Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:9])[NH2:8])[CH3:6])[OH:3].C([O:21][P:22](O)([OH:24])=[O:23])[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O.P(O)(O)(O)=O.O=C(CN(C(=N)N)C)O.[P:40]([O:48][CH2:49][C@H:50]1[O:54][C@@H:53]([N:55]2[C:64]3[N:63]=[CH:62][N:61]=[C:59]([NH2:60])[C:58]=3[N:57]=[CH:56]2)[C@H:52]([OH:65])[C@@H:51]1[OH:66])([O:43][P:44]([OH:47])([OH:46])=[O:45])(=[O:42])[OH:41].C(N[C@H](C(O)=O)CS)(=O)C>>[P:40]([O:48][CH2:49][C@H:50]1[O:54][C@@H:53]([N:55]2[C:64]3[N:63]=[CH:62][N:61]=[C:59]([NH2:60])[C:58]=3[N:57]=[CH:56]2)[C@H:52]([OH:65])[C@@H:51]1[OH:66])([O:43][P:44]([O:46][P:22]([OH:24])([OH:23])=[O:21])([OH:47])=[O:45])(=[O:41])[OH:42].[O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:8])[NH2:9])[CH3:6])[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: CN(CC(=O)O)C(=N)N
Agent: O=P(O)(O)O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 37 °C

Procedure:
Numerous applications for bound or immobilized enzymes are known. The present invention is especially suited for the analysis of creatine phosphokinase (CPK). Such analysis can be carried out by preparing a single polyurethane tube having a mixture of hexokinase and glucose-6-phosphate dehydrogenase (G6PDH) bound on the interior surface thereof. With reference to the FIGURE there is described, schematically, a mechanical system for continuous analyses of a large number of serum samples. Such devices are well known, e.g., the Technicon AAII by Technicon Corp., Tarrytown, N.Y. In the FIGURE, the serum sample is placed in sample tray I, which delivers the sample through line 3 to unified pumping head 5 at a rate of 0.32 cc/min. Simultaneously a mixture of creatine phosphate, adenosine diphosphate, Mg++ and N-acetylcysteine is monitored (0.60 cc/min.) through line 7 into pumping head 5, and air is monitored through line 9 at a rate of 0.32 cc/min. N-acetylcysteine (N-Ac) is required as a CPK 15 activator. The air and CP/ADP/N-Ac/Mg++ streams are mixed in coil 11 and subsequently combined with sample stream 3. The unified stream is passed through heater bath 13 wherein the stream is heated to about 37° C. Thereafter the heated stream is passed into the upper chamber 15 of dialyzer 16. Any CPK present in the sample catalyzes reaction between the CP and ADP to produce ATP and creatine. The ADP, ATP and creatine diffuse through membrane 17 into the second chamber 19 of dialyzer 16. The second chamber of the dialyzer also contains NAD/glucose/Mg++ mixture injected into the system through line 21 (1.00 cc/min.) via pumping head 5. The NAD/glucose/Mg++ mixture is mixed with air injected via line 23 (0.32 cc/min.) through pumping head 5. The NAD/glucose Mg++ air stream procedes via line 25 into dialyzer chamber 19 and is combined with ATP from the upper chamber 15. Thereafter the unified stream is passed through line 31 through coiled tube 33 and flow cell 41. Thereafter the sample is passed through line 51 and pumping head 5 to a waste receptacle.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:9]=[N:8]1)(=O)C.C1COCC1.[Li+].[OH-].Cl>O>[CH3:19][C:14]1([CH3:20])[C:15]([CH3:17])([CH3:18])[O:16][B:12]([C:10]2[CH:9]=[N:8][N:7]([CH2:6][CH2:5][OH:4])[CH:11]=2)[O:13]1
