Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[N:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:16]3=[O:26])=[CH:10][CH:9]=2)[CH:7]=[N:6][N:5]=[N:4]1.CCN(C(C)C)C(C)C.Cl[C:37]1[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=1.O>CN(C=O)C>[N:3]1([C:8]2[N:13]=[CH:12][C:11]([O:14][CH:15]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:21][CH2:22][N:23]([C:37]5[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=5)[CH2:24][CH2:25]4)[C:16]3=[O:26])=[CH:10][CH:9]=2)[CH:7]=[N:6][N:5]=[N:4]1
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C1C(Oc2ccc(-n3cnnn3)nc2)CCN1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(N3CCC(Oc4ccc(-n5cnnn5)nc4)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
To a solution of 3-(6-(1H-tetrazol-1-yl)pyridin-3-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one bishydrochloride salt (101 mg, 0.25 mmol) and DIEA (0.30 mL, 1.75 mmol) in DMF (3 mL) was added 2-chloro-5-ethylpyrimidine (71 mg, 0.50 mmol). The reaction was heated at 100° C. for 6 hours. The reaction was cooled to ambient temperature and diluted by the addition of water (5 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The material was purified by silica gel chromatography eluting with a gradient of 2:1 hexanes/EtOAc up to 100% EtOAc to yield 3-(6-(1H-tetrazol-1-yl)pyridin-3-yloxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (52 mg, 48%) as an off white solid. Mass spectrum (apci) m/z=383.2 (M-N3CH+3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[CH2:13][N:14]1[CH:19]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:17][CH2:16][CH:15]1[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1.[Li+].[BH4-]>C1COCC1.[OH-].[Na+]>[CH3:26][C:25]1[C:20]([CH:19]2[CH2:18][CH2:17][CH2:16][CH:15]([C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)[N:14]2[CH2:13][C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][CH3:12])=[CH:9][C:4]=2[CH2:3][OH:2])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(C(=O)OC)c1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(CO)c1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
To a solution of 2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-5-methoxymethyl-benzoic acid methyl ester (0.191 g, 0.42 mmol) in THF (8 mL) was added LiBH4 (89 mg, 4.07 mmol) and the mixture was heated to reflux for 3 hours then cooled to room temperature. The mixture was diluted with 1.0 N NaOH (5 mL) and extracted with CH2Cl2 (5×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 20:1:1 CH2Cl2—CH3OH—NH4OH) gave 153 mg (83%) of [2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-5-methoxymethyl-phenyl]-methanol as a white solid. 1H NMR (CDCl3) δ 1.61-1.73 (m, 3H), 2.02-2.14 (m, 1H), 2.29-2.42 (m, 2H), 2.50 (s, 6H), 3.19 (s, 3H), 3.65 (s, 2H), 4.03 (d, 2H, J=10.8 Hz), 4.17 (s, 2H), 4.35 (s, 2H), 5.09 (br s, 1H), 6.63 (d, 1H, J=7.5 Hz), 6.74 (d, 1H, J=7.5 Hz), 6.82-6.86 (m, 3H), 7.23 (d, 2H, J=7.2 Hz), 8.22 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 19.44, 25.66, 30.06, 54.39, 57.89, 62.89, 67.47, 74.45, 122.08, 126.07, 128.95, 129.20, 131.76, 136.26, 138.42, 139.05, 146.82, 160.11; ES-MS m/z 432 (M+H). Anal. Calcd. For C27H33N3O2.0.6H2O: C, 73.31; H, 7.79; N, 9.50. Found: C, 73.20; H, 7.60; N, 9.36.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:25][CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]([OH:16])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 105.9 %

Procedure:
To a solution of tert-butyl 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoate (example 194a, 0.47 g, 1.09 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3.73 g, 2.52 ml, 32.8 mmol) and the reaction mixture was stirred at room temperature for 14 hours. Volatiles were removed in vacuo and the residue was dissolved in toluene followed by evaporation to dryness. The procedure was repeated twice to yield the title compound (432 mg) as a crude solid which was used without any purification. MS (ESI, m/z): 373.5 (M−H+).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[Ca+2].[N+]([O-])([O-])=O.[NH2:10][CH:11]([P:15]([OH:18])([OH:17])=[O:16])[C:12]([OH:14])=[O:13]>>[OH2:2].[NH2:10][CH:11]([P:15]([OH:18])([OH:17])=[O:16])[C:12]([OH:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Agent: NC(C(=O)O)P(=O)(O)O
Agent: [Ca+2]
Product: O

Procedure:
