Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([CH3:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([NH:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])[C:4]1=[O:25])#[N:2]>C(O)(C(F)(F)F)=O>[C:1]([C:3]1([CH3:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:4]1=[O:25])#[N:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccccc2C(C)(C#N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C#N)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccccc21
Reaction time: 0.75 h

Procedure:
1,1-Dimethylethyl N-((1-cyano-4-hydroxy-1-methyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.100 g, 0.28 mmol) was placed in a 25 mL round bottom flask and TFA (10 mL) was added. The resulting mixture was then stirred for 45 minutes. TFA was then removed under vacuum, and DCM was used to azeotrope off TFA (3×) resulting in a yellow solid. MS (m/z)=301 (M+H)+. Calculated for C15H12N2O5 300.07.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][O:22]1>CC(C)=O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:20][CH:21]2[CH2:23][O:22]2)=[CH:8][CH:9]=1
Reactant: BrCC1CO1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)Oc1ccc(OCC2CO2)cc1
Temperature: 59 °C
Reaction time: 36 h

Procedure:
A mixture of 4-trifluoromethoxyphenol (0.152 mL, 1.17 mmol), K2CO3 (260 mg, 1.17 mmol) and 2-(bromomethyl)oxirane (76) (0.30 mL, 3.51 mmol) in anhydrous acetone (3 mL) was stirred in a sealed vial at 59° C. for 36 h. The resulting mixture was filtered, washing with CH2Cl2, and then the filtrate was evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-15% CH2Cl2/pentane firstly gave foreruns, and then further elution with 20-25% CH2Cl2/pentane gave 2-{[4-(trifluoromethoxy)phenoxy]methyl}oxirane (77) (similarly prepared by Cao et al., WO 2008112483A2 using epichlorohydrin) (260 mg, 95%) as an oil; 1H NMR (CDCl3) δ 7.14 (br dd, J=9.0, 0.6 Hz, 2H), 6.91 (dt, J=9.1, 3.0 Hz, 2H), 4.23 (dd, J=11.1, 3.1 Hz, 1H), 3.94 (dd, J=11.1, 5.7 Hz, 1H), 3.34 (m, 1H), 2.91 (dd, J=4.8, 4.2 Hz, 1H), 2.75 (dd, J=4.9, 2.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([CH:14]=O)=O)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:14][NH:19][CH2:16][CH2:17][NH:18]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(C(=O)C=O)ccc1[N+](=O)[O-]
Reactant: NCCN
Product: COc1cc(C2CNCCN2)ccc1[N+](=O)[O-]

Procedure:
(RS)-2-(3-Methoxy-4-nitrophenyl)piperazine was prepared according to the method described in Patent Application FR 2,351,108, but starting with 3-methoxy-4-nitrophenylglyoxal (36 g) and ethylenediamine (12.1 g). The crude product is purified by chromatography on 230-400 mesh silica (800 g) suspended in a mixture of dichloromethane (70%), ethanol (26%) and triethylamine (4%) and elution with the same mixture (2 liters). After concentration of the eluate under reduced pressure (20 kPa) at approximately 50° C., the expected product (18 g) is obtained in the form of a red oil, which was used without further purification for the subsequent steps.
Reaction SMILES: [N:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]2[CH2:13][CH2:12][C:11](=[N:14]O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:1]1([CH:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ON=C1CCC(C(c2ccccc2)N2CCOCC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1CCC(C(c2ccccc2)N2CCOCC2)CC1
Reaction time: 4 h

Procedure:
A solution of 4-(morpholin-4-yl-phenylmethyl)cyclohexanone oxime (1.20 g, 4.16 mmol) in absolute tetrahydrofuran (12 ml) was added dropwise at 60° C., under argon, to a suspension of lithium aluminium hydride (316 mg, 8.32 mmol) in absolute tetrahydrofuran (40 ml), and stirring was carried out for 4 h at that temperature. After cooling, water (1.5 ml) and 4 N sodium hydroxide solution (0.4 ml) were added dropwise. The suspension was filtered, and the filtrate was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13](O)=O)[C:10](O)=O)=[CH:5][CH:4]=1.BrC1C=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19]C=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:19][C:20]([CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:13]=2)=[CH:7][CH:8]=1
Reactant: Brc1ccc(CCOCc2ccccc2)cc1
Reactant: COc1ccc(C(C(=O)O)C(=O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(CCOCc3ccccc3)cc2)cc1
Yield: 80 %

