Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=2)[CH:9]([CH3:11])[CH3:10])[CH2:3]1.[H-].[Na+].[CH3:26]I>C1COCC1>[F:23][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]([N:12]([CH3:26])[C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=2)[CH:9]([CH3:11])[CH3:10])[CH2:3]1
Reactant: Cc1ccc(C(=O)N[C@H](CN2CCC(F)(F)C2)C(C)C)cc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(C)[C@H](CN2CCC(F)(F)C2)C(C)C)cc1C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
To a mixture of (S)—N-(1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-yl)-3,4-dimethylbenzamide (Compound P) (167 mg, 0.51 mmol) in THF (1 mL) was sodium hydride (0.024 mL, 0.51 mmol) added. After 30 min was MeI (0.032 mL, 0.51 mmol) added and the resultant mixture was stirred at rt overnight. Additional sodium hydride (0.013 mL, 0.51 mmol) and MeI (0.032 mL, 0.51 mmol) was added and the resulting mixture stirred for 2 h. The reaction was quenched with MeOH (0.5 mL). The solvent was removed under reduced pressure and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (47 mg, 27%). HRMS (M+H)+: calculated 339.2248. found 339.2277.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].NC1C=CC(C=CC(O)=O)=CC=1.P(Cl)(OCC)(OCC)=O.[CH3:37][N:38]([CH3:49])[CH2:39][CH2:40][NH:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:37][N:38]([CH3:49])[CH2:39][CH2:40][N:41]([C@H:42]1[CH2:43][CH2:44][C@H:45]([CH3:48])[CH2:46][CH2:47]1)[C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:15][CH:14]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: CC(=O)Nc1ccc(C=CC(=O)O)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: Nc1ccc(C=CC(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
Using 2.0 g of 4-acetylaminocinnamic acid derived from 4-aminocinnamic acid by the acetylation thereof, 1.9 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 60 ml of methylene chloride, 2.3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.04 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.08 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-acetylaminocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:66])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:64])[C:57]4[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:65])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:66])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:64])[C:57]4[CH:58]=[CH:59][C:60]([CH3:63])=[CH:61][CH:62]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:65])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: Cc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1
Yield: 84 %

Procedure:
The compound of example 112 was prepared analogous to compound of example 98 by hydrolysis of compound of example 111.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:6]([O:16][CH3:17])=[C:7]([CH:9]([O:13]CC)OCC)[CH:8]=1.C[Mg]Br.[O:25]1[CH2:29]CCC1.Cl.[O:31]1CCCC1>>[CH:18]1([C:5]2[CH:4]=[C:3]([CH:8]=[C:7]([CH:9]=[O:13])[C:6]=2[O:16][CH3:17])[C:29]([OH:25])=[O:31])[CH2:19][CH2:20][CH2:21]1
Reactant: C1CCOC1
Reactant: CCOC(OCC)c1cc(Br)cc(C2CCC2)c1OC
Agent: C[Mg]Br
Agent: Cl
Agent: [Mg]
Product: COc1c(C=O)cc(C(=O)O)cc1C1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To magnesium (106 mg), tetrahydrofuran (3.5 mL), 5-bromo-3-cyclobutyl-1-diethoxymethyl-2-methoxybenzene (1.33 g) and a 0.97M methylmagnesium bromide-tetrahydrofuran solution (1.32 mL) was added, and then the mixture was stirred at room temperature for 1.5 hours. The reaction solution was cooled to 0° C. and stirred under a carbon dioxide atmosphere for 15 hours, and then 2N hydrochloric acid (10 mL) was added and the mixture was stirred at mom temperature for 1 hour. The organic solvent was distilled off under reduced pressure and then extracted with diisopropylether. The organic layer was extracted with 1N sodium hydroxide added thereto, and then the aqueous layer was washed twice with diisopropylether. The aqueous layer was acidified with 4N hydrochloric acid added thereto, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (458 mg) as a brown solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][C:11]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:18]2[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=2)[N:12]=1.O>CN(C)C=O>[N:3]1([CH2:9][CH2:10][C:11]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:36][CH3:37])[CH:17]=3)[N:12]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1c(CCBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CCn2ccnc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