50 mls. of the calcium nitrate solution are placed in a 120 g glass bottle fitted with a screw cap. To this solution is added that volume of solution (c) required to produce a concentration of 2-amino-phosphonoacetic acid monohydrate of 5 ppm, 7.5 ppm or 10 ppm, respectively, in the final volume (100 ml) of test solution (e.g. 1.0 ml of 0.1% of solution (c) produce a concentration of 10 ppm of 2-amino-phosphonoacetic acid monohydrate in the test solution). 50 ml of solution (b) are added and the mixture is shaken. The test solution is stored in a constant temperature bath, maintained at 25° C., for 24 hours.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:3]#[CH:4].C[O:18][C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O.CC([O-])=O.[Na+]>CCCCCCC>[CH3:15][C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][C@H:2]([CH2:3][CH2:4][CH2:20][C:19]([CH3:21])=[O:18])[CH3:1]
Reactant: C#CC(C)(O)CCC=C(C)CCC=C(C)C
Reactant: C=C(C)OC
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCCCCCC
Product: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
44.1 g 3,7,11-trimethyl-6,10-dodecadien-1-in-3-ol, 50.5 g isopropenyl methyl ether and 80 mL n-heptane were initially introduced into a 500 ml flask. 29 mg methanesulfonic acid were added, while stirring. The reaction mixture was stirred under reflux for 6 hours. After the end of the reaction, the mixture was cooled to room temperature, neutralized with 2.5 ml methanolic NaOAc solution (10 g/1) and evaporated. The residue was hydrogenated in 2-propanol with 10% Pd/A-charcoal. Phytone was obtained in a yield of 76%.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC.[CH2:36]([O:43][C@H:44]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:47]([CH2:57][O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:46][CH:45]1Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC#N>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:45]3[O:46][C@H:47]([CH2:57][O:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C@@H:48]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C@@H:44]3[O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:6]=2[N:7]=1
Reactant: BrC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Nc1nc(Cl)c2ccnc-2[nH]1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-amino-4-chloro-1H-pyrrolo[2,3-d]pyrimidine [Liebigs Ann. Chem.1:137 (1983)] (3.03 g, 18 mmol) in anhydrous MeCN (240 mL), powdered KOH (85%; 4.2 g, 60 mmol) and tris[2-(2-methoxyethoxy)-ethyl]amine (0.66 mL, 2.1 mmol) were added and the mixture was stirred at room temperature for 10 min. Then a solution of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide [prepared from corresponding 1-O-p-nitrobenzoate (11.43 g, 20.1 mmol) according to Seela et al., J. Org. Chem. (1982), 47, 226] in MeCN (10 mL) was added and stirring continued for another 40 min. Solid was filtered off, washed with MeCN (2×25 mL) and combined filtrate evaporated. The residue was purified on a silica gel column with a solvent system of hexanes/EtOAc:7/1, 6/1 and 5/1. Two main zones were separated. From the more rapidly migrating zone was isolated the α anomer (0.74 g) and from the slower migrating zone the desired β anomer (4.01 g).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:28]1[CH:37]=[N:36][C:35]2[NH:34][C:33](=[O:38])[C:32]([CH3:40])([CH3:39])[O:31][C:30]=2[CH:29]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:39][C:32]1([CH3:40])[O:31][C:30]2[CH:29]=[C:28](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]3[O:9][C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[C:12]=3[CH3:13])=[O:6])[CH:37]=[N:36][C:35]=2[NH:34][C:33]1=[O:38]
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: CC1(C)Oc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OC(C)(C)C(=O)N3)oc2ccccc12
Yield: 44.6 %

Procedure:
A solution of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.231 g, 1.01 mmol) in propionitrile (4 mL) and DMF (0.8 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.28 mL, 1.64 mmol) and 7-bromo-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.200 g, 0.775 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.017 g, 0.078 mmol) and P(o-tol)3 (0.047 g, 0.15 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with H2O (100 mL). The resulting solids were collected by filtration and washed with Et2O (50 mL). Residual palladium was removed by silica gel plug (silica gel, 95:5, CH2Cl2/MeOH) the resulting solution concentrated to reveal a light orange solid. The solid was triturated with Et2O and dried to give the title compound (0.14 g, 46%) as a light pink solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.20-8.19 (m, 1H), 7.97-7.93 (m, 1H), 7.57-7.48 (m, 3H), 7.28-7.23 (m, 3H), 5.00-4.78 (m, 2H), 3.17-2.92 (m, 3H), 2.62 (s, 3H), 1.44 (m, 6H); MS (ESI) m/e 406 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1.[OH-].[Na+].S(Cl)(Cl)=O>C(O)CCC>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:14][CH2:3][CH2:4][CH3:5])=[O:15])[N:2]=1