Procedure:
1.57 g (10.3 mmol) of 4-methoxyphenyl malonic acid, 3.0 g (10.3 mmol) of 2-(4-bromophenyl) ethylbenzylether, 0.38 g of tetrakis (triphenylphosphine) palladium, 15 ml of 2M-sodium carbonate solution, 15 ml of toluene and 10 ml of ethanol were heated at 80° C. for 4 hours under presence of nitrogen. After reactions had been completed, extraction with toluene was performed. Then, the extracted solution was dried with anhydrous sodium sulfate. The solvent was removed by filtration, and then refining was performed with a silica gel column chromatography (developing solvent: toluene) and by recrystallization (ethanol) so that 2.63 g of 2-{4-(4-methoxyphenyl) phenyl}ethylbenzylether was obtained (yield 80%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1Br)[CH:10]([NH:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[C-:30]#[N:31].N>CN1C(=O)CCC1.[Cu]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:30]#[N:31])[CH:10]([NH:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1Br)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Reactant: [C-]#N
Agent: [Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[N-(5-acetamido-6-bromoindan-1-yl)amino]-2-fluorobenzoate (0.420 g, 0.90 mmol) in NMP (10 ml) was added copper(l) cyanide (0.137 g, 1.53 mmol). The reaction mixture was placed in an oil-bath preheated to 145° C. and stirred at this temperature for 2 hours. The reaction mixture was allowed to cool to room temperature, then poured into a mixture of aqueous ammonia (d=0.88, 5 ml) and ice (˜15 ml) and the resulting brown mixture was stirred at room temperature for ˜5 min. The brown solid was collected by filtration washed with water, then suspended in dichloromethane (60 ml). The mixture was stirred at room temperature for 5 min, dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography, on elution with 40% ethyl acetate in hexane, afforded a solid that was triturated with diethyl ether/hexane. The desired compound was obtained as a white solid: 0.202 g, (55%) m.p. 172-173° C.; 1H-NMR (250 MHz, CDCl3, TMS) 1.57 (s(obscured by water peak), 9H, C(CH3)3), 2.27 (s, 3H, COCH3), 1.96, 2.65 (2×m, 2H, indanyl 2-H), 3.00 (m, 2H, indanyl 3-H), 4.30 (d, J=8.40 Hz, 1H, N-H), 4.99 (q, J=7.80 Hz, 1H, indanyl 1-H), 6.38 (m, 2H, 3,5-H), 7.52, 8.33, 7.62 (3×s, each 1H, indanyl 4-H, 7-H, CONH), 7.74 (t, J=8.60 Hz, 1H, 6-H); MS (ESL, m/z) 432 {(M+Na)+, 100%}; Found: C, 67.44; H, 5.88; N, 10.25; P, 4.63; C23H24FN3O3 requires C, 67.47; H, 5.91; N, 10.26%; F, 4.64%.
Reaction SMILES: O.Cl.C[O:4][CH:5](OC)[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH:20](OC)[O:21]C)[N:13]=[C:12]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]([O:32]C)OC)[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:32][CH:29]1[CH2:28][CH2:27][CH2:26][N:25]1[C:12]1[N:13]=[C:14]([N:16]2[CH2:17][CH2:18][CH2:19][CH:20]2[OH:21])[N:15]=[C:10]([N:9]2[CH2:8][CH2:7][CH2:6][CH:5]2[OH:4])[N:11]=1
Reactant: COC(CCCNc1nc(NCCCC(OC)OC)nc(NCCCC(OC)OC)n1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OC1CCCN1c1nc(N2CCCC2O)nc(N2CCCC2O)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Water (50 ml) containing 37 weight % hydrochloric acid (6 ml) was added in one portion to a stirred solution of the tris-(4,4-dimethoxybutylamino)-1,3,5-triazine of Example 1 (6.0 g; 0.0127 mole) in acetone (50 ml) under nitrogen. The reaction mixture was stirred at room temperature for four days and thereafter neutralized with solid potassium carbonate. The solution was then transferred to a separatory funnel and extracted with ethyl acetate (2×150 ml). The organic layer was separated, dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to give 2,4,6-tris-(2-hydroxypyrrolidin-1-yl)-1,3,5-triazine as a solid (2.7 g; 64% isolated yield). The structure of the product was confirmed from the 1H NMR spectrum which exhibited the characteristic absorption for the --NCHO-- group at (δ) 5.6 (m, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[C:16]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:29])[CH2:28][O:27][CH2:26]4)=O)[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].B.C([O-])(O)=O.[Na+].OO>[OH-].[Na+].C1COCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[C:16]3[CH2:22][CH2:21][N:20]([CH2:23][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)C2(C)COC2)C3)cc1
Agent: B
Agent: O=C([O-])O
Agent: OO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC(C)(C)CO)C3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
A solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(3-methyloxetane-3-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (jl) (Example 213) (30 mg, 0.061 mmol), borane (0.5 mL of 1.0 M in THF, 0.5 mmol) and THF (1.5 mL) was heated at reflux for 7 h). Further borane (0.3 mL of 1.0 M in THF, 0.3 mmol) was added, and the solution heated at reflux for 15 h. After cooling to rt, sat. NaHCO3 (1 mL) and 3% aq hydrogen peroxide (1 mL) were added and the mixture stirred vigorously for 3 h. The mixture was diluted with 1 N NaOH (20 ml) and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine (1×10 mL) dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC to afford 8 mg (26%) of the title compound as a colorless solid: 1H NMR (400 MHz, MeOD) δ 8.23-8.09 (m, 2H), 7.53-7.36 (m, 2H), 4.29-4.08 (m, 1H), 3.93 (d, J=11.1Hz, 1H), 3.86-3.61 (m, 6H), 3.58-3.45 (m, 1H), 3.24 (q, J=7.2 Hz, 2H), 2.94-2.77 (m, 1H), 2.77-2.68 (m, 3H), 2.49 (s, 2H), 1.32 (t, J=6.2 Hz, 3H), 1.24-1.06 (m, 3H), 0.95 (s, 6H); LC-MS: m/z=+483 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH3:36][O:37][P:38]([CH2:58][NH2:59])([CH2:40][CH:41]([C:46](=[O:57])[NH:47][C@H:48]([C:53](=[O:56])[NH:54][CH3:55])[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39]>O1CCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:17](=[O:19])[NH:59][CH2:58][P:38]([O:37][CH3:36])([CH2:40][CH:41]([C:46](=[O:57])[NH:47][C@H:48]([C:53](=[O:56])[NH:54][CH3:55])[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])[CH2:13][CH:14]([CH3:15])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)OC
Reaction time: 3.5 h
Yield: 64 %