Oily sodium hydride (60%, 0.044 g) was added to a solution of imidazole (0.075 g) in N,N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-(2-bromoethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.46 g) was added. The mixture was stirred at 80° C. for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (10/1, v/v) gave ethyl 2-[2-(1-imidazolyl)ethyl]-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.295 g, 66%) which was then recrystallized from ethyl acetate-hexane. Colorless prisms. mp. 173°-174° C.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[N:19]([CH3:20])[CH:18]=[C:17]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[N:13]=[C:14]([CH3:16])[N:15]=1>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[C:11]2[N:19]([CH3:20])[CH:18]=[C:17]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[N:13]=[C:14]([CH3:16])[N:15]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(-c2cn(C)c3c(Cl)nc(C)nc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc2c(-c3c(C)cc(C)cc3C)cn(C)c12
Reaction time: 0.08 h

Procedure:
To a solution of 3-pentanol (0.09 ml, 0.883 mmol) in dry THF was added 60% NaH in oil (20 mg, 0.500 mmol) and stirred for 5 min. A solution of 4-chloro-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine (50 mg, 0.166 mmol) in dry THF was added to the reaction mixture and the resulting mixture was heated at reflux for 2 hr. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, separated, dried and concentrated to dryness to give the title compound as a white solid. 1H NMR (CDCl3) ä 6.92(s, 3H), 5.43(m, 1H), 4.02(s, 3H), 2.56(s, 3H), 2.29(s, 3H), 2.08(s, 6H), 1.80(m, 4H), 0.99(t, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[CH:21]([NH2:23])=[O:22]>CO.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[NH:23][CH:21]=[O:22]
Reactant: Cc1ccc(S(=O)O)cc1
Reactant: NC=O
Reactant: O=Cc1ccc(F)cc1F
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(F)cc2F)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
To a round bottom flask was added 4-methylbenzenesulfinic acid (5.00 g, 32.0 mmol), (1S)-(+)-10-camphorsulfonic acid (0.074 g, 0.320 mmol), 2,4-difluorobenzaldehyde (3.85 mL, 35.2 mmol) and formamide (6.38 mL, 160 mmol). The reaction mixture was stirred at about 65° C. for about 16 h. The reaction mixture had solidified overnight. The solid was broken up and suspended in MeOH. The chunks of solid were ground to a powder with a spatula and the solid was filtered and washed with MeOH. The filter cake was dried under vacuum at about 60° C. to give the title compound (7.31 g, 70.2%) as a white powder. LC/MS (Table 1, Method a) Rt=2.37 min; MS m/z: 343.1 (M+NH3)+.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].Cl[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:20]2[NH:21][C:22](=[O:29])[C:23]([CH:26]([CH3:28])[CH3:27])([CH3:25])[N:24]=2)[N:12]=1.Cl>CN(C)C=O.O>[CH:26]([C:23]1([CH3:25])[C:22](=[O:29])[NH:21][C:20]([C:13]2[N:12]=[C:11]([O:7][CH2:1][CH:2]3[O:6][CH2:5][CH2:4][CH2:3]3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[N:24]1)([CH3:28])[CH3:27]
Reactant: OCC1CCCO1
Reactant: CC(C)C1(C)N=C(c2nc(Cl)ccc2C(=O)O)NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C1(C)N=C(c2nc(OCC3CCCO3)ccc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 ml (0.01 mol) tetrahydrofurfuryl alcohol are added to a mixture of 1.0 g (0.033 mol) sodium hydride (80%) in 10 ml dimethylformamide and after-stirred for 1 hour. Then, 2.95 g (0.01 mol) 6-chloro-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-nicotinic acid, dissolved in 10 ml dimethylformamide, are added dropwise. The mixture is then stirred for 1 hour at 50°-60° C., cooled to room temperature, then 10 ml water is added, followed by acidifying with concentrated hydrochloric acid. The product is extracted with methylene chloride, the extract is dried across magnesium sulfate, filtered and compressed. After a certain period the product crystallizes from the obtained oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:6](Br)[CH:5]=1.[CH3:17][Zn]C.CO>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([CH3:17])[C:7]([O:11][CH2:12][O:13][CH3:14])=[C:8]([F:10])[CH:9]=1
Reactant: COCOc1c(F)cc(C(=O)OC)cc1Br
Reactant: C[Zn]C