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O=S(Cl)Cl
Product: CCCCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Yield: 134.2 %

Procedure:
Compound 17 (2.1 g, 10 mmol), NaOH (0.8 g, 20 mmol), n-butanol (100 ml) and thionyl chloride (5 ml) were added into a 250 ml round-bottom flask. The mixture was refluxed for 6 h. Excessive n-butanol was then removed in reduced pressure. The residues were dissolved in water followed by the addition of ethyl acetate. While being stirred, the mixture was adjusted to pH 8 with NaHCO3 solution. The organic layer was isolated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, decolorized with activated carbon and concentrated in vacuum. The residues were dissolved in ethyl acetate, and purified by silica gel column chromatography with ethyl acetate as the eluent, the recrystallized with ethyl ether/petroleum ether (2:5) to afford white needle crystals (1.8 g, 67%), and mp 211-212° C. (reference [1]: 210-211° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:18]=2)[C:13]1=[O:30].C(N(CC)CC)C.[N:38]1([CH2:44][C:45]#[CH:46])[CH2:43]COC[CH2:39]1>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:39][N:38]([CH3:43])[CH2:44][CH2:45][CH2:46][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:13]2=[O:30])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2=O)c1
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(CCCN(C)C)cc3c2=O)c1
Temperature: 80 °C
Yield: 86.9 %

Procedure:
A mixture of the methyl 4-methyl-3-[1-oxo-7-{[(trifluoromethyl)sulfonyl]oxy} isoquinolin-2(1H)-yl]benzoate (400 mg), PdCl2(PPh3)2 (16 mg), CuI (9 mg) and triethylamine (632 μl) were stirred in acetonitrile (10 ml) for 10 minutes. 3-(4-morpholinyl)-1-propyne (114 mg) in acetonitrile (4 ml) was then added dropwise and the reaction was heated at 80° C. for 18 hours and then concentrated. The residue was dissolved in ethyl acetate, washed with water (×3), brine, dried (magnesium sulfate) and concentrated to a brown oil. The oil was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to yield methyl 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoate as a brown oil (298 mg); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.55 (m, 4H), 3.57 (s, 2H), 3.63 (m, 4H), 3.87 (s, 3H), 6.78 (d, 1H), 7.42 (d, 1H), 7.60 (d, 1H), 7.79 (m, 2H), 7.86 (s, 1H), 7.99 (d, 1H), 8.24 (s, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([C:14]1([CH2:20][OH:21])[CH2:18][O:17][C:16](=[O:19])[NH:15]1)[CH3:13].Cl>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:12]([C:14]1([CH2:20][O:21][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH2:18][O:17][C:16](=[O:19])[NH:15]1)[CH3:13]
Reactant: CCC1(CO)COC(=O)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC(=O)N1
Temperature: 0 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
Tosyl chloride (142.2 g, Aldrich) was added to an ice-chilled solution of the product from step (a) (102.7 g) dissolved in pyridine (175 ml. Aldrich). The reaction mixture was stirred at ice bath temperature for six hours, then allowed to come to room temperature. The heterogeneous mixture was added to 1500 ml of a solution of brine and 1N HCl. stirred until solids appeared, filtered and washed with diethyl ether to give 194.6 g of a beige solid as the title product. 1H NMR consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].Cl[CH2:15][O:16][CH3:17].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:15][O:16][CH3:17])[CH:5]=[O:6]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(C=O)cc1C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
A solution of 9.0 g of 3,5-dimethyl-4-hydroxybenzaldehyde in 20 ml of dimethylformamide was added dropwise and whilst ice-cooling to a suspension of 3.14 g of a 55% w/w dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture was then stirred for 20 minutes, after which 5.8 g of methyl chloromethyl ether were added, whilst ice-cooling. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to give 11.0 g of the title compound.