Reactant: CC(=O)OCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 50 mL roundbottom flask was charged 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl acetate (2.11 mmol, 591 mg), a solution of 2:1 THF:H2O (15 mL), and 1N LiOH(aq) (4.82 mmol, 4.82 mL). The resulting solution was stirred at room temperature for 48 hours. At 48 hours, the reaction was quenched with 1N HCl(aq) (4.82 mmol, 4.82 mL) and the solvent removed in vacuo. The product was taken forward without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>CO>[CH2:13]([O:12][C:10]([NH:9][C@H:4]([CH2:3][NH:2][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][Cl:27])[C:5]([O:7][CH3:8])=[O:6])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@@H](CN)NC(=O)OCc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](CNC(=O)CCCCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A solution of (R)-methyl 3-amino-2-(benzyloxycarbonylamino)propanoate hydrochloride (4.0 g, 0.014 mol) in methanol (80 mL) was cooled to 0° C. To this mixture was added Et3N (3.3 g, 31 mmol), followed by 4-chlorobutanoyl chloride (2.3 g, 15.0 mmol). The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction was quenched with saturated brine (200 mL), the organic layer extracted with CH2Cl2, washed with 1N HCl, saturated brine, dried over MgSO4 and concentrated to give crude (R)-methyl 2-(benzyloxycarbonylamino)-3-(4-chlorobutanamido)propanoate (5.0 g) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.45-7.35 (m, 5H) 6.01 (s, 1H), 5.84 (d, 1H), 5.11 (d, 2H), 4.42 (t, 5H), 3.68-3.50 (m, 6H), 2.32 (t, 2H), 2.08 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][C@H:22]([CH2:26][OH:27])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:35]1[CH2:39][CH2:38][CH2:37][C@@H:36]1[C:40](O)=[O:41])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:40]([C@H:36]4[CH2:37][CH2:38][CH2:39][NH:35]4)=[O:41])[C@H:22]([CH2:26][OH:27])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN[C@H](CO)C3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a stirred solution of the ((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)piperazin-2-yl)methanol (0.072 g, 0.18 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.078 g, 0.36 mmol) in dichloromethane (2.0 mL) was added HATU (0.14 g, 0.36 mmol) and iPr2NEt (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 30 min, and was then diluted with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 30-100% ethyl acetate in hexanes) to afford the desired product (0.072 g, 0.12 mmol, 30% for 2 steps).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[OH-].[Na+]>CCOCC.O>[O:12]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCCCN
Reactant: O=C1CCC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butylamine (9.05 g, 0.1225 mole) was dissolved in Et2O (30 ml). Succinic anhydride (5 g, finely powdered) was added portionwise. After addition was complete, the heterogeneous mixture was stirred 1 hour at room temperature. The reaction mixture was then poured into 10% NaOH in H2O (10 ml) and Et2O (30 ml). The layers were separated and the ether layer was extracted with additional 10% NaOH (10 ml). The combined aqueous layers were washed with ether (30 ml) and acidified with concentrated HCl to give a layer of oil above the water layer. This was extracted with Et2O (50 ml×2). The ether extracts were washed with saturated NaCl solution (3×30 ml) and dried (MgSO4). The solvent was removed in vacuo to give a white solid (7.5 g) which was recrystallized from benzene to give title acid as needle shaped crystals (4.83 g, 56%), m.p. 93.5°-94.5° C.
