Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>O1CCCC1.CN(C)C=O>[F:14][C:15]([F:17])([F:16])[CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[OH:7]
Reactant: O=Cc1ccsc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OC(c1ccsc1)C(F)(F)F
Yield: 53 %

Procedure:
According to Reference Example 8-2, by use of thiophene-3-carbaldehyde (300 mg, 2.67 mmol) dissolved in tetrahydrofuran (4.5 mL) and N,N-dimethylformamide (1.5 mL), potassium carbonate (74 mg, 0.53 mmol) and (trifluoromethyl)trimethylsilane (0.772 mL, 5.34 mmol), the mixture was stirred and reacted at room temperature for 16 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 2,2,2-trifluoro-1-(thiophen-3-yl)ethanol (Compound DO) (258 mg, yield: 53%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:5][CH:4]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C)C=O>[C:22]1(=[O:32])[N:26]([CH2:2][C:3]2[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]3[C:13](=[O:14])[C:12]4=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]4[C:10]3=[O:19])=[CH:5][CH:4]=2)[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
A mixture of N-(4-chloromethylbenzyloxy)phthalimide (18.5 g.) and potassium phthalimide (15.4 g.) in N,N-dimethylformamide (180 ml.) was stirred at 60° C. for 5 hours. The mixture was poured into ice-water and the precipitates were collected by filtration. The precipitates were washed with water and acetone in turn to give N-(4-phthalimidomethylbenzyloxy)-phthalimide (21.0 g.).
Reaction SMILES: [H-].[Na+].O1CCCC1.[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:18]([Sn:22]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23]I)[CH2:19][CH2:20][CH3:21]>C(OCC)(=O)C>[CH2:18]([Sn:22]([CH2:23][O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH3:21]
Reactant: OCCCN1CCOCC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCCCN1CCOCC1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 150 %

Procedure:
To a mixture of sodium hydride (60%, 278 mg, 6.96 mmol) and tetrahydrofuran (20 ml) was added N-(3-hydroxypropyl)morpholine (963 μl, 6.96 mmol) at room temperature. Then, the reaction mixture was stirred at 45° C. (external temperature) for 10 minutes. To the reaction mixture was added tributyl-iodomethyl-tin (2.0 g, 4.64 mmol) at 0° C. (external temperature). Then, the mixture was stirred at 45° C. for 1 hour. The reaction mixture was cooled at room temperature, diluted with ethyl acetate, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, heptane:ethyl acetate=9:1) to obtain the title compound (2.08 g, 6.96 mmol, 100%).
Reaction SMILES: [C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]1OCC[O:26]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[C:1]([N:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccccc1C1OCCO1)c1ccccc1Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N(Cc1ccccc1C=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
In 40 ml of acetone was dissolved 2.81 g of N-acetyl-N-[2-(1,3-dioxolan-2-yl)benzyl]-2-phenoxyaniline synthesized in the same manner as in Example 3, and then 0.10 g of p-toluenesulfonic acid monohydrate was added, followed by stirring at room temperature for 6 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, the acetone was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3), dried and allowed to stand at room temperature to give 2.12 g of N-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline as crystals.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].O.[N+:6]([C:9]1[CH:18]=[C:17]2[C:12]([NH:13][C:14](=[O:20])[C:15](=[O:19])[NH:16]2)=[CH:11][C:10]=1[S:21](Cl)(=[O:23])=[O:22])([O-:8])=[O:7]>>[OH:2][CH2:1][CH2:3][NH:4][S:21]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[N+:6]([O-:8])=[O:7])[NH:16][C:15](=[O:19])[C:14](=[O:20])[NH:13]2)(=[O:22])=[O:23]
Reactant: NCCO
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)NCCO)cc2[nH]c1=O
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of 6.11 g (0.1 mole) of ethanolamine in 40 ml of water 6.11 g (0.02 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added under stirring, the reaction mixture is stirred at room temperature for 6 hours and then allowed to stand for 16 hours. The separated crystals are filtered off, washed with acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from this solution with 2-propanol. Thus 3.70 g (56%) of 1,2,3,4-tetrahydro-N-(2-hydroxyethyl)-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 281-289° C.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C([NH:39][C:40]1C=[CH:44][C:43]([C:46](=[O:51])NCCC)=[CH:42][CH:41]=1)=O)C2>>[N:39]1[CH:40]=[CH:41][CH:42]=[C:43]([C:46]([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])[CH2:9][CH2:10]2)=[O:51])[CH:44]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(NCCCCC1CCNCC1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(NCCCCC1CCN(C(=O)c2cccnc2)CC1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting nicotinoyl chloride hydrochloride for acetyl chloride and N-[4-(piperidin-4-yl)butyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.58-8.71 (m, 2H) 7.87 (d, J=7.5 Hz, 1H) 7.52 (dd, J=7.5, 4.8 Hz, 1H) 7.22-7.36 (m, 4H) 6.28 (br m, 1H) 4.56 (s, 4H) 4.44 (br m, 1H) 3.38-3.57 (br m, 1H) 2.95-3.15 (br m, 2H) 2.68-2.84 (br m, 1H) 0.95-1.84 (br series of m, 12H); MS (ESI(+)) m/e 407 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:25])=[O:11])=[CH:8][C:7]=1[S:28](=[O:31])(=[O:30])[NH2:29].[CH3:32]O>>[Cl:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH3:32])=[O:23])=[CH:21][C:16]=3[N:15]=[C:14]2[CH3:25])=[O:11])=[CH:8][C:7]=1[S:28](=[O:31])(=[O:30])[NH2:29]
Reactant: Cc1nc2cc(C(=O)O)ccc2n1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)nc(C)n2NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Yield: 75 %