Procedure:
A solution of 0.53 g of N-[(benzyloxy)carbonyl]-L-leucine in 10 ml of dry tetrahydrofuran was cooled to -30° C. and there was then added 0.23 g of N-ethylmorpholine followed by 0.27 g of isobutyl chloroformate. After stirring at -30° C. for 5 minutes a solution of 0.6 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester, prepared as described in Example 2(A)(i), and 0.23 g of N-ethylmorpholine were added. The mixture was left to come to room temperature and was stirred at this temperature for 3.5 hours. The mixture was then diluted with 50 ml of dichloromethane, washed with 20 ml of 10% sulfuric acid, 20 ml of sodium chloride solution and 20 ml of saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and evaporated to give a colorless gum. This gum was purified by flash chromatography on silica gel using 10% methanol in ethyl acetate for the elution to give 0.645 g of benzyl[(S)-1-[[[methoxy[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinyl]methyl]carbamoyl]-3-methylbutyl]carbamate in the form of a white foam.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[CH:28]1([C:34]#[CH:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.S>CN(C)C=O.C(Cl)(Cl)Cl.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>[CH:28]1([C:34]#[C:35][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: S
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(C#CC2CCCCC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
1.95 g (5 mmol) of 2-iodoadenosine was dissolved in 20 ml of N,N-dimethylformamide (DMF), to which were added 0.18 g of bis(triphenylphosphine)palladium dichloride, 0.1 g of cuprous iodide, 2.8 ml of triethylamine and 0.8 ml of cyclohexylacetylene. The resulting mixture was stirred at a temperature of 90° C. for two hours. The reaction solution after being allowed to cool, was concentrated to dryness. The residue obtained was dissolved in chloroform, into which was vigorously introduced hydrogen sulfide gas over one minute. The solution was then dried under reduced pressure. The residue was purified by silica gel column chromatography, followed by recrystallization from ethanol-water, thereby obtaining 1.11 g (2.97 mmol) of crystalline 2-(cyclohexylethynyl)adenosine (yield: 59%).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17]Br>C(Cl)(Cl)Cl>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][N:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: C1CNCCNCCNCCN1
Solvent: ClC(Cl)Cl
Product: COc1ccc([N+](=O)[O-])cc1CN1CCNCCNCCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a stirred chloroform solution (20 ml) containing 2.9 g of 1,4,7,10-tetraazacyclododecane (16.8 mmole) was added a chloroform solution (20 ml) containing 2.1 g of 2-methoxy-5-nitrobenzyl bromide (8.5 mmole) in one portion. After stirring at room temperature for three hours the reaction mixture was filtered and the filtrate concentrated (in vacuo) to give a residue which was chromatographed (silica, Solvent System 3). The monoalkylated product was isolated in 79 percent yield (MP=154°-156° C.), and characterized by:
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.[I-].C[S+](C)(C)=O.[CH2:13]([S:15][C:16]([F:28])([F:27])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])=[O:18])[CH3:14]>C1COCC1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:17]1([C:16]([S:15][CH2:13][CH3:14])([F:27])[F:28])[CH2:3][O:18]1
Reactant: CCSC(F)(F)C(=O)c1ccc(F)cc1F
Reactant: CS(C)=O
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A suspension of 60% NaH (876 mg, 0.022 mol) in THF (30 ml) —DMSO (50 ml) was heated to an external temperature of 50° C., followed by the addition of trimethylsulfoxonium iodide (4.8 g, 0.022 mol) in portions. After stirring at the same temperature for one hour, the reaction mixture was cooled to −20° C. and added dropwise with a solution of 2-ethylthio-2,2,2′,4′-tetrafluoroacetophenone (4.6 g, 0.018 mol) in THF (20 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water, followed by extraction with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby 2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane (4.3 g, yield: 90.0%) was obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[S:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])(=[O:32])=[O:31]>CS(C)=O>[CH3:33][S:30]([N:34]1[CH2:39][CH2:38][N:37]([C:2]2[N:3]([CH2:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:7]=[C:6]([C:17]2[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=2)[N:5]=3)[CH2:36][CH2:35]1)(=[O:32])=[O:31]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CCOC2)CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
Dimethyl sulfoxide (1 ml) was added to a mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.24 mmol) and N-mesylpiperazine (118 mg, 0.72 mmol) and the resulting mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled and then partitioned with chloroform and water, and the organic layer was washed with water again and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (chloroform:methanol=10:0 to 25:1 to 20:1) to give the title compound (50 mg, 45%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH2:23]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O)[CH:24]([CH3:26])[CH3:25].[O-]CC.[Na+]>C(O)C>[CH2:23]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1/[CH:30]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: COc1cccc(C=O)c1OCC(C)C
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC(C)C
Yield: 33.8 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (312 mg, 1.516 mmol) in the presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure of Example 24 to give 187 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.90-0.99 (m, 6H), 1.80-1.86 (m, 1H), 3.58-3.65 (m, 2H), 3.77 (s, 3H), 6.85-6.93 (m, 2H), 6.99-7.06 (m, 2H), 7.40-7.50 (m, 5H), 7.96-8.02 (m, 1H), 8.09-8.14 (m, 1H); ESI-MS (m/z) 517.18 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
To a suspension of tert-butyl chloroacetate (3.49 g, 34.9 mmol) and potassium carbonate (5.50 g, 39.8 mmol) in acetonitrile (300 mL) was added dropwise 1-methylpiperazine (5.00 g, 33.2 mmol), and the mixture was stirred with heating at 50° C. for 16 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated. Water (150 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (5.63 g, 79%) as a pale-yellow oil. The compound was used for the next reaction without further purification operation.
Reaction SMILES: [CH2:1]([CH:6]([C:12]([O:14]CC)=[O:13])[C:7]([O:9]CC)=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]>[OH-].[Na+]>[CH2:1]([CH:6]([C:12]([OH:14])=[O:13])[C:7]([OH:9])=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)C(CCC(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCC(C(=O)O)C(=O)O

