Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[Cl:21][C:22]1[CH:23]=[CH:24][C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([NH2:28])[CH:27]=1.C(=O)([O-])O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:28][C:26]1[CH:27]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC1(C)OB(c2ccc(Cl)cc2N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(Cl)cc3N)[nH]c2c1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (5.20 g, 15.4 mmol) obtained in the same manner as in the method described in WO03/010140 and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (4.11 g, 16.2 mmol) in 1,2-dimethoxyethane (20 ml) and water (10 ml) were added sodium hydrogen carbonate (4.10 g, 48.6 μmmol) and tetrakis(triphenylphosphine)palladium (1.87 g, 1.62 mmol) and the mixture was heated under reflux for 12 hr. The mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give methyl 2-(2-amino-4-chlorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.17 g, yield 100%).
Reaction SMILES: Br[C:2]([F:21])([F:20])[CH:3](F)[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=[CH:9][N:8]=1>CO.[Zn].[I-].[Zn+2].[I-]>[F:21][C:2]([F:20])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[N:10]=[CH:9][N:8]=1
Reactant: FC(CCSc1cc(OCC(F)(F)F)ncn1)C(F)(F)Br
Agent: [I-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: CO
Product: FC(F)=CCCSc1cc(OCC(F)(F)F)ncn1
Reaction time: 6 h

Procedure:
The product from step 1 (2.8 g) was treated with zinc powder (1.376 g) in methanol (100 cm3) containing zinc iodide (catalytic amount). The mixture was heated under reflux for 7 hours and glc then indicated that only about 70% conversion had occurred. A further 0.459 g of zinc powder was added and heating continued for 6 hours. The cooled reaction mixture was filtered through a plug of celite, which was washed with more ethanol. The combined organic solutions were evaporated under reduced pressure to give a yellow oil. Purification by chromatography on silica gel, eluting with 1:10 ethyl acetate:hexane gave Compound No. 13 (1.1 g). M+ =300; 1H NMR (CDCl3): δ2.4(2H,m); 3.2(2H,t); 4.2-4.35(1H,m); 4.78(2H,q); 6.7(1H,s); 8.55(1H,s); (oil).
Reaction SMILES: I[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.C1(P([C:41]2[CH:46]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:25][Si:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][O:21][CH2:20][N:4]1[C:5]2[CH:6]=[N:7][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:11])[C:10]=2[C:2]([C:41]#[C:46][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCC[Si](C)(C)C)c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 60 °C
Reaction time: 24 h
Yield: 439.2 %

Procedure:
To 50 ml of tetrahydrofuran solution containing 16.6 g (purity: 78.4%, 25.0 mmol) of 3-iodo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 18-(b) were added 880 mg (1.25 mmol) of bis(triphenylphosphine)palladium dichloride, 620 mg (3.25 mmol) of cuprous iodide, 1.31 g (5.00 mmol) of triphenylphosphine and 10.5 ml (75.3 mmol) of triethylamine, and the mixture was degassed under reduced pressure and replaced with argon. Then, 11 ml of trimethylsilylacetylene was added to the mixture, and the mixture was stirred at 60° C. for 24 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 10.8 g of the title compound as a yellowish solid. (Yield: 88%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:18]1([C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1cccc(-c2ccccc2)c1
Yield: 35.2 %

Procedure:
A solution of (±) N-tert-butoxycarbonyl-1,2-iminoindane (5 g, 22 mmol), 3-phenylphenol (3.75 g, 22 mmol) and pyridinium p-toluenesulfonate (114 mg) in chloroform (150 ml) was heated at reflux for 2 h. On cooling, the solution was washed sequentially with 10% aq. NaOH, water and then brine. After drying over MgSO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (3.11 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:31]3[CH2:30][C:29]4[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH:28]=4)[CH2:32]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3Cc4ccc(CNC(C)=O)cc4C3)c(F)cc2c1=O
Yield: 56.1 %