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: COCOc1c(C)cc(C(=O)OC)cc1F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-5-fluoro-4-methoxymethoxybenzoic acid methyl ester (301 mg) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)(42 mg) in dioxane (5 mL) was added dimethylzinc (2M toluene solution) (2.1 mL). The mixture was stirred at 120° C. for 3 hours under heating and then cooled down to 0° C., and methanol (0.3 mL) was added thereto. The mixture was diluted with ether, washed with 1M hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=50:1, v/v) to give the title compound (197 mg).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29]>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:29][CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: NCc1ccccn1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccccn3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted with 3.0 g of 2-picolyl amine and 5 g of triethyl amine as prescribed in Example 76 and the end product precipitating as crystals was filtered off. Melting point: 166° C (decomposition).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:10]([OH:11])=[C:9]([C:12]([NH:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:13])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:6]1=[O:33])([CH3:4])[CH3:3].CC(N1C(=O)CC(=O)N(CC2C=CC(C(C)(C)C)=CC=2)C1=O)(C)C.C(N(C(C)C)CC)(C)C.N(CC(OCC)=O)=C=O>C(Cl)(Cl)Cl>[CH3:4][C:2]([N:5]1[C:10]([OH:11])=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[C:8](=[O:21])[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[C:6]1=[O:33])([CH3:1])[CH3:3]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C(C)(C)C)c(=O)n(Cc2ccc(C(C)(C)C)cc2)c1=O
Agent: CC(C)(C)c1ccc(CN2C(=O)CC(=O)N(C(C)(C)C)C2=O)cc1
Agent: CCOC(=O)CN=C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C(C)(C)C)c2=O)cc1
Reaction time: 3 h

Procedure:
Ethyl N-[(1-(1,1-dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate. 1-(1,1-Dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-2,4,6(1H,3H,5H)-pyrimidinetrione (1.3 g, 3.93 mmoles) and diisopropylethylamine (1.36 mL, 7.86 mmoles) were stirred together in dry chloroform (25 mL) and treated with ethyl isocyanatoacetate (335 uL, 3.93 mmoles). The mixture was stirred for 3 hours, washed twice with 1 molar hydrochloric acid, dried and evaporated to give the title compound (1.8 g, quant.) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.07 Hz, 3 H) 1.71 (s, 9 H) 1.73 (s, 9 H) 4.28-4.34 (m, 2 H) 5.03-5.07 (m, 2 H) 7.33-7.39 (m, 4 H) 10.21-10.30 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.[C:19](OCC)(=O)C>ClCCl>[CH3:4][C:3]1([CH3:5])[O:6][CH2:7][C:10](=[CH2:9])[C@@H:11]2[C@@H:19]([C@H:8]([CH3:18])[CH2:13][CH2:12]2)[CH2:1][O:2]1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(C)(C)OC
Solvent: ClCCl
Product: C=C1COC(C)(C)OC[C@@H]2[C@H](C)CC[C@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
2-[(1S, 2R, 3R)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]-2-propen-1-ol (100 mg, 0.00059 mol) obtained in Definite Example 47 was dissolved in 3 ml of dichloromethane, and after 2 ml of 2,2-dimethoxypropane was added, 5 mg of p-toluenesulfonic acid wad added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 50 ml of ethyl acetate, and organic layer was washed with a mixed aqueous solution of saturated sodium bicarbonate solution (10 ml) and saturated sodium chloride solution (20 ml), was dried by adding magnesium sulfate, was filtered and was thereafter concentrated under a reduced pressure The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=9:1 eluent was distilled off. A colorless oily substance was thus obtained, i.e., (1R, 8S, 11R)-4, 4, 11-trimethyl-7-methylene-3, 5-dioxabicyclo[6. 3. 0]undecane (108 mg, yield=87.4%). This (1R, 8S, 11R)-4, 4, 11-trimethyl-7-methylene-3, 5-dioxabicyclo[6, 3, 0]undecane had the following physicochemical properties:
Reaction SMILES: [N+:1]([O:4][C@H:5]([CH3:16])[CH2:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])([O-:3])=[O:2].B(F)(F)F.CCOCC>C(Cl)Cl>[N+:1]([O:4][C@H:5]([CH3:16])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2]
Reactant: C[C@H](CCCC(=O)OC(C)(C)C)O[N+](=O)[O-]
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](CCCC(=O)O)O[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of crude (R)-tert-butyl 5-nitrooxyhexanoate (31 mmol) in CH2Cl2 (50 mL) at 0° C., was added BF3.Et2O (5.1 mL, 40 mmol). After 1 hour, the mixture was then washed with brine, dried over Na2SO4, and the volume of the solvent reduced. The resultant solution was used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:10][C:8]1([CH3:11])[C:7](=[O:12])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[CH:19]=[CH:20][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:3][C:4]=2[O:9]1
Reactant: CC1(C)Oc2cc(N)ccc2N(c2ccccc2)C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-amino-2,2-dimethyl-4-phenyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 1(3), 50 mg) in chloroform (2 mL) were added dropwise successively methanesulfonyl chloride (22 μL) and pyridine (30 μL) under ice-cooling and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added a saturated sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The organic layer was washed successively with water, 10% HCl solution and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (solvent; n-hexane/ethyl acetate=1/1→ethyl acetate) to give N-(2,2-dimethyl-3-oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanesulfonamide (55 mg) as a colorless powder. MS (APCI) m/z: 347 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][C:25]([C:23]4[CH:24]=[C:19]([N:16]5[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]5)[N:20]=[C:21]([NH2:35])[N:22]=4)=[CH:26][CH:27]=3)[CH2:32]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)c3ccc(Cl)cc3)CC4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
