]1
Reactant: COc1ccccc1-c1cnco1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1cnco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol), tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate (10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6 hours. The solvent is removed under reduced pressure and the residue poured into ice-water (800 ml). The precipitate is collected by filtration, washed with water, and dried in vacuo to give 9.05 g of 5-(2-methoxyphenyl)oxazole (70%). Boron tribromide (1M in dichloromethane, 36 ml) is added slowly to a cold solution (0° C.) of the above oxazole (3.0 g, 17.1 mmol) in dichloromethane (215 ml). After stirring overnight at room temperature, ice-water (50 ml) is added carefully. The aqueous layer is extracted with dichloromethane (50 ml), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The precipitate which formed after addition of dichloromethane (70 ml) is collected by filtration, heated with dichloromethane (15 ml), and filtered again to give 3.16 g of 2-(5-oxazolyl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 400 mg of the title epoxide (9.5%).
Reaction SMILES: [C:1](Cl)(=O)C.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])=[O:12]>CO>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([O:13][CH3:1])=[O:12]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cnccn1
Solvent: CO
Product: COC(=O)c1cnccn1
Reaction time: 8 h

Procedure:
Acetyl chloride (50 ml) was added very slowly to methanol (500 ml), and the mixture was allowed to cool before pyrazine-2-carboxylic acid (15 g, 124 mmol) in methanol (15 ml) was added. The reaction mixture was left to stand at room temperature overnight. The methanol was removed in vacuo to give the required product (22 g). 1H NMR (250 MHz, DMSO) δ 3.95 (3H, s), 8.82 (1H, m), 8.90 (1H, d, J=2.5 Hz), 9.21 (1H, d, J=2.5 Hz); MS (ES+) m/e 153 [MH+].
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:29])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N3CCCC3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1csc(N2CC(O)C2)n1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (775 mg, 1.58 mmol) (obtained as described in Reference Example 26(1)) in anhydrous tetrahydrofuran (30 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (2.01 ml, 2.01 mmol) in an ice bath, and then the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (20:1) as the eluant to afford 3-hydroxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (290 mg, yield 72%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:43])[C:12](=[O:42])[C:13]([CH3:41])=[C:14]2[C:19]=1[C:18](=[O:20])[N:17](CC1C=CC(OC)=CC=1)[C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=1.[Cl-].[Al+3].[Cl-].[Cl-].CO>C1(OC)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:43])[C:12](=[O:42])[C:13]([CH3:41])=[C:14]2[C:19]=1[C:18](=[O:20])[NH:17][C:16](=[O:30])[N:15]2[C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(NC(C)=O)c3)c2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CO
Product: CC(=O)Nc1cccc(-n2c(=O)[nH]c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Yield: 78.1 %

Procedure:
To a suspension of N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 88 (960 mg) in anisole (10.0 ml) was added aluminum chloride (1.94 g) with stirring in a water bath. The mixture was stirred at room temperature for 37 hrs, methanol (12.0 ml) was added dropwise, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (12.0 ml), and 2N hydrochloric acid (20.0 ml) was added dropwise with stirring in a water bath. The mixture was stirred at room temperature for 1 hr, hexane (10.0 ml) was added, and the mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed with hexane, water and methanol, and dried to give N-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 89 (620 mg, yield 78.1%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1Cc2ccccc2C1
Product: c1ccc2c(c1)CC(Nc1nc3ccccc3[nH]1)C2

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2-aminoindane by Procedure A (15 min at 150° C.). The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 246-249° C.). MS(ES+) m/z 250 ([M+1]+, 100). 1NMR (DMSO-d6) δ 2.91 (dd, 2H), 3.29 (dd, 2H), 4.35 (m, 1H), 6.80-6.92 (m, 3H), 7.10-7.17 (m, 4H), 7.22-7.25 (m, 2H), 10.60 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[CH2:29][NH2:30].[CH:31](OCC)=[O:32]>>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]=[CH:4][C:3]=1[CH2:29][NH:30][CH:31]=[O:32]
Reactant: CCOC=O
Reactant: NCc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Product: Nc1c(CNC=O)cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A suspension of {5-amino-1-[2-(trityloxy)ethyl]pyrazol-4-yl}methylamine (19.7 g, 49.4 mmol) in ethyl formate (500 ml) was stirred at 50° C. for 3 hours. After evaporation of the solvent in vacuo, the residue was triturated with diisopropyl ether to give N-{5-amino-1-[2-(trityloxy)ethyl]pyrazol-4-yl}methylformamide (7.99 g) as a solid.