Procedure:
A mixture of 310 mg of 1-cyclopropyl-6-fluoro-7- chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 745 mg of 5-acetamidomethylisoindoline, 0.56 ml of triethylamine, and 5 ml of anhydrous chloroform was heated at 60°-70° C. for 0.5 hours while stirring. The resulting reaction mixture was diluted with 25 ml of chloroform. The mixture was washed with 5% acetic acid and brine in this order, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of ethylether. The crystals were collected by filtration and recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 260 mg of 7-(5- acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH2-].[Na+].C1([O:21][C:22](=O)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)C=CC=CC=1>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:22](=[O:21])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: COc1ccc(C(=O)Oc2ccccc2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2Cc3cc(OC)ccc3C2=O)cc1
Temperature: 0 °C
Yield: 51 %

Procedure:
A solution of 22.2 g (137 mmol) of 1-oxo-5-methoxyindane in tetrahydrofuran was added dropwise to a cold suspension of 11 g (274 mmol) of sodium amide in tetrahydrofuran. The resulting mixture was stirred for ten minutes and a solution of 31.3 g (137 mmol) of phenyl-4-methoxybenzoate in tetrahydrofuran was added. Cooling was discontinued and a slight exothermic reaction occurred. The mixture was stirred at ambient temperature for an additional two hours. A thick precipitate developed and the reaction mixture was poured into ice-water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was evaporated to dryness to obtain 20.7 g of the title compound. mp: 160° C.-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=4[CH3:33])[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CCCCC2)CC1

Procedure:
Example 85 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H, J=1.6 Hz), 7.42–7.39 (m, 2H), 7.31–7.21 (m, 4H), 7.08 (d, 1H, J=8.0 Hz), 6.78 (br s, 1H), 3.29 (dd, 2H, J=6.0, 12.0 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.65 (m, 1H), 2.50 (m, 1H), 2.34–2.30 (m, 4H), 2.28 (s, 3H), 2.00–1.88 (m, 4H), 1.74–1.59 (m, 12H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 538.3 (M+H)+.
Reaction SMILES: CO[CH:3]([O:13]C)[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[F:12].[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].N1CCCCC1.Cl>C(O)C>[F:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[CH:3]=[O:13])[CH:8]=[C:19]1[S:15][C:16](=[O:21])[NH:17][C:18]1=[O:20]
Reactant: O=C1CSC(=O)N1
Reactant: COC(OC)c1ccc(C=O)cc1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.9 %

Procedure:
To a mixture of 4-dimethoxymethyl-3-fluorobenzaldehyde obtained in Example 37 (1.12 g, 5.66 mmol) and 2,4-thiazolidindione (795 mg, 6.79 mmol) in ethanol (20 mL) was added piperidine (0.68 mL, 6.8 mmol), and the mixture was heated to reflux for 13 h. Hydrochloric acid (1 mol/L) was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue were added tetrahydrofuran (25 mL) and hydrchloric acid (1 mol/L; 5 mL), and the mixture was stirred at room temperature for 20 h. Water was added, and the precipitated products were collected by filtration to afford 3-fluoro-4-formylbenzylidene-2,4-thiazolidinedione (696 mg, 49%).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].O.[CH3:12]I>C(O)C>[CH3:12][S:3][C:2]1[NH:4][C:5](=[O:6])[CH:7]=[CH:8][N:1]=1
Reactant: CI
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nccc(=O)[nH]1
Temperature: 30 °C
Yield: 42.2 %