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[NH:11][C:10](=[O:12])[N:9]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[N:7]=1>[OH-].[Pd+2].[OH-].O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[N:7]=[CH:6][NH:11][C:10](=[O:12])[N:9]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc(Cl)[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
An acetic acid (15 mL)-water (35 mL) mixed solution of 6-chloro-4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (1.00 g, 3.23 mmol) synthesized in Reference Synthesis Example 2 and palladium hydroxide-activated carbon catalyst (100 mg) was stirred under hydrogen atmosphere at room temperature for 3 days. After completion of the reaction, the reaction solution was filtered with Celite and the filtered residue was washed with methanol, followed by concentrating the obtained solution under reduced pressure. Toluene was added to the residue and the mixture was azeotropically dehydrated four times. The obtained residue was dried under reduced pressure to obtain the title compound (876 mg, yield 99%).
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[O:13]([CH2:31][CH2:32][N:33]([CH3:55])[C:34]([C:36]1[O:37][C:38]2[C:44](F)=[C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:42]([CH3:52])=[C:41]([C:53]#[N:54])[C:39]=2[N:40]=1)=[O:35])[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl-].[Na+].O>[C:53]([C:41]1[C:39]2[N:40]=[C:36]([C:34]([N:33]([CH2:32][CH2:31][OH:13])[CH3:55])=[O:35])[O:37][C:38]=2[C:44]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42]=1[CH3:52])#[N:54]
Reactant: CN(C)[C@@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)CCO)nc2c1C#N
Reaction time: 0.33 h
Yield: 41.6 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3R)-3-(dimethylamino)pyrrolidine (76 μl, 598 μmol) was added at 150° C. to a dimethyl sulfoxide (9 ml) solution of N-[2-(tert-butyldiphenylsiloxy)ethyl]-4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-124) (295 mg, 499 μmol) and triethylamine (90 μl, 649 μmol), followed by stirring at the same temperature for 20 minutes. After pooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave the entitled compound (93 mg, 42%) as an amorphous substance.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[C:1](=[O:11])[NH:5][C:4]2=[O:6])([O-:19])=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
In a dried 50 mL two necked round-bottom flask equipped with an addition funnel and CaCl2 drying tube was placed 2.0 g (13.6 mmol) of phthalimide. The flask was then cooled to 0° C. in a salt and ice bath. An ice cold mixture of concentrated sulfuric acid and fuming nitric acid (1:1 v/v) 8 mL was gradually added with constant stirring. The mixture was then stirred for 30 min. at 0° C. and allowed to slowly warm to room temperature with stirring over a period of 1 h. The reaction mixture was then poured into ice. The resulting solid product was filtered and dried to give 1.6 g (61.3%) of 5-nitro-1H-isoindole-1,3(2H)-dione as a yellow colour solid.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1N.[C:9]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[F:22])[C@H:15]([OH:23])[CH2:14][C@@H:13]1[CH3:24])(=[O:11])[CH3:10]>>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[F:22])[C@H:15]([O:23][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=2)[CH2:14][C@@H:13]1[CH3:24])(=[O:11])[CH3:10]
Reactant: Nc1ccccc1F
Reactant: CC(=O)N1c2c(F)cccc2[C@H](O)C[C@@H]1C
Product: CC(=O)N1c2c(F)cccc2[C@H](Oc2ccccc2)C[C@@H]1C
Yield: 39 %

Procedure:
Cis-1-acetyl-8-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline was obtained in the same manner as in Example 17, using 2-fluoroaniline. A compound was produced in the same manner as in Example 1, using 100 mg of cis-1-acetyl-8-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydro quinoline, and thus 52 mg (39%) of the title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:10])([CH3:9])[C:7](=[O:11])[NH:6][C:5]1=[O:12].CO.C(N(CC)C(C)C)(C)C.[CH2:24]([C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][N:39]=[C:38](Cl)[N:37]=2)=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(O)C>[CH2:24]([C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([NH:1][CH2:2][CH2:3][N:4]3[C:8]([CH3:9])([CH3:10])[C:7](=[O:11])[NH:6][C:5]3=[O:12])[N:37]=2)=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: Clc1nccc(-c2ccc(Cc3ccccc3)s2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(Cc3ccccc3)s2)n1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A 10% (w/v) solution of 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione in MeOH (0.93 mL, 0.54 mmol) was added to a 5 mL microwave vessel. The MeOH was evaporated with a stream of N2 to leave an oily solid which was dissolved in 94 μl (0.54 mmol) of N,N-diisopropylethylamine and 2 mL of iPrOH, to which was added 0.15 g (0.54 mmol) of 4-(5-benzylthiophen-2-yl)-2-chloropyrimidine. The reaction solution was heated in a microwave to 170° C. for 20 min and then allowed to stand at rt for 2 h to give a precipitate which was collected by filtration and purified by C-8 prep HPLC to give the title compound. MS (M+H)+ 422.