Procedure:
Diethyl isoamylmalonate (71.7 g) was added to a 50% aqueous solution of sodium hydroxide (60 ml), and the mixture was heated under reflux for 6 h. After cooling, the mixture was extracted with ether; the water layer was acidified with hydrochloric acid and, after saturation with sodium chloride, was extracted with ether. The extracts from the acidic aqueous layer were concentrated under reduced pressure to give isoamylmalonic acid. The obtained dicaboxylic acid was heated at 180° C. for 2 h. After distillation under reduced pressure, 5-mehyl-caproic acid was obtained. Yield: 30 g (75%), b.p. 107°-108° C./11 mmHg.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CN(C)C=O.C1([O:16][C:17](=O)[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[C:33]([C:36]#[N:37])[CH:34]=4)[N:29]=[CH:28][CH:27]=3)=[C:21]([CH3:46])[C:20]=2[CH3:47])C=CC=CC=1.O>C(OCC)(=O)C>[CH2:39]([O:38][C:32]1[CH:31]=[C:30]2[C:35]([C:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([NH:18][C:17]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:16])=[C:20]([CH3:47])[C:21]=3[CH3:46])=[CH:27][CH:28]=[N:29]2)=[CH:34][C:33]=1[C:36]#[N:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1c(NC(=O)Oc2ccccc2)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Reactant: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclopropylamine (1 ml) was added to dimethylformamide (10 ml), and then (4-(7-benzyloxy-6-cyano-quinolin-4-yloxy)-2,3-dimethylphenyl)carbamic acid phenyl ester (1.99 g) was added thereto and the mixture was stirred at room temperature for 10 minutes. Water (30 ml) and ethyl acetate (30 ml) were added, and the precipitated crystals were filtered out and washed with ethyl acetate to obtain the title compound (1660 mg).