Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1C=O.ClC1C=C(C=CC=1)C(OO)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[OH:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of 2-methoxy-4-(trifluoromethyl)benzaldehyde (1.0 g, 4.90 mmol) in dichloromethane (15 mL) was added m-chloroperoxybenzoic acid (1.48 g, 6.61 mmol). The resulting clear solution was stirred for 16 hours at room temperature. Overnight a white precipitate had formed that was filtered off. The filtrate was evaporated to a white solid, which was dissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulphate, and evaporated to a white solid. This solid was redissolved in methanol (15 mL), and treated with triethylamine (2 mL, 10 mmol). After stirring for two hours, the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (25 mL), and washed with 1N citric acid solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulphate, and evaporated to an oil. This crude material was then purified by eluting through a short pad of silica with dichloromethane, which afforded the title compound as a clear oil (536 mg, 57%)
Reaction SMILES: [NH2:1][CH2:2][C:3]#[CH:4].C(N(CC)CC)C.[O:12]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[O:12]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][CH2:2][C:3]#[CH:4])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a dichloromethane (25 mL) solution of amino-2-propyne (0.96 g, 17.43 mmol) and triethylamine (3.33 mL, 23.7 mmol) at 0° C. was added 3-phenoxybenzoyl chloride (3.68 g, 15.8 mmol) in dichloromethane (25 mL) in a dropwise fashion. The reaction was stirred for 1 h after removing the cooling bath and partitioned between dichloromethane and 10% aqueous HCl. The layers were separated and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed (1×, saturated sodium bicarbonate; 1×, brine), dried (MgSO4), and concentrated under vacuum to give a golden oil. Recrystallization with ehter ethyl acetate provided the title compound as a colorless solid (2.95 g, 74%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:9][C@@H:8]1[CH3:35])=[O:6])([CH3:3])[CH3:2].[F:36][C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>N1C=CC=CC=1>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([N:19]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:40](=[O:41])[C:39]2[CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=[C:37]([F:36])[CH:38]=2)[CH2:9][C@@H:8]1[CH3:35])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: COc1ccc2c(n1)[C@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cc(F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Yield: 85.2 %

Procedure:
Prepare the title compound by essentially following the procedure described for the synthesis of Example 47, using (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.210 g, 0.415 mmol), 3-fluoro-5-trifluoromethyl benzoyl chloride (0.095 mL, 0.631 mmol) and pyridine (0.10 mL). Purify using silica gel column chromatography (gradient eluent, 0-30% ethyl acetate in hexane) to provide the title compound (0.246 g, 88%). MS (ES+): 696 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=[O:22])[CH2:20][CH3:21])[C:15](=[O:18])[CH2:16][CH3:17])=[CH:4][CH:3]=1.[CH2:23]([O:25][CH2:26][CH2:27]Br)[CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:23]([O:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15](=[O:18])[CH2:16][CH3:17])[C:19](=[O:22])[CH2:20][CH3:21])=[CH:6][CH:7]=1)[CH3:24]
Reactant: CCOCCBr
Reactant: CCC(=O)C(CCCCCCc1ccc(O)cc1)C(=O)CC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCOc1ccc(CCCCCCC(C(=O)CC)C(=O)CC)cc1
Reaction time: 72 h

Procedure:
A mixture of 3.9 g. of 4-[6-(4-hydroxyphenyl)hexyl]3,5-heptanedione, 12 g. of 2-bromoethyl ethyl ether, 4 g. of potassium carbonate and 1 g. of potassium iodide in 40 ml. of acetone was heated at reflux for 48 hours and then allowed to stand at room temperature for three days. The reaction mixture was then filtered and concentrated to remove the solvent. The residue was distilled at 200°-205° C. (0.001 mm.) to give 4-{6-[4-(2-ethoxyethoxy)phenyl]hexyl}-3,5-heptanedione as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]#[N:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]#[N:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Product: N#CCc1c[nH]c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (1.5 g, 74.5 mL) and 10% Pd—C (300 mg) in EtOH (50 mL) was stirred at room temperature under H2 (1 atm) for 5 h. Pd—C was removed via filtration and the filtrate was evaporated to give (6-amino-1H-indol-3-yl)-acetonitrile (B-9) (1.1 g, 90%). 1H NMR (DMSO-d6) δ 10.4 (br s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.94 (s, 1H), 6.52 (s, 1H), 6.42 (dd, J=8.4, 1.8 Hz, 1H), 4.76 (s, 2H), 3.88 (s, 2H); ESI-MS 172.1 m/z (MH+).
Reaction SMILES: [CH2:1]([O:17][CH:18]1[O:23][CH:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[CH:20]=[CH:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:28]Cl.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:17][CH:18]1[O:23][CH:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[C:20]([Cl:28])=[CH:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC1C=CC(=O)C(C(C)C)O1
Reactant: ClCl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC1C=C(Cl)C(=O)C(C(C)C)O1
Yield: 99.4 %

