Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CN(C)C=O>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccccc1Br
Yield: 46.7 %

Procedure:
2-Bromophenol (1.88 g), anhydrous potassium carbonate (1.51 g), (2-bromoethoxy)-(tert-butyl)dimethylsilane (2.61 g) and dimethylformamide (30 ml) were heated for 20 h at 90° C., cooled, poured into water (100 ml), extracted with ethyl acetate, the organic phase washed with water, brine, dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography eluting with 1:9 ether/isohexane to give the product as a crystalline solid (1.68 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](=O)[CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[NH:34][NH2:35].CCCCCC>C(O)CC>[CH2:1]([O:8][C:9]1[C:14]([C:15](=[N:35][NH:34][C:33]([O:37][CH2:38][CH3:39])=[O:36])[CH3:16])=[C:13]([OH:18])[C:12]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Reactant: CCOC(=O)NN
Solvent: CCCO
Solvent: CCCCCC
Product: CCOC(=O)NN=C(C)c1c(OCc2ccccc2)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Temperature: 75 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of 1-[6-benzyloxy-2-hydroxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethanone (1.50 g) in n-propanol (15 mL) was added ethyl carbazate (432 mg). The mixture was stirred under an argon atmosphere at 75° C. overnight and cooled to room temperature. Adding hexane (30 mL), the reaction mixture was stirred for 1 hour. The precipitate was filtrated to give ethyl N′-{1-[6-benzyloxy-2-hydroxy-3-(5-methyl-7-nitroindan-4-yloxy)phenyl]ethylidene}hydrazinecarboxate (1.16 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][C:12](=[CH:14][CH3:15])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:11][C:12]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:13])[CH2:14][CH3:15]
Reactant: CC=C(C)C
Reactant: COC(=O)c1c[nH]nc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(C)(C)n1cc(C(=O)OC)c(C)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (10.8 g) synthesized in Example 1(3) was dissolved in acetonitrile (100 mL), 2-methyl-2-butene (16.3 mL) and p-toluenesulfonic acid monohydrate (4.4 g) were added, and the mixture was stirred in a sealed tube at 120° C. for 4 hr. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (4.6 g, 29%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18]N)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:21].Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][CH2:23][C:24]#[N:25])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:21]
Reactant: N#CCBr
Reactant: Cc1ccc2c(c1C)N(CCCN)c1ccccc1S2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1C)N(CCCCC#N)c1ccccc1S2=O
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
2.25 g of 1,2-dimethyl-10-(3-aminopropyl)phenothiazine-5-oxide synthesized in Example 8, 990 mg of bromoacetonitrile and 1.2 g of potassium carbonate were dissolved in 50 ml of N,N-dimethylformamide followed by stirring at 80° C. for 10 min. Then the reaction mixture was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 670 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CC1COCCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH:23]2[CH3:28])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1COCCN1
Product: CC1COCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methylmorpholine and isolated as light-yellow gum (12.7 mg, 67%). MS (m/e): 401.5 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:15][CH2:16][OH:17].[OH-].[K+].C(O)(=O)C>O>[CH3:1][O:2]/[N:3]=[C:4](/[C:5]1[O:17][CH2:16][CH2:15][O:14][N:13]=1)\[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6]
Reactant: CON=C1C(=NOCCO)Oc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CO/N=C(/C1=NOCCO1)c1ccccc1O
Temperature: 10 °C
Yield: 69.1 %