4-Chlorobenzoic acid chloride (4.4 μL, 0.034 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (16 μL, 0.12 mmol) in tetrahydrofuran (0.3 mL). After 30 min, the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=463.3/465.3
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:30]=[C:29]3[C:20]([NH:21][C:22]4[C:27]([O:28]3)=[CH:26][CH:25]=[C:24]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:23]=4)=[N:19][C:18]2=[O:40])[CH2:13][CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:30]=[C:29]3[C:20]([NH:21][C:22]4[C:27]([O:28]3)=[CH:26][CH:25]=[C:24]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:23]=4)=[N:19][C:18]2=[O:40])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(CCc4cccc(F)c4)ccc2O3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(CCc4cccc(F)c4)ccc2O3)CC1
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of [3-(4-{7-[2-(3-fluoro-phenyl)-ethyl]-2-oxo-2,9-dihydro-10-oxa-1,3,9-triaza-anthracen-3-yl}-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester (94 mg, 0.167 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C. was added trifluoroacetic acid (4.0 mL). The reaction was stirred for 30 min then concentrated. The residue was dissolved in water (10 mL) then treated with 1.0 N aqueous hydrochloric acid (2.0 mL). The resulting solution was concentrated, and then the residue was re-dissolved in water (10 mL), treated with hydrochloric acid (2.0 mL) and concentrated. The residue was dissolved in water (10 mL) and then the resulting solution was frozen and then lyophilized to give 88 mg (0.165 mmol, 99%) of the desired product (dihydrochloride salt) as a yellow solid. LCMS (EI): 464.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:29])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1.C(N(CC)C(C)C)(C)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>ClCCl>[C:42](=[O:43])([O:41][CH2:39][CH3:40])[O:29][C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:18]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:1])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=2
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CN4CCCC4)c3)c2n1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Oc1nc2c(N)nc(OCCOC)nc2n1Cc1cccc(CN2CCCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
6-Amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H-purin-8-ol (Example A) (60 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (0.1 mL) was added and the mixture was cooled to 0° C. Ethylchloroformate (0.04 mL, 0.42 mmol) was added. After stirring for 30 minutes, the reaction was quenched with water and concentrated under vacuum. Purification by preparative reverse phase HPLC (5-45% acetonitrile/40 mM aqueous HCl) gave 9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-purin-8-yl ethyl carbonate (Example Q) (24 mg) as a white glassy solid, HCl salt.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][CH:6]=1.[CH2:14]=[O:15]>CC(C)=O>[Br:1][C:2]1[C:3]([C:7]([F:13])([F:12])[C:8]([F:9])([F:10])[F:11])=[N:4][N:5]([CH2:14][OH:15])[CH:6]=1
Reactant: FC(F)(F)C(F)(F)c1n[nH]cc1Br
Reactant: C=O
Solvent: CC(C)=O
Product: OCn1cc(Br)c(C(F)(F)C(F)(F)F)n1
Temperature: 130 °C
Reaction time: 5 h
Yield: 50.3 %

Procedure:
The mixture of 13.72 g of 4-bromo-3-(pentafluoroethyl)-1H-pyrazole and 3.00 g of paraformaldehyde was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered. The filtrate was concentrated under reduced pressure. Hexane was added to the filtrate, as a result, a crystal was formed. The crystal was collected to obtain 7.69 g of 4-bromo-3-(pentafluoroethyl)-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.[CH3:19]O>[Pd]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH3:19])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reactant: CO
Agent: [Pd]
Product: CNc1ccc(NC)c(N2CCCCC2)c1
Yield: 100 %

Procedure:
Using a procedure similar to Example 3, step (c), dimethyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (100 mg, 0.4 mmol, as prepared in the previous step) was stirred with 80 mg 5% Pd—C in 5 mL MeOH under H2 to afford 89 mg (100%) of the title compound as an oil, which was used immediately without further purification. Mass spectrum (ESI, m/z) calcd. for C13H21N3, 220.1 (M+H), found 220.1.