Procedure:
After dropping 1.46 ml of thionyl chloride to a solution containing 8.2 g of 1-(4'-chloro-3'-sulfamoylbenzoyl)amino-2-methyl-5-carboxybenzimidazole in 50 ml of methanol while stirring, the reaction mixture was refluxed for 5 hours. The clear solution obtained was evaporated to dryness under reduced pressure and the solid residue was triturated with 1N sodium bicarbonate solution. After decanting the solution from the solid product, the residue was recrystallized from a mixture of dioxane and water (1:1). Thus, 6.35 g (75%) of 1-(4'-chloro-3'-sulfamoylbenzoyl)amino-5-methoxycarbonyl-2-methylbenzimidazole were obtained, m.p.: 251°-252° C. (with decomposition).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]#[C:10][C:11]2[C:12]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>C(Cl)Cl>[CH:20]1([NH:19][C:12]2[C:11]([C:10]#[C:9][CH2:8][O:7][C:6]3[CH:26]=[CH:27][C:3]([CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:4][CH:5]=3)=[CH:16][N:15]=[C:14]([C:17]#[N:18])[N:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#Cc1ncc(C#CCOc2ccc(CCl)cc2)c(NC2CCCCC2)n1
Reactant: CN1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(OCC#Cc3cnc(C#N)nc3NC3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
5-[3-(4-Chloromethyl-phenoxy)-prop-1-ynyl]4-cyclohexylamino-pyrimidine-2-carbonitrile (0.050 mmol) is dissolved in CH2Cl2 (2 ml) and 1-methyl-piperazine (0.10 mmol) is added at room temperature and the mixture is stirred at room temperature for overnight. Water is added and the organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 40% yield.
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([NH:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[N:13]=[C:12](O)[N:11]=1)[CH2:7][CH3:8]>O1CCOCC1>[S:2]([O:5][C:12]1[N:13]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[N:15]=[C:10]([NH:9][CH2:6][CH2:7][CH3:8])[N:11]=1)([OH:1])(=[O:4])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: CCCNc1nc(O)nc(NCCC)n1
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(OS(=O)(=O)O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
95% H2SO4 (28 μL, 0.52 mmol) was added to the suspension of 4,6-bis(propylamino)-1,3,5-triazin-2-ol (CLXXVIII) (110 mg, 0.52 mmol) in 1,4-dioxane (2 mL). The mixture was stirred for 30 min at room temperature. The resultant precipitate were filtered, washed with Et2O and dried to afford 4,6-bis(propylamino)-1,3,5-triazin-2-ol hydrogen sulfate (CLXXIX) in quantitative yield. 400 MHz 1H NMR (CD3OD+CF3COOD, ppm) 3.35-3.45 (3.2H, m), 3.22-3.27 (0.8H, m), 1.58-1.70 (4H, m), 0.91-1.0 (6H, m). ESI-MS (m/z): 212 [M+H]+. Major Fragments (M+H) 170, 128, 86.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1>FC(F)(F)C(O)=O.CO>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2c(Br)n[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@@H](OCC1(c2ccc(F)cc2)CCNCC1)c1cc(Br)cc2c(Br)n[nH]c12
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 4-((1-(3,5-dibromo-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (99 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 6 mL) and stirred for 30 min. The reaction was concentated and the resulting residue loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated to give 82 mg (94%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.62 (d, J=1.5 Hz, 1H), 7.25 (dd, J=9.5, 5.8 Hz, 2H), 7.12 (d, J=1.5 Hz, 1H), 7.03 (dd, J=8.6, 8.6 Hz, 2H), 4.46 (q, J=6.7 Hz, 1H), 3.44 (s, 2H), 3.36 (d, J=8.9 Hz, 1H), 3.24 (d, J=9.2 Hz, 1H), 2.87 (m, 2H), 2.68 (m, 2H), 2.14 (m, 1H), 2.03 (m, 1H), 1.84 (m, 2H), 1.41 (d, J=6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 139.3, 137.3, 128.7, 128.61, 128.57, 127.7, 125.3, 121.7, 121.6, 115.6, 115.5, 114.3, 79.0, 77.8, 50.5, 42.5, 42.4, 41.4, 33.7, 33.4, 22.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][CH2:10][NH:9][C:7]=2[N:8]=1>C(Cl)Cl.CCOCC.O=[Mn]=O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH:11]=[CH:10][NH:9][C:7]=2[N:8]=1
Reactant: COc1ncc2c(n1)NCC2
Agent: O=[Mn]=O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ncc2cc[nH]c2n1
Reaction time: 8 h
Yield: 90 %