Reaction SMILES: [C:1]1(=[CH:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:10]([CH3:13])([O-:12])=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:10]([CH2:13][C:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:12])=[O:11]
Reactant: N#CC=C1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 70.7 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C([O:9][C:10](=O)[CH:11]([Cl:15])[C:12](=O)[CH3:13])C.C(O)(=O)C>CCO>[Cl:15][C:11]1[C:12]([CH3:13])=[N:1][C:2]2[N:3]([N:4]=[CH:5][CH:6]=2)[C:10]=1[OH:9]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccnn2c(O)c1Cl
Temperature: 120 °C
Yield: 93.7 %

Procedure:
A mixture of 3-aminopyrazole (10.0 g, 120.3 mmol), 2-chloro-3-oxo-butyric acid ethyl ester (16.7 mL, 120.3 mmol), and glacial acetic acid (103 mL) was heated to 120° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOH and concentrated. Trituration with Et2O gave 20.7 g (94%) desired product. MS APCI (+) m/z 184, 186 (M+, Cl pattern) detected; 1H NMR (400 mHz, CD3OD) δ 7.90 (d, 1H), 6.17 (d, 1H), 2.53 (s, 3H).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[C:20]3[N:21]=[CH:22][CH:23]=[C:24]([OH:25])[C:19]=3[CH:18]=[N:17]2)=[CH:13][CH:12]=1.O>CN(C=O)C>[Cl:8][C:23]1[CH:22]=[N:21][C:20]2[N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:27][CH:26]=3)[N:17]=[CH:18][C:19]=2[C:24]=1[OH:25]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc3c(O)c(Cl)cnc32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
NCS (1.57 g, 11.8 mmol) was added in one portion to a solution of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.00 g, 11.8 mmol) in DMF (30 mL) at room temperature. The mixture was stirred at 60° C. for 1 hour and then cooled to room temperature. After 18 hours, an additional lot of NCS (0.5 eq.) was added to the reaction mixture and stirred at room temperature for an additional 48 hours. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed once with water (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 2% MeOH/CH2Cl2 to provide 5-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (466 mg, 1.61 mmol, 13.7% yield). LCMS (APCI+) m/z 290 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:5]=1[C:6](=[O:15])[C:7](=[O:14])[NH:8]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(OCC)C>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:5]=1[C:6](=[O:15])[C:7](=[O:14])[N:8]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C1Nc2c(Cl)ccc(Cl)c2C1=O
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCN1C(=O)C(=O)c2c(Cl)ccc(Cl)c21
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a mixture of sodium hydride (0.17 g, 6.94 mmol, 60% dispersion in mineral oil) in anhydrous N,N-dimethylformamide (5.00 mL) was added a solution of 4,7-dichloro-1H-indole-2,3-dione (1.00 g, 4.60 mmol) in N,N-dimethylformamide (5.00 mL) at 0° C. The brown reaction mixture was stirred for 0.5 h followed by the addition of a solution of 1-bromopentane (0.84 g, 5.55 mmol) in anhydrous N,N-dimethylformamide (5.00 mL). The reaction mixture was stirred at ambient temperature for 16 h and poured into wet ethyl ether (30.0 mL). After the organic layer was separated, it was washed with water (2×20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The gummy residue was dried under vacuum and the solid was triturated with ether to give the title compound (0.98 g, 98%): MS (ES+) m/z 286.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]([OH:34])/[C:4](=[N:32]\[H])/[C:5](=[N:12]\[O:13][CH2:14][C:15]1[N:16]=[C:17]([NH:20]C(=O)OCCC2C=CC=CC=2)[S:18][CH:19]=1)/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>C(#N)C>[NH2:20][C:17]1[S:18][CH:19]=[C:15]([CH2:14][O:13]/[N:12]=[C:5](/[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)\[C:4]2[N:3]([CH2:1][CH3:2])[O:34][C:35](=[O:36])[N:32]=2)[N:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: [H]/N=C(C(=N\OCc1csc(NC(=O)OCCc2ccccc2)n1)/c1ccccc1)\N(O)CC
Solvent: CC#N
Product: CCn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
To a solution of 2-phenylethyl (4-{[({(1Z,2Z)-2-[ethyl(hydroxy)amino]-2-imino-1-phenylethylidene}amino)oxy]methyl}-1,3-thiazol-2-yl)carbamate (160 mg, 71% purity, 0.24 mmol, 1 eq.) in acetonitrile (3 ml), was added 1,1′-carbonyldiimidazole (555 mg, 0.342 mmol, 1.4 eq.). After stirring at 80° C. for 6 hour, the reaction was quenched by addition of water and extracted with EtOAc. The organics were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-ethyl-1,2,4-oxadiazol-5(2H)-one (70 mg, 55% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13]([F:16])([F:15])[F:14])[C:11]=1F)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:11]=1[N:31]1[CH2:32][CH2:33][CH2:34][N:28]([C:23]3[N:22]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:29][CH2:30]1)[N:8]([CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21]
Reactant: c1cnc(N2CCCNCC2)nc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C(F)(F)F)c21
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCN(c4ncccn4)CC3)c(C(F)(F)F)c21
Temperature: 105 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
In 12 ml of pyridine were dissolved 0.8 g (0.0026 mole) of 6,7-difluoro-8-trifluoromethyl-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid and 2.1 g (0.0118 mole) of 1-(2-pyrimidinyl)homopiperazine, the mixture was stirred at 105° C. for 3 hours, and then the solvent was removed by evaporation under reduced pressure. The residue was applied to silica gel column chromatography (eluent; a chloroform:methanol=9.5:0.5 mixed solution) to obtain 0.45 g of 6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-1-methyl-7-[4-(2-pyrimidinyl)homopiperazin-1-yl)quinoline-3-carboxylic acid as yellow powder.
