Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:12]=1[C:13](O)=O>>[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Nc1cccnc1N
Reactant: COc1ccc(NS(C)(=O)=O)cc1C(=O)O
Product: COc1ccc(NS(C)(=O)=O)cc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 14 from 2,3-diaminopyridine and 2-methoxy-5-methanesulfonylamino-benzoic acid,
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:53]([C:55]1[CH:60]=[CH:59][C:58]([S:61]([NH2:64])(=[O:63])=[O:62])=[CH:57][CH:56]=1)#[N:54]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([NH:64][S:61]([C:58]3[CH:57]=[CH:56][C:55]([C:53]#[N:54])=[CH:60][CH:59]=3)(=[O:62])=[O:63])=[O:18])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)NS(=O)(=O)c2ccc(C#N)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 48 h

Procedure:
A mixture of [6-(4-cyanophenyl)-5-(2-furoyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phen-yl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (Example 29A) (75 mg, 0.14 mmol), 1,3-dicyclohexyl-carbodiimide (33 mg, 0.16 mmol), 4-cyanobenzene-1-sulfonamide (30 mg, 0.16 mmol) and 4-dimethylaminopyridine (20 mg, 0.16 mol) in dichloromethane (4 ml) is stirred for 48 hours. The product is extracted with dichloromethane, washed with 2 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC(RP18 column; eluent: acetonitrile/water 10:90→90:10).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].Cl.[Br:17][CH2:18][CH2:19]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:19][CH2:18][Br:17])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: OCCBr
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Agent: Cl
Product: O=C(O)c1cc(OCCBr)c2ccccc2c1O
Reaction time: 2 h
Yield: 50 %

Procedure:
To 150 ml of 2-bromoethanol, 60 g (0.3 mol) of 1,4-dihydroxy-2-naphthoic acid was added, and the reaction was carried out at 90° C. with stirring for 2 hours while introducing hydrogen chloride gas. After being cooled (10°-20° C.), precipitated crystals were separated by filtration to obtain 47.4 g (50% yield) of 1-hydroxy-4-(β-bromoethoxy)-2-naphthoic acid.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[F:19][CH:20]([F:30])[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH:20]([F:30])[F:19])=[CH:29][CH:28]=1)=[O:3]
Reactant: OCc1ccc(OC(F)F)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1ccc(OC(F)F)cc1
Product: Cl