Procedure:
In 50 ml of carbon tetrachloride was dissolved 3.8 g of 6-cetyloxy-2-isopropyl-2H-pyran-3(6H)-one with stirring. Into the solution was gradually introduced chlorine gas (0.71 g) at a temperature below 10° C. and after the subsequent stirring for 30 minutes was added dropwise 0.8 g of pyridine maintaining the temperature below 15° C. A crystal from the reaction mixture was separated by suction filter. The filtrate was washed with 5% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. By the distillation of solvent was obtained 4.12 g of 6-cetyloxy-4-chloro-2-isopropyl-2H-pyran-3(6H)-one [compound 2] in a yellow viscous oily form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([Cl:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([Cl:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([C:5]1[C:6]([O:20][CH3:21])=[N:7][C:8]2[N:9]([CH:12]=[C:13]([C:15](OCC)=[O:16])[N:14]=2)[C:10]=1[CH3:11])[CH3:4].[BH4-]>O1CCCC1>[CH2:3]([C:5]1[C:6]([O:20][CH3:21])=[N:7][C:8]2[N:9]([CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)[C:10]=1[CH3:11])[CH3:4]
Reactant: CCOC(=O)c1cn2c(C)c(CC)c(OC)nc2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(OC)nc2nc(CO)cn2c1C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
11.55 g (0.0525 mol) of lithium borohydride were added portionwise over 1 hour to a stirred solution of 19.7 g (75 mmol) of ethyl 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylate in 300 ml of dry tetrahydrofuran and after stirring at room temperature for 18 hours the excess borohydride was destroyed by dropwise addition of 300 ml of saturated sodium chloride solution. Then, the mixture was stirred for 30 minutes before separating the organic layer. The aqueous layer was extracted with chloroform and the combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to obtain 15.4 g of (6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)methanol (93% yield) as a white crystalline solid metling at 186°-188° C. (decomp.).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@@H:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([O:38]CC)=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[N:46]=2)[CH:7]=1)[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@@H:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([OH:38])=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[N:46]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@@H]2CCN(CCN3CCOCC3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C[C@@H]2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
(R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-(2-morpholinoethyl)pyrrolidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 235, 320 mg) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). To this solution was added 24 wt % sodium hydroxide (1 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to remove the organic solvents. Water (10 mL) was added and the aqueous layer was acidified to pH 6˜7 with 1N hydrochloric acid. The solution was centrifuged to help isolate the solid that precipitated, and the precipitate was washed with cold water once to give a light yellow solid (260 mg, 86.9%) after drying.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]4[CH2:29][O:28]4)[N:22]=3)[N:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:5]>CO>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([OH:28])[CH2:29][N:2]([CH3:3])[CH3:1])[N:22]=3)[N:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:5]
Reactant: CNC
Reactant: CCOc1ccc(-c2nc(-c3cccc(C4CO4)n3)cs2)cc1OCC
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)CN(C)C)n3)cs2)cc1OCC

Procedure:
2.4 g of a 50% aqueous dimethylamine solution was added to a solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(6-oxiranyl-2-pyridyl)thiazole dissolved in 200 ml of methanol. The mixture was refluxed overnight. The resulting precipitate was removed by filtration. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (elutant: dichloromethane/methanol=20/1) and silica gel thin-layer chromatography and then recrystallized from diethyl ether-dichloromethane to obtain 140 mg of 2-(3,4-diethoxyphenyl)-4-[6-(1-hydroxy-2-dimethylaminoethyl)-2-pyridyl]thiazole (A). Further, recrystallization from diethyl ether-n-hexane was conducted to obtain 28 mg of 2-(3,4-diethoxyphenyl)-4-[6-(1-dimethylamino-2-hydroxyethyl)-2-pyridyl]thiazole (B).
Reaction SMILES: [CH2:1]([CH:4]1[S:9][CH2:8][CH2:7][CH2:6][S:5]1)[CH2:2][CH3:3].C([Li])CCC.[CH:15](=[O:17])[CH3:16]>CCCCCC>[OH:17][CH:15]([C:4]1([CH2:1][CH2:2][CH3:3])[S:9][CH2:8][CH2:7][CH2:6][S:5]1)[CH3:16]
Reactant: CCCC1SCCCS1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCC1(C(C)O)SCCCS1
Yield: 86.9 %

Procedure:
The synthesis was carried out in a similar manner to Example 4/(a), but using 8 g (49.3 mmol) of 2-n-propyl-1,3-dithian, 52 mmol of n-butyllithium (32.5 ml of a 1.6 M solution in n-hexane) and 2.5 g (56.8 mmol) of acetaldehyde. 8.84 g of 2-(1-hydroxyethyl)-2-n-propyl-1,3-dithian were obtained as a colorless oil.
Reaction SMILES: Br.[CH3:2][O:3][C:4]([C:6]1[CH2:7][NH:8][CH2:9][CH2:10][CH:11]=1)=[O:5].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34][CH2:33]2)(=O)=O)=CC=1>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:31][CH:32]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34][CH2:33]2)[CH2:9][CH2:10][CH:11]=1)=[O:5]
Reactant: COC(=O)C1=CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CC2COc3ccccc3C2)C1
Reaction time: 15 h
Yield: 82.4 %