Procedure:
MnO2 (1.720 g, 20 mmol) was added to 2-methoxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine in 20 mL of anhydrous CH2Cl2 at room temperature. The mixture was stirred for 8 h, diluted with anhydrous ether (50 mL), and filtered through a pad of Celite. The filtrate was concentrated in vacuo, and the residue was purified on a silica gel column eluting with MeOH/CH2Cl2 (1:9) to give 2-methoxy-7H-pyrrolo[2,3-d]pyrimidine (0.149 g, 90%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29]([OH:31])=O)[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:32])[C@@H:14]([C@@H:19]([C:29](=[O:31])[NH:41][O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C2CNCCN2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
A solution of 0.415 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(carboxy)-4-phenyl-3-butenyl]-4-methylvaleramide in 0.25 ml of dimethylformamide was treated with 0.461 g of O-benzylhydroxylamine and 0.173 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and stirred at room temperature for 4 hours. Evaporation gave a residue which was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave a residue which was triturated with diethyl ether to give 0.160 g of (E)-N-(1,2,3,5,6,7,8,8a(RS)-octahydro-1,3-dioxoimidazo[1,5-a]pyrazin-2-yl)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si:15]([CH3:32])([CH3:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH3:14][Si:15]([CH3:31])([CH3:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A solution of 8.2 g. of 4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate, dried, and evaporated to yield ethyl 4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.7 g. of 14-(trimethylsilyl)tetradecyl bromide, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized yielding ethyl 4-[14-(trimethylsilyl)tetradecylamino]phenylacetate. A mixture of 6.0 g. of this ester, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with concentrated hydrochloric acid.. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields the title product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[S:19]>C(Cl)(Cl)Cl>[CH3:16][NH:17][C:18]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[S:19]
Reactant: CN=C=S
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Solvent: ClC(Cl)Cl
Product: CNC(=S)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C