Procedure:
4-Difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 4-difluoromethoxybenzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a white solid (0.202 g, 58% overall); (Found: C, 51.4; H, 6.2; N, 8.0%. C15H20F2N2O3.HCl requires C, 51.4; H, 6.0; N, 8.0%); δH (400 MHz, DMSO-d6) 9.87 (2H, br), 7.44 (2H, d, J 8.8 Hz), 7.24 (1H, t, J 74 Hz), 7.19 (2H, d, J 8.8 Hz), 5.11 (2H, s), 4.32 (2H, m), 3.14 (2H, d, J 13.2 Hz), 3.06 (2H, dd, J 5.2 and 13.2 Hz), and 1.31 (6H, d, J 7.2 Hz).
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:25].[CH2:26](Br)[CH:27]=[CH2:28]>O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH:27]=[CH2:28]
Reactant: C=CCBr
Reactant: COCCOCCOCCOCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
An oven-dried 100 mL round bottom flask was charged with t-BuOK (13 mmol), dry THF (30 mL), purged with argon and cooled to 0° C. in an ice bath. Tetraethyleneglycol monomethyl ether (10 mmol) was then added dropwise to the solution and the reaction stirred at 0° C. for 1 h under argon. Allyl bromide (13 mmol) was added dropwise, and the solution was warmed to R.T. and allowed to stir for 24 h under argon. Deionized water (2 mL) was then added and the reaction stirred for 10 min. All liquid were then removed in vacuo and the residue redissolved in ethyl acetate (50 mL). The organic was washed three times with water (20 mL), dried over Na2SO4, filtered over Celite and then concentrated in vacuo to yield clear/light yellow oil (47%). 1HNMR (400 MHz, CDCl3): δ=5.90 (m, 1H), 5.23 (dd, 1H, 3JHHtrans=17.3 Hz, 2JHHgem=1.7 Hz), 5.15 (dd, 1H, 3JHH=10.4 Hz, 2JHHgem=1.5 Hz), 4.00 (dd, 2H, 3JHH=5.89 Hz, 4JHH=1.5 Hz), 3.65 (m, 12H), 3.59 (m, 2H), 3.53 (m, 2H), 3.36 (s 3H) ppm. 13CNMR (400 MHz, CDCl3): δ=134.8, 117.0, 72.2, 71.9, 70.6, 70.6, 70.6, 70.5, 69.4, 59.0 ppm. HRMS-ESI: Calculated [M+Na]+: 271.1516. found: 271.1516.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([F:13])[F:12])(=O)=O.[N:15]1[S:19][N:18]=[C:17]2[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:16]=12.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[N:15]1[S:19][N:18]=[C:17]2[CH:20]=[C:21]([C:24]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([F:13])[F:12])=[O:25])[CH:22]=[CH:23][C:16]=12
Reactant: O=C(O)c1ccc2nsnc2c1
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCOC(=O)c1ccc2nsnc2c1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To 30 ml of ethanol was dissolved 2.0 g (10 mmol) of methyl benzo[1,2,5]thiadiazole-5-carboxylate, followed by the addition of 3.3 g of a 25% aqueous solution of sodium hydroxide and stirring at room temperature for 3 hours. To the reaction liquid was added 50 ml of water and a dilute hydrochloric acid to make pH of 2. Crystal precipitated was filtered off and dried under reduced pressure to obtain 1.7 g (yield: 92%) of benzo[1,2, 5]thiadiazole-5-carboxylic acid. In a separate reactor, 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.43 g (2.4 mmol) of benzo[1,2,5]thiadiazole-5-carboxylic acid were dissolved in 7 ml of N,N-dimethylformamide, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.44 g (yield: 64%) of 6,6-difluoro-5-methyl-5-hexenyl benzo[1,2,5]thiadiazole-5-carboxylate.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]=1[CH2:21][CH3:22].[H-].[Na+].[CH3:25][C:26]1([CH3:34])[O:31][CH2:30][CH:29]([CH2:32][OH:33])[CH2:28][O:27]1>C(OCC)(=O)C>[CH3:25][C:26]1([CH3:34])[O:31][CH2:30][CH:29]([CH2:32][O:33][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]=2[CH2:21][CH3:22])[CH2:28][O:27]1
Reactant: CCc1c(Cl)ccnc1C(=O)N(C(C)C)C(C)C
Reactant: CC1(C)OCC(CO)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1c(OCC2COC(C)(C)OC2)ccnc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 36.9 %

Procedure:
To a dimethylsulfoxide (20 ml) solution of the 4-chloro-3-ethyl-N,N-diisopropylpyridine-2-carboxamide (1 g, 3.72 mmol) obtained in the step (92b) above, oily sodium hydride, in oil (195 mg, 4.46 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, the (2,2-dimethyl-1,3-dioxan-5-yl)methanol (598 mg, 4.09 mmol) obtained in Example (11a) was added and the mixture was stirred at room temperature for 16.5 hours. Ethyl acetate was added to the reaction mixture. The mixture was washed twice with a saturate saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated. The residue was washed with diethyl ether to obtain the title compound (520 mg, yield: 36.9%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:12])[CH3:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][C:27]=1[F:28])[NH:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19]>C(O)(=O)C>[NH2:13][C:14]1[CH:15]=[C:16]([NH:17][S:18]([C:21]2[C:22](=[O:23])[O:12][C:5]3[C:6]([CH:7]=2)=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][CH2:1][CH3:2])(=[O:20])=[O:19])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CCOc1cccc(C=O)c1O
Reactant: Nc1cc(NS(=O)(=O)CC(=O)O)ccc1F
Solvent: CC(=O)O
Product: CCOc1cccc2cc(S(=O)(=O)Nc3ccc(F)c(N)c3)c(=O)oc12

Procedure:
A solution of 3-ethoxysalicylaldehyde (1 mmol) and 3-amino-4-fluoroanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 160-162° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:17])[CH2:12][O:13]C(=O)C)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C1C=CC=CC=1.C=O.C(C1C=CC([C@@H](C)CO)=CC=1)(C)C>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:17])[CH2:12][OH:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC[C@@H](C)c1ccc(CC(C)C)cc1
Agent: C=O
Agent: CC(C)c1ccc([C@@H](C)CO)cc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1ccc(C(C)CO)cc1