Procedure:
A solution of 25.6 g (0.1084 mol) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) and 14.2 g (0.216 mol) of potassium hydroxide pellets in 250 ml of water is stirred at 60° C. for 195 minutes. The solution is cooled to 10° C. and acidified to pH 5-6 with glacial acetic acid. The crystalline product is filtered off with suction, washed with 200 ml of water a little at a time and dried at 45° C. in a vacuum drying oven. 17.7 g (67.7% of theory) of E-(5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[CH3:30][N:31]([C@@H:48]([C:56](=[O:59])[NH:57][CH3:58])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:32](=[O:47])[C@H:33]([NH:45][CH3:46])[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[CH:14][C:15](=[O:17])[N:45]([CH3:46])[C@@H:33]([C:32](=[O:47])[N:31]([CH3:30])[C@@H:48]([C:56](=[O:59])[NH:57][CH3:58])[CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)O)CC1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
4-Carboxymethylenepiperidine-1-carboxylic acid tert-butyl ester (0.60 g; 2.45 mmol) was dissolved in methylene chloride (50 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) was added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.5 g; 1.24 mmol, prepared as in example 1) was added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (50 mL; 10%), an aqueous solution of sodium hydrogen carbonate (50 mL; sat.), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2×20 cm) using ethyl acetate as eluent to afford 0.270 g of 4-((N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methyl-carbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methylene)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CC3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) was dissolved in DMSO (20 mL). Sodium tert-butoxide (153 mg, 1.588 mmol) was added followed by 4-methylbenzene-1-sulfonyl chloride (278 mg, 1.456 mmol). The reaction mixture was heated to 50° C. and stirred for 18 hours. Additional 4-methylbenzene-1-sulfonyl chloride (0.5 eq) was added and the reaction mixture was stirred for 18 hours at 50° C. The reaction mixture was subsequently quenched with aqueous saturated NH4Cl, diluted with ethyl acetate, and washed with aqueous saturated NH4Cl (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (68 mg, 14%). ESI-MS m/z [M+H]+ calc'd for C16H17ClN4O3S, 381.07. found 381.3.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(Br)nn1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanone and 3-bromo-6-methylpyridazine. MS (ESI) 405 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:25])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of methyl 2-(1H-indazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (69 mg, 0.18 mmol) in MeOH (20 mL) was added sodium hydroxide (21.6 mg, 0.54 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (5 mL) and adjusted pH to 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(1H-indazol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (29 mg, 43%).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:50][NH:51][O:52][CH3:53]>C(Cl)Cl>[CH3:53][O:52][N:51]([CH3:50])[C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1N HCl (3×120 mL), H2O (3×120 mL), saturated NaHCO3 aqueous solution (3×120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 27 as a white solid (20 g, 80%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:21]1([CH2:27][C:28](=O)[C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:27]([C:28]1[C:29](=[O:30])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: Nc1cccnc1Nc1cccc(-c2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1c(Cc2ccccc2)nc2cccnc2n1-c1cccc(-c2cccnc2)c1
Yield: 56.9 %

Procedure:
A mixture of 3-amino-2-[3-(3-pyridyl)phenylamino]pyridine (150 mg) and 3-phenylpyruvic acid (113 mg) in ethanol (4 ml) was stirred under reflux for 2 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 2-benzyl-4-[3-(3-pyridyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (127 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:44]=[CH:45][CH:46]=1)[CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[C:25]4[CH:30]=[CH:29][C:28]([N:31]([C:37](=[O:42])[CH2:38][CH2:39][NH:40][CH3:41])[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)=[C:12]2[CH:11]=[N:10]1)[CH3:3].[Cl:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[ClH:47].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:44]=[CH:45][CH:46]=1)[CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:43])[C:25]4[CH:26]=[CH:27][C:28]([N:31]([C:37](=[O:42])[CH2:38][CH2:39][N:40]([CH3:41])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[CH:29][CH:30]=4)[CH2:20][CH2:19]3)=[C:12]2[CH:11]=[N:10]1)[CH3:3]
Reactant: CCOc1cccc(Cn2ncc3c(N4CCN(C(=O)c5ccc(N(CCN(C)C)C(=O)CCNC)cc5)CC4)ncnc32)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(C)CCC(=O)N(CCN(C)C)c1ccc(C(=O)N2CCN(c3ncnc4c3cnn4Cc3cccc(OCC)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of the compound obtained in Example 725 (50 mg) in methylene chloride (3 mL) is added ethyl chloroformate (10 μL) and triethylamine (22 μL) and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with a saturated sodium hydrogencarbonate solution and the mixture is extracted with chloroform. The organic layer is evaporated to remove solvent and the residue is purified by column chromatography on silica gel (solvent; chloroform/methanol=10:1), and the resultant product is treated in the same manner as described in Example 4 (3) to give 1-(3-ethoxybenzyl)-4-[4-[4-[N-[3-[N-methyl-N-(ethoxycarbonyl)amino]-propionyl)-N-[2-(dimethylamino)ethyl]amino]benzoyl]piperazin-1-yl]-1H-pyrazolo-[3,4-d]pyrimidine hydrochloride (17 mg, yield; 30%) as an amorphous powder. MS (APCI) m/z: 686 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([CH:25]=3)[C:21]([O:23][CH3:24])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28].C1COCC1>C(OCC)(=O)C>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([NH:15][S:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([N:1]=[C:27]=[S:28])=[CH:3][CH:4]=3)[CH:9]=2)(=[O:14])=[O:13])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N)cc3c2)ccc1Cl
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N=C=S)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To 4.5 g (11.5 mmol) of compound 134 and 9.01 g (50.6 mmol) of 1,1′-thiocarbonyldiimidazole was added 50 mL of THF. The solution was allowed to stir at ambient temperature for 1.5 hours. Then, the reaction was poured into 300 mL of ethyl acetate and extracted with 1N HCl, water, and brine. The organic layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation to yield 4.77 g of compound 135.
Reaction SMILES: [CH:1](N1CCCC1=O)=[CH2:2].[C:9]1([N:15]=[N+:16]=[N-:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([N:15]2[CH:2]=[CH:1][N:17]=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C=CN1CCCC1=O
Solvent: CCO
Product: c1ccc(-n2ccnn2)cc1