Procedure:
1.3 g. (6.3 mmol) 7-Amino-4,4-dimethyl-isoquinolin-1,3-dione were dissolved in 30 ml. chloroform, mixed with 1.4 g. methyl isothiocyanate and boiled under reflux for 6 hours. The reaction mixture was then cooled and the precipitate was filtered off with suction and recrystallised from ethanol. Yield: 0.8 g. (46% of theory); m.p. 206°-207° C.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:24](=[O:26])[CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCCNCc1ccccc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccccc1)C(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
N-hexylbenzylamine (0.6 g, 3.136 mmol) and 3-(4-hydroxyphenyl)propionic acid (0.52 g 3.136 mmol) were mixed in DMF (10 ml) and the mixture was cooled. HOBT (0.424 g, 3.136 mmol) and the TBTU (1 g, 3.136 mmol) reagent were added followed by DIPEA (1.216 g, 9.409 mmol). The mixture was stirred at room temperature overnight and then evaporated. The resulting mixture was partitioned between ethyl acetate and sodium hydrogencarbonate aqueous solution (sat.). The aqueous portion was extracted with ethyl acetate and the combined organic extracts dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using ethyl acetate/heptane (10:90, then 25:75) as eluant gave 760 mg the desired product, yield 71%.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH2:8][C:9]([C:11]1[C:20]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1)=[O:10].[H][H]>CN(C=O)C.[C].[Pd]>[CH3:22][O:21][C:14]1[C:15]2[O:16][CH2:17][CH2:18][O:19][C:20]=2[C:11]([C:9](=[O:10])[CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=2)=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCCO2
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cc2ccncc2)c2c1OCCO2
Yield: 40.6 %

Procedure:
Compound 178 (1.1 g) obtained in Example 178 was dissolved in DMF (10 ml), mixed with palladium carbon (containing 50% water) (0.2 g), and stirred at room temperature for 24 hours in a hydrogen atmosphere. The reaction solution was filtered with Celite. The filtrate was mixed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate anhydride, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (ethyl acetate) to give 2,3-dihydro-5-methoxy-8-[1-oxo-2-(4-pyridyl)ethyl]-1,4-benzodioxine (0.36 g, 41%) as colorless crystals. The thus-obtained compound was dissolved in ethyl acetate and mixed with a saturated hydrochloric acid ethyl acetate solution. The precipitated crystals were filtered and washed with ethyl acetate to give Compound 179 as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30].CO>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([N:29]([CH3:30])[CH3:28])=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-n2nc(N(C)C)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 150 °C
Yield: 11 %

Procedure:
According to Scheme 2 Step 4: To a solution of 2(C) (100 mg, 0.22 mmol) in 0.5 mL of DMF was added dimethylamine 2M solution in methanol (0.56 mL, 1.11 mmol). The reaction was heated 5 h at 150° C. under microwave irradiation. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 5 g column (Eluant: DCM/MeOH 98/2). 10 mg, (11% yield) of N-(3-(4-(4-chlorobenzyl)-6-(dimethylamino)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 2(D) were obtained.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]#[N:25])[CH:22]=3)[CH:16]=2)[N:11](C(OC(C)(C)C)=O)[N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]#[N:25])[CH:22]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nn(C(=O)OC(C)(C)C)c2ccc(-c3cnn(CC#N)c3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCn1cc(-c2ccc3[nH]nc(N)c3c2)cn1
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-5-(1-(cyanomethyl)-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate (0.30 g, 0.557 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0 mL). After about 45 minutes, the reaction was slowly quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (3×25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude solid. A white precipitate that was suspended in both the initial aqueous layer and the brine layer was filtered and added to the crude solid. The resulting solid was triturated with dichloromethane/methanol (19:1). The remaining solid was collected by vacuum filtration and dried in a vacuum oven at about 70° C. to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H) 7.49-7.41 (m, 1H), 7.24 (d, J=8.71 Hz, 1H), 5.52 (s, 2H), 5.31 (s, 2H). MS (ESI+) m/z 239.1 (M+H)+.