Procedure:
A mixture of 12.8 g (99.9 mmol) of 2-thiouracil and 4.3 g (108 mmol) of sodium hydroxide was placed in 500 ml Erlenmeyer flask, and dissolved on the oil bath with a minimum amount of water. Twice the volume of 99% ethanol was then added, the solution cooled to 30° C., and 6.3 ml (99.9 mmol) of methyl iodide added. The solution was heated to 60° C. for 20 min, then cooled to room temp. The precipitate was filtered off, and, after acidifying the filtrate with acetic acid, the excess solvent was removed in vacuo. The combined precipitates were thoroughly washed with water and recrystallized from ethanol to give 6.0 g (47%) of product.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:15]=[C:16]1[CH:23]2[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:25][CH:17]1[CH2:18]3)[CH2:22]2.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([O:6][C:16]1([CH3:15])[CH:17]2[CH2:25][CH:21]3[CH2:20][CH:19]([CH2:24][CH:23]1[CH2:22]3)[CH2:18]2)=[O:5]
Reactant: C=C1C2CC3CC(C2)CC1C3
Reactant: C=C(C(=O)O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC1(C)C2CC3CC(C2)CC1C3)C(F)(F)F
Temperature: 5 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 70.0 g (0.50 mol) of α-trifluoromethylacrylic acid (supplied from Tosoh F-tech Inc.), 1.0 g (10 mmol) of sulfuric acid and 100 g of toluene. Separately 88.8 g (0.60 mol) of 2-methyleneadamantane, prepared by the same procedures as described in Reference Example 1, was dissolved in 100 g of toluene. The obtained solution of 2-methyleneadamantane in toluene was dropwise added to the content in the flask over a period of about 3 hours, while the content was maintained at a reaction temperature of about 5° C. Then the content was stirred for 15 hours at the same temperature. After completion of the reaction, the residual catalyst was neutralized by adding 40.0 g (50 mmol) of a 5% aqueous sodium hydroxide solution, and the neutralized liquid was washed with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 133.9 g (yield: 93.0%) of the object 2-methyl-2-adamantyl α-trifluoromethylacrylate was obtained.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:14]CC(O)=O)[C:9]1=[O:19].C(Cl)Cl>CN(C)C=O>[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:14][CH2:1][C:2]([Cl:4])=[O:3])[C:9]1=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1C(=O)CN(CCC(=O)O)C1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C(=O)CN(CCC(=O)Cl)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
340.9 g (2.6857 mol) of oxalyl chloride are added dropwise over the course of 18 minutes at an internal temperature of 19°-23° C. to a solution of 100.0 g (0.537 mol) of 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionic acid, synthesized as described in Example 6, 350 ml of methylene chloride and 1 ml of dimethyl formamide, and the mixture is subsequently stirred at room temperature for 5 hours and 10 minutes. When the reaction is complete, the reaction mixture is evaporated in a rotary evaporator, the residue is stripped 3 times at 50° C. under reduced pressure with 100 ml of toluene in each case, and the residue is dried at 60° C./0.1 mbar to constant weight, giving 106.1 g (97.3% of theory) of solid, brownish 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionyl chloride having the following analytical data:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH:18]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:18])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.00 g, 4.11 mmol) is dissolved in THF (10 mL) and cooled to −78° C. 2.0 M Lithium diisopropyl amide in THF is added dropwise, then stirred for 1 hour. Iodomethane (0.563 mL, 9.04 mmol) is added and the mixture is stirred for 1 hour. The cold bath is removed and the reaction stirred for an additional 0.5 hour. The reaction mixture is quenched with saturated ammonium chloride (3 mL), concentrated, taken up in dichloromethane, and chromatographed on silica gel, eluting with EtOAc in dichloromethane 0-5%, to give the title compound as a slightly yellow oil. (680 mg, 64% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1.C(O[C:22](OCC)(OCC)[CH2:23][CH3:24])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:23]([C:24]1[O:8][C:7]2[C:2]([N:1]=1)=[CH:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=2)[CH3:22]
Reactant: CCOC(=O)c1cc(N)c(=O)[nH]c1C(=O)OCC
Reactant: CCOC(CC)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)c1cc2nc(CC)oc2nc1C(=O)OCC
Yield: 84.8 %

Procedure:
Diethyl 5-amino-1,6-dihydro-6-oxo-pyridine-2,3-dicarboxylate (7.57 g, 0.030 mol), is suspended in 60 mL triethylorthopropionate (TEOP 0.30 mol). A small amount of p-toluenesulfonic acid is added and the mixture is heated at reflux for 65 hours. The triethylorthopropionate is removed in vacuo and the resulting oil is purified by column chromatography. The tractions containing the pure desired product are combined and stripped to a honey-colored oil weighing 7.38 g, yield 84.8%.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]4[O:22][CH2:23][O:24][C:17]=34)=[N:10][CH:11]=[N:12]2)=[C:7]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:6]=1)(=O)C.N>>[CH2:23]1[O:22][C:18]2[C:17](=[C:16]([CH:21]=[CH:20][CH:19]=2)[NH:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([OH:4])=[CH:6][C:7]=3[O:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:12]=[CH:11][N:10]=2)[O:24]1
Reactant: CC(=O)Oc1cc(OC2CCOCC2)c2c(Nc3cccc4c3OCO4)ncnc2c1
Agent: N
Product: Oc1cc(OC2CCOCC2)c2c(Nc3cccc4c3OCO4)ncnc2c1