Reaction SMILES: [CH3:1][C:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=1[CH3:26]>>[CH3:1][CH:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=3[CH3:26])[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCCC2)O1
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C1(CCCCC1)OC(C)N2

Procedure:
The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclohexane] and 5-bromo-4-methyl-2-thiophenecarbonitrile. A brown solid: 1H-NMR (DMSO-d6) δ 7.78 (s, 1H), 7.17 (d, 1H, J=1.8 Hz), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 6.64 (s, 1H), 6.63 (d, 1H, J=8.2 Hz), 4.74 (m, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 8H), 1.31 (d, 3H, J=5.3 Hz); MS (ESI) m/z 337 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[S:12].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[S:10][C:11](=[S:12])[NH:13][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
10 g of 4-fluorobenzaldehyde was dropwise added at room temperature to a solution having 10.8 g of rhodanine and 20 g of sodium acetate suspended in 100 ml of acetic acid. The obtained mixture was reacted under reflux for two hours and then cooled to room temperature. Then, this reaction mixture was put into about 500 ml of water, and a solid product thereby obtained was collected by filtration, washed with water and dried to obtain 16.4 g of 5-(4-fluorobenzylidene)rhodanine.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[OH:14])[N:6]2[N:5]=1)=O.[CH2:21]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[N:26]1([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([CH:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[OH:14])[N:6]4[N:5]=3)=[CH:31][CH:32]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CS(=O)c1ncc2ccc(C(O)c3ccccc3)n2n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: OC(c1ccccc1)c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Yield: 4.7 %

Procedure:
(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol (86.0 mg, 0.299 mmol), 4-(4-morpholino)aniline (107 mg, 0.598 mmol) and N,N-Diisopropylethylamine (0.156 mL, 0.898 mmol) were suspended in 1-Methoxy-2-propanol (0.750 mL, 7.67 mmol) and the reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced under nitrogen. The crude reaction mixture was purified via Gilson reverse phase chromatography to afford 5.69 mg of [2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl-methanol as a lyophilized powder. (M+H)=402.1. 1H NMR (400 MHz, DMSO, d6) δ 9.49 (s, 1H), 9.16 (s, 1H), 7.79 (d, 2H, J=7.12 Hz), 7.67 (m, 1H), 7.58 (m, 2H), 7.50 (d, 2H, J=7.89 Hz), 7.11 (m, 1H), 6.89 (m, 1H), 6.75 (d, 2H, J=8.44 Hz), 3.73 (m, 4H), 3.30 (m, 1H), 3.02 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)[N:3]=1.[CH3:27][C:28](=O)[C:29](=O)[CH3:30]>CO>[CH3:27][C:28]1[N:8]=[C:7]2[CH:6]=[CH:5][C:4]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:19])[CH2:11][CH2:10]3)=[N:3][C:2]2=[N:1][C:29]=1[CH3:30]
Reactant: CC(=O)C(C)=O
Reactant: Nc1ccc(N2CCN(CCCC(=O)c3ccc(F)cc3)CC2)nc1N
Solvent: CO
Product: Cc1nc2ccc(N3CCN(CCCC(=O)c4ccc(F)cc4)CC3)nc2nc1C

Procedure:
9 g 4-[4-(2,3-Diamino-pyridin-6-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone and 2.6 g butane-2,3-dione in 250 ml methanol are stirred under reflux for 1 hour. The solvent is evaporated. The residue is dissolved in hot ethyl acetate and treated with active charcoal, filtered and cooled to give the title compound, m.p. 155°-156°.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:13]([O:15]C)=O.[CH:17]([NH2:19])=O>>[CH3:12][O:11][C:7]1[C:6]2[C:2]3[N:1]=[CH:17][NH:19][C:13](=[O:15])[C:3]=3[S:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1sc2cccc(OC)c2c1N