Procedure:
In the method of preparation, the reaction between the N-vinylpyrrolidinone and the phenyl azide is carried out at room temperature in ethanol as solvent, and allowed to stand in the dark for several weeks, depending on the reactivity of the phenyl azides. Refluxing the reaction mixture eliminates the 5-(2-oxo-1-pyrrolidino) group and yields the 1-phenyl triazole.
Reaction SMILES: C([O:3][C:4](=[O:29])/[CH:5]=[C:6](\[CH3:28])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:27])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]([F:24])([F:23])[F:22])=[C:15]([CH3:25])[C:14]=1[CH3:26])C.O1CCOCC1.[OH-].[K+].S(=O)(=O)(O)O>CCCCCC>[CH3:28]/[C:6](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:27])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]([F:22])([F:24])[F:23])=[C:15]([CH3:25])[C:14]=1[CH3:26])=[CH:5]\[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CC(/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C)=C\C=C\C(C)=C\C(=O)O

Procedure:
A mixture of 15.3 g (0.0375 mol) of ethyl-(2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoate, 76.5 ml of dioxane and 30 ml of 2N methanolic KOH was heated to reflux for 4 hours. The mixture was then poured into 300 ml of ice-H2O and acidified to pH 2 with 2N sulfuric acid. The yellow precipitate was extracted with 3×200 ml of chloroform, washed with sodium chloride solution and dried (MgSO4). Evaporation of the solvent gave a yellow solid, which was treated with 150 ml of hexane and filtered to give 12 g of crude (2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoic acid. Recrystallization from 200 ml of ethyl acetate gave 9.25 g of (2E,4E,6E,8E,)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoic acid; mp 190°-193° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:15]=[C:16]([C:22]6[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=6)[S:17][C:18]=5[CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:7]=[N:6]2)[CH2:2]1.CO.C(N(CC)C(C)C)(C)C.[CH3:44][C:45]1([O:48][CH2:47]1)[CH3:46]>>[CH:28]([N:23]1[C:22]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH:3]6[CH2:4][N:1]([CH2:44][C:45]([CH3:47])([OH:48])[CH3:46])[CH2:2]6)[CH:9]=5)[CH:32]=[CH:31][C:13]=4[C:14]=3[N:15]=2)=[N:26][C:25]([CH3:27])=[N:24]1)([CH3:29])[CH3:30]
Reactant: CC1(C)CO1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CNC5)c4)ccc2-3)n(C(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CN(CC(C)(C)O)C5)c4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a slurry of 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.232 g, 0.000519 mol) in methanol (3.0 mL, 0.074 mol) was added N,N-Diisopropylethylamine (0.108 mL, 0.000623 mol) then isobutylene oxide (0.330 mL, 0.0037 mol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and purified by reverse-phase HPLC to give 480 (24.3 mg) as a colorless solid. MS(ESI+) 520.2. 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.31 (d, J=8.3, 1H), 8.01 (s, 1H), 7.47 (dd, J=8.3, 1.8, 1H), 7.35 (d, J=1.8, 1H), 5.86-5.68 (m, 1H), 4.97 (p, J=6.9, 1H), 4.39 (t, J=5.0, 2H), 4.11 (s, 1H), 3.79 (dd, J=8.0, 7.3, 2H), 3.49 (dd, J=8.0, 6.8, 2H), 3.44 (t, J=5.0, 2H), 2.44 (s, 2H), 2.32 (s, 3H), 1.53 (d, J=6.6, 6H), 1.08 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[C:25](Cl)(=[O:27])[CH3:26]>C1C=CC=CC=1>[C:25]([N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:9][CH2:10]1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: O=C(c1cccc(C(F)(F)F)c1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)N1CCC(C(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
To a solution of 32.1 g (0.125 mole) of 4-(m-trifluoromethylbenzoyl)piperidine in 75 ml of benzene and 21.2 g (0.2 mole) of Na2CO3, was added dropwise a solution of ten g (0.127 mole) of acetyl chloride in 75 ml of benzene. The mixture was refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated under vacuum giving crude 1-acetyl-4-(m-trifluoromethylbenzoyl)piperidine. Yield 37.3 grams.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](O)(=[O:14])[C:11]([CH3:13])=O>CO>[Cl:9][C:3]1[C:2]2=[N:1][C:10]([OH:14])=[C:11]([CH3:13])[N:8]=[C:7]2[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccnc(Cl)c1N
Reactant: CC(=O)C(=O)O
Solvent: CO
Product: Cc1nc2ccnc(Cl)c2nc1O
Temperature: 50 °C
Yield: 65.7 %

Procedure:
A mixture of 3,4-diamino-2-chloropyridine (2.1 g, 14.63 mmol) (Sigma Aldich) and pyruvic acid (1.22 mL, 17.55 mmol) (Acros, New Jersey) in MeOH (40 mL) in a sealed glass tube was heated at 50° C. for 2 h. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was triturated with ether and the suspension was filtered to give 1.88 g of crude product. MS (ESI, pos. ion) m/z: 196.1 (M+1).