Procedure:
Using an analogous procedure to that described in the last paragraph of Note [22] immediately above, 7-acetoxy-4-(2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline was reacted with a saturated methanolic ammonia solution to give 4-(2,3-methylenedioxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline; NMR Spectrum: (DMSOd6) 1.8–1.95 (m, 2H), 2.1–2.2 (m, 2H), 3.52 (m, 2H), 3.8 (s, 3H), 3.9 (m, 2H), 4.95 (m, 1H), 6.7 (s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 7.6 (d, 1H), 7.88 (s, 1H), 8.4 (s, 1H), 9.65 (s, 1H), 10.6 (br s, 1H); Mass Spectrum: M+H+ 382.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]23[O:21][CH:20]2[CH:19]2[CH2:22][CH2:23][CH:16]3[CH2:17][CH2:18]2)=[O:14])=[CH:8][C:7]=1[C:24]([F:27])([F:26])[F:25])([O-:5])=[O:4].C1(P([NH:42]O)(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:13]([C:15]23[O:21][CH:20]2[CH:19]2[CH2:18][CH2:17][CH:16]3[CH2:23][CH2:22]2)=[O:14])[NH2:42])=[CH:8][C:7]=1[C:24]([F:27])([F:25])[F:26])([O-:5])=[O:4]
Reactant: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C12OC1C1CCC2CC1
Reactant: O=P(NO)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NN(C(=O)C12OC1C1CCC2CC1)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
NaH (60% in mineral oil, 7.9 mg, 0.20 mmol, 1.4 eq) was added to the solution of 11E (50 mg, 0.14 mmol, 1 eq) in DMF (3 mL). The reaction mixture was heated at 70° C. for 2 h. The reaction was cooled to rt and diphenylphosphinylhydroxylamine (52 mg, 0.22 mmol, 1.6 eq, made according to the procedure of Colvin, E. W. et. al. Tetrahedron Lett. 23, 3835-6 (1982)) was added. The reaction mixture was stirred at rt overnight and quenched by addition of water (3 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with H2O (25 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 10% EtOAc/CH2Cl2 gave 8.0 mg (0.022 mmol, 15.4%) of compound 11F as a yellow solid. HPLC conditions: 93% at 3.54 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% H3PO4, detecting at 220 nm).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([N:23]([CH3:22])[CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: CNCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(CCc1ccccc1)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 160 °C
Yield: 14.1 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), N-methyl-2-phenylethanamine (300 mg, 2.22 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. for in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (50 mg) as a yellow solid. LC-MS (ES) m/z=360 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.85 (t, J=7.6 Hz, 2H), 3.0 (s, 3H), 3.76 (t, J=7.6 Hz, 2H), 5.37 (s, 2H), 6.04 (s, 2H), 6.39 (s, 1H), 7.19-7.23 (m, 1H), 7.30-7.32 (m, 4H), 7.53 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][CH:20](N)[CH:21]([CH3:23])[NH2:22]>C(O)C>[CH3:23][CH:21]1[CH:20]([CH3:19])[NH:18][C:4](=[N:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[NH:22]1
Reactant: CC(N)C(C)N
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Agent: I
Solvent: CCO
Product: CC1NC(=Nc2ccccc2N2CCOCC2)NC1C

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (7.6 g prepared as described in Example 166), 1,2-dimethylethylenediamine (5.3 g and ethanol (90 ml) was heated under reflux for 70 hours to give a solid which was recrystallised from ethylacetate to give 4-[2-(4,5-dimethyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 142°-143° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:6][C:7]=1[C:8]([OH:10])=O.[C:17]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([N:28]2[CH2:33][CH2:32][C@@H:31]([NH:34][CH3:35])[C@H:30]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:29]2)=[O:27])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]>>[C:17]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]([N:28]2[CH2:33][CH2:32][C@@H:31]([N:34]([CH3:35])[C:8]([C:7]3[S:6][C:5]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:4][C:3]=3[O:2][CH3:1])=[O:10])[C@H:30]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:29]2)=[O:27])[CH2:24][CH2:25]1)(=[O:19])[CH3:18]
Reactant: COc1nc(-c2ccccc2)sc1C(=O)O
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: COc1nc(-c2ccccc2)sc1C(=O)N(C)[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in step 1 and the compound obtained in Example 78, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.