Procedure:
The following are obtained: 590 mg of (S)-2-(4- isobutyl-phenyl)-1-acetoxy-propane, as a colorless oil with [α]D20 -7.0° (C=1, benzene), ee 98%, H-NMR (90 MHz in COCl3) (ppm): 0.9 (6H, d, CHHD 3CHCHHD 3; 1.3 (3H, d, CHHD 3CH); 1.5-2.0 (1H, m, CH3CHH3); 2.1 (3H, s, COCH3 ; 2.4 (2H, d, C6H4CHHD 2); 3.1-2.7 (1H, m, C6H4CHHD 2); 4.1 (2H, d, CH2O); 7.0 (4H, s, aromatics); and 490 mg of (R)-2-(4-isopropyl-phenyl)-propan-1-ol as a colorless oil with [α]D20 +12.8° (C=1, CHCl3), ee 97%, H-NMR (90 MHz in COCl3)δ(ppm): 0.9 (6H, d, CHHD 3CHCHHD 3); 1.3 (3H, d, CHHD 3CH), 1.7-2.2 (1H, m. CH3CHH3); 2.5 (2H, d, C6H4CH2); 2.7-3.2 (1H, m, C6H4CH); 3.7 (2H, d, CH2O); 7.0 (4H, s, C6H4).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:15]([NH2:16])=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:13][N:12]=1.O>N1C=CC=CC=1>[CH3:10][C:11]1[C:15]([NH:16][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:13][N:12]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Solvent: c1ccncc1
Solvent: O
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
205 mg of isonicotinoyl chloride*HCl were added to a solution of 200 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 2 ml of pyridine and the mixture was then stirred at RT for 12 h; water was then added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 27. C16H14N4O (278.32); MS (ESI) 279 (M+H)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=O)=[C:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=[C:32]5[NH:26][C:27](=[O:28])[NH:29][C:30]5=[O:31])=[C:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=C1CNC(=O)N1
Reactant: CN1CCN(c2ccc(Nc3ccn4ncc(C=O)c4n3)cc2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCN(c2ccc(Nc3ccn4ncc(C=C5NC(=O)NC5=O)c4n3)cc2)CC1
Temperature: 70 °C

Procedure:
To 5-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (56 mg, 0.167 mmol) in EtOH was added hydantoin (17 mg, 0.167 mmol) and piperidine (17 μL, 0.167 mmol). The mixture was heated at 70° C. Solvent was removed under reduced pressure and then the solid was redissolved in MeOH and sonicated. Insolubilities were filtered off and the filtrate was purified by HPLC to yield 5-((5-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=419)
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[N:34]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:38]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)=[O:39])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Cn1cc(C(=O)O)cn1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
A solution of 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.12 mmol) in N,N-dimethylformamide at 25° C. was treated with a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (15 mg, 0.12 mmol), O-benzotriazol-1-yl-N,N.N′N′-tetramethyluronium hexafluorophosphate (49.7 mg, 0.13 mmol), and N,N-diisopropylethylamine (62 μL, 0.36 mmol). The resulting solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in chloroform and then was washed with a 1N aqueous hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 760mesh, 5:95 methanol/dichloromethane) afforded 1-methyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (13.5 mg, 21.5%) as a tan solid: EI-HRMS m/e calcd for C28H26N7O3 (M+) 527.2081, found 527.2083.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[C:20]([C:21](=[O:32])[C:22](=[CH:28]N(C)C)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][C:18]2[C:13](=[C:14]([F:35])[C:15]([F:34])=[C:16]([F:33])[CH:17]=2)[N:12]=1>ClC(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:11]2[N:12]=[C:13]3[C:14]([F:35])=[C:15]([F:34])[C:16]([F:33])=[CH:17][C:18]3=[CH:19][C:20]=2[C:21](=[O:32])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28]1
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
5.2 g of 2,4-difluoroaniline were added, at a temperature around 20° C., to a solution of 7.7 g of ethyl 3-(2-chloro-6,7,8-trifluoro-3-quinolyl)-2-dimethylaminomethylene-3-oxopropionate in 50 cm3 of trichloromethane and the reaction mixture was left stirring at this temperature for 8 hours. The trichloromethane was concentrated under reduced pressure (20 kPa) at a temperature around 40° C. 120 cm3 of ethanol and 4.5 cm3 of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to the mixture, which was heated at a temperature around 80° C. for approximately 1 hour. After cooling to a temperature around 10° C., the product was filtered off and washed 2 times with 50 cm3 of ethanol and 2 times with 50 cm3 of isopropyl ether. 5 g of ethyl 1-(2,4-difluorophenyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at about 304-306° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:14]([NH2:20])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27](O)=O.CO.C(Cl)Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]4[C:14](=[CH:15][C:16]=32)[N:20]=[C:26]([CH3:27])[N:21]4[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CNc1cc2c(cc1N)C1CC2CN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cc1nc2cc3c(cc2n1CC(C)C)C1CC3CN(C(=O)OC(C)(C)C)C1