Reactant: NC=O
Product: COc1cccc2sc3c(=O)[nH]cnc3c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A mixture of methyl 3-amino-4-methoxybenzothiophene-2-carboxylate (202mg, 0.85mmol) and formamide (2mL) is heated at 135 C. for 1 hr and the temperature is raised to 190 C. After 8 hr the reaction is cooled to r.t. Upon cooling, black solid forms and is collected by filtration. The precipitate is air dried to give 9-methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine (45 mg, 22.5%). 1H NMR (DMSO) δ12.0 (1H, brs), 8.31 (1H, s)7.70-7.55 (2H, m), 7.10 (1H, d, J=7.7 Hz), 3.97 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[C:18]1[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C(OC(N1C=C(C2N(C(OC(C)(C)C)=O)C3C=C(NC4C=CC(C(=O)N(C)C)=CC=4)N=CC=3C=2)C=N1)=O)(C)(C)C>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]3[CH:15]=[C:14]([NH:41][C:40]4[CH:39]=[CH:38][C:37]([CH2:36][N:33]5[CH2:32][CH2:31][O:30][CH2:35][CH2:34]5)=[CH:43][CH:42]=4)[N:13]=[CH:12][C:11]=3[CH:10]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2C(=O)OC(C)(C)C)cn1
Agent: CN(C)C(=O)c1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(CN5CCOCC5)cc4)cc3n2C(=O)OC(C)(C)C)cn1
Yield: 19 %

Procedure:
The title compound was prepared in 19% yield from compound (17) and 4-(morpholinomethyl)aniline using the method described for compound (49). 1H-NMR (500 MHz, CDCl3) 1.51 (s, 9H), 1.69 (s, 9H), 2.47 (br t, J=4.2 Hz, 4H), 3.49 (s, 2H), 3.72 (t, J=4.7 Hz, 4H), 6.58 (d, J=0.5 Hz, 1H), 6.66 (s, 1H), 7.31 (br s, 4H), 7.61 (s, 1H), 7.82 (d, J=0.5 Hz, 1H), 8.22 (d, J=0.5 Hz, 1H), 8.45 (d, J=0.7 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8]Cl)(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)[OH:22]>O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=[O:22])(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)OCC=C(C)CCl
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(=O)OCC=C(C)C=O
Temperature: 35 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Crude 4-acetoxy-2-methyl-1-chloro-2-butene (194 g, Purity: 83.8%, 1 mol) was added to hexamethylenetetramine (168 g, 1.2 mol)/water (1 liter), and the mixture was stirred at 35° C. for 4 hours and then separated into aqueous and organic layers. 1,2-Dichloroethane (1 liter) was added to the aqueous layer, the mixture was subjected to reaction at 72° C. for 6 hours while adjusting the pH with 1N sulfuric acid. The 1,2-dichloroethane layer was separated, 1,2-dichloroethane (1 liter) was added, and the reaction was carried out again. The 1,2-dichloroethane layers were combined and concentrated. The residue was distilled under reduced pressure to give 4-acetoxy-2-methyl-2-buten-1-al (98 g, 69%). bp.0.2-0.3 : 58°-66° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1.S(Cl)([Cl:18])=O>>[Cl:18][CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ccccc2SC1CCCO
Product: O=C1Nc2ccccc2SC1CCCCl
Yield: 59.1 %

Procedure:
By a process similar to that in Reference Example 13-(2), 2-(3-hydroxypropyl)-2H-1,4-benzothiazin-3(4H)-one was allowed to react with thionyl chloride to obtain 2-(3-chloropropyl)-2H-1,4-benzothiazin-3(4H)-one. The yield was 59.1%. Recrystallization from ethyl acetate-hexane gave prisms, m.p. 98°-99° C.