Procedure:
First 5.55 g (25 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 11.31 g (87.5 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 7.96 g (25 mmol) of 3-(p-toluenesulphonyloxymethyl)chroman in 100 ml of dimethylformamide. The mixture is stirred for 15 hours at 50° and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The organic phases are washed with water and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 5.92 g (83%) of 1-(chroman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a pale yellow oil. The 1-(chroman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether melts at 158°-159° after crystallisation from methanol/diethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[S:12]([N:15]=C=O)(=[O:14])=[O:13]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][S:12](=[O:14])(=[O:13])[NH2:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc([N+](=O)[O-])c1

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 13.9 g (0.1 mole) of 3-nitrophenol and 14.8 g (0.105 mole) of chlorosulfonyl isocyanate in 100 ml of toluene gave 16.9 g (78%) of tan flakes, mp 118°-120° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].Br[CH2:32][CH:33]1[CH2:35][CH:34]1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:9]([C:22]3[CH:26]=[N:25][N:24]([CH2:32][CH:33]4[CH2:35][CH:34]4[C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:44])[F:45])[CH:37]=4)[CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3]
Reactant: FC(F)(F)c1cccc(C2CC2CBr)c1
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC4c4cccc(C(F)(F)F)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 52.5 °C
Yield: 379.1 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.23 mmol), 1-(2-bromomethyl-cyclopropyl)-3-trifluoromethyl-benzene (0.64 g, 0.23 mmol), K2CO3 (0.063 g, 0.46 mmol) and acetone (10 ml) were heated at 50-55° C. for 16 hrs. Reaction mixture was cooled to 20-25° C. and filtered off. The filtrate was evaporated and residue was purified by column chromatography to afford 1,3-dipropyl-8-{1-[2-(3-trifluoromethyl-phenyl)-cyclopropylmethyl]-1H-pyrazol-4-yl}-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.55 g, 58%).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=O)[CH2:3][CH2:2]1.[CH3:14][N:15]([CH3:33])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:33])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)[C:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[S:1][CH2:2][CH2:3]2)=[O:13])=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCSc2ccccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCSc3ccccc32)cc1
Yield: 28.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using thiochroman-4-carboxylic acid (0.55 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.63 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)thiochroman-4-carboxamide (0.3 g) was obtained. melting point: 118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1.[O:26]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC([N+]([O-])=O)=CC=2)=[N:27]1.C(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:24]([C:32]([NH:31][C:28]3[CH:29]=[CH:30][O:26][N:27]=3)=[O:33])[CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1
Reactant: O=C(Nc1ccon1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1OC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4C(=O)Nc3ccon3)c2cc1OC
Temperature: 35 °C
Reaction time: 15 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.2955 mmol) and 4-nitrophenyl isoxazol-3-ylcarbamate (294 mg, 1.182 mmol) in CH2Cl2 (3 mL) DIPEA (269 μL, 2.069 mmol) was added at RT. The reaction mixture was stirred at 35° C. for 15 h before the solution was concentrated in vacuo and purified with column chromatography using 100% EtOAc→10%→30%→50% 19:1 EtOAc:MeOH to yield the title compound. MS (ESI, pos. ion) m/z: 449 (M+1). Mass calc'd for C23H20N4O6: 448.44.
Reaction SMILES: [CH:1]([C:9]1=[CH:10][C:11]([O:13][C:14]1=[O:15])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[OH:17]>>[CH:1](/[C:9](/[C:14]([OH:13])=[O:15])=[CH:10]/[C:11]([OH:17])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Product: O=C(O)/C=C(/C=Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 30 h

Procedure:
1.8 g of the styrene-maleic anhydride polymer (molecular weight: 1600) was mixed with 5.4 g of the polyethyleneoxyglycol (molecular weight: 600). The mixture was dropped on a glass substrate and heated in an oven at 100° C. under nitrogen stream. After 30 hours, the mixture was cooled down to room temperature, immersed into methanol and dried. A thin membrane of the styrene-maleic acid polyethyleneoxy ester crosslinked copolymer of an excellent adhesive strength and mechanical strength was prepared.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)[C:2]#[CH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][CH2:1][C:2]#[CH:3])=[CH:7][CH:8]=1
Reactant: C#CCOCc1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C#CCOCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
A mixture of (4-prop-2-ynyloxymethyl-phenyl)-methanol (190 mg, 1.1 mmol) described in Manufacturing Example 194-1-1, triphenylphosphine (340 mg, 1.3 mmol), and carbon tetrachloride (3 mL) was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature, after which the reaction mixture was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:10) to obtain the title compound (180 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:14][C:15]([F:39])([F:38])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]>>[F:14][C:15]([F:38])([F:39])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:9][CH2:10]2)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cc1ccccc1N1CCNCC1
Product: Cc1ccccc1N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 b from 1-(2-methyl-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.