Procedure:
4-Amino-5-isobutylamino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (250 mg, 0.74 mmol) from Example 19B was dissolved in ethanol (10 mL) and HOAc (2 mL) and treated with 1-ethoxyethylenemalononitrile (118 mg, 0.87 mmol). The reaction proceeded as in Example 18C (18 h) and was worked up similarly to provide product (TLC 3% methanol/CH2Cl2 (NH3) Rf 0.57).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.CCCCCC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12
Reactant: N#Cc1cnc2c(oc3ccccc32)c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: N#Cc1cnc2c(oc3ccccc32)c1Cl
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2.10 g (11.0 mmol) of 4-hydroxybenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile in 15 mL of phosphorous oxychloride is heated at reflux temperature for 1.5 hours, then cooled to room temperature. Hexane is added and the solid is collected by filtration, dissolved in ethyl acetate and washed with cold 1 N NaOH. The organic layer is dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo to give 1.55 g (65%) of a red solid, mp 229–231° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:16])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(N)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 2-(4-aminophenyl)acetic acid (B−1) (10 g, 66.16 mmol) in methanol (50 mL) was added dropwise SOCl2 (5 mL). The mixture was stirred at 60° C. for 6 h. After evaporated the solvent, the residue was recrystallized with Et2O to afford the product (10.9 g, 99%) as a yellow solid. LC-MS: (M+H)+=166;
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][C:5]([NH:7]CC)=[O:6].Cl>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][C:5](=[O:6])[NH2:7].[CH2:2]([NH2:1])[CH3:3]
Reactant: CCNC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Product: CCN
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
When applied to an amino acid analyzer and a paper chromatography, the isolated substance exhibited the same behavior as a standard substance of theanine. Furthermore, hydrolysis of the isolated substance using hydrochloric acid or glutaminase yielded L-glutamine and ethylamine at a ratio of 1:1. Thus, since hydrolysis of the isolated substance by glutaminase was thus possible, ethylamine was proved to be combined with the gamma-position of L-glutamine. Furthermore, it was confirmed by L-glutamic acid dehydrogenaze (GluDH) that glutamine yielded by hydrolysis was of L-type. FIG. 4 shows infrared absorption spectrometry (IR) spectra of theanine sample and isolated substance. Both substances exhibited spectra similar to each other. Consequently, the isolated substance was proved to be theanine.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13].O.[NH2:23][NH2:24]>CCO>[NH2:2][C:1]1[NH:24][N:23]=[C:7]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: NN
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-Nitroaniline (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:13](=[N:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(CN=Cc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 g of 2,4-dimethoxybenzylamine hydrochloride is added to 100 ml of 1N sodium hydroxide solution and the mixture is extracted with 125 ml of ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and stripped of solvent to give 10.2 g of 2,4-dimethoxybenzylamine as an oil. This amine is dissolved in 150 ml of benzene; 6.47 g of benzaldehyde and 0.6 g of p-toluenesulfonic acid monohydrate are added. The mixture is heated under reflux removing water with a Dean-Stark separator and in two hours the calculated amount of water (1.1 ml) separates out. The mixture is cooled to room temperature. Upon further cooling the benzene solution deposits some precipitate. Benzene is removed under reduced pressure and 60 ml of petroleum ether is added to the residue. An oily layer separates out with more precipitate. Benzene (10 ml) is added to make the layers homogeneous and the remaining precipitate is filtered. The filtrate is stripped of solvent to give 14.2 g of the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[C:1]1([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][OH:13])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: c1ccc(-c2cc[nH]n2)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: OCn1ccc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
The mixture of 2.88 g of 3-phenyl-1H-pyrazole, 0.67 g of paraformaldehyde and 0.3 ml of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. After the mixture was filtered, hexane was added to the filterate to produce a crystal. The crystal was collected to obtain 2.64 g of 3-phenyl-1H-pyrazole-1-ylmethanol.