Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]3[O:34][C:35]4[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:36]=4[N:37]=3)=[CH:28][CH:27]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]3)[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33]4[O:34][C:35]5[C:41]([CH3:42])=[CH:40][C:39]([CH3:43])=[CH:38][C:36]=5[N:37]=4)=[CH:30][CH:31]=3)[C:10]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CN1CCC(n2nc(I)c3c(N)ncnc32)C1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
rac-N2-{4-[4-Amino-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from rac-3-iodo-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.581 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine (0.265 g, 0.726 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white powder (0.062 g, 23%). 1H NMR (DMSO-d6, 400 MHz) 2.39 (s, 3H), 2.32-2.40 (m, 3H), 2.40 (s, 3H), 2.75-2.80 (m, 2H), 3.08 (t, 1H), 3.26 (s, 3H), 5.40 (m, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.24 (s, 1H), 10.85 (s, 1H); RP-HPLC Rt 10.905 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 455 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:1][CH2:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (0.650 g, 2.99 mmol) in dichloromethane (10 mL) was added Et3N (1.25 mL, 8.98 mmol). MeSO2Cl (0.35 mL, 4.5 mmol) was added dropwise at 0° C. under N2 and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was diluted with dichloromethane, washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by silica gel chromatography (1:1 hexane/EtOAc) to give (S)-tert-butyl 3-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (0.720 g, 81%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:20])[C:17]([OH:19])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N[C:24]1C=CC2NC(=O)OC=2[CH:25]=1>>[CH2:24]([O:18][C:17](=[O:19])[C:16]([N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][C:8]2[CH:21]=[CH:22][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)=[O:20])[CH3:25]
Reactant: CC(C)(C)c1ccc(CC2CCN(C(=O)C(=O)O)CC2)cc1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Product: CCOC(=O)C(=O)N1CCC(Cc2ccc(C(C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-tert-butyl-benzyl)-piperidin-1-yl]-oxo-acetic acid and 6-amino-3H-benzoxazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 168° C. (diethylether-hexane-diisopropyl ether).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([SH:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH2:30][CH2:31]I)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([CH2:30][CH2:31][S:14][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]3)=[CH:10][CH:9]=2)([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)N1CCc2ccc(S)cc2C1
Reactant: CCOC(=O)C1(CCI)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCSc2ccc3c(c2)CN(C(C)=O)CC3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Crude crystals (1.26 g) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-thiol were dissolved in dimethylformamide (15 ml) and thereto were added 60% sodium hydride (243 mg) and 4-ethoxycarbonyl-4-(2-iodoethyl)piperidine-1-carboxylic acid tert-butyl ester (1 g), and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and dried under reduced pressure to give the title compound (535 mg).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[CH2:32](OCOCC)C>>[C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[C:18](=[CH2:32])[CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CCOCOCC
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12

Procedure:
1.0 g of 17,21-diacetoxy-4-pregnene-3,20-dione is reacted analogously to Example 9 with formaldehyde diethylacetal, and worked up, thus obtaining 790 mg of 17,21-diacetoxy-6-methylene-4-pregnene-3,20-dione, mp 227°-228° C.
Reaction SMILES: [C:1]([S:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[C:1]([S:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[S:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)SC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)SC(=S)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of S-t-butyl thiobenzoate (1.94 g, 0.01 mol) and Lawesson's reagent (2.43 g, 0.006 mol) in anhydrous toluene (10 mL) was refluxed for 25 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue subjected to column chromatography (Kieselgel-60, 70-230 mesh, petroleum spirit/diethyl ether 19:1) The title compound was obtained as an oil, 1.37 g (65.5%). 1H-nmr (CDCl3) d (ppm): 1.69 (s, 9H, 3×CH3), 7.36 (m, 2H, meta-ArH), 7.50 (m, 1H, para-ArH) and 7.88 (d, 2H, ortho-ArH).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:19]3[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]3)=[CH:28][CH:27]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(Cl)nc21
Temperature: 78 °C
Yield: 86.4 %

Procedure:
To a reaction vial was added 2,6-dichloro-9-isopropyl-9H-purine (containing 6.3 mmol), 4-(4-methylpiperazin-1-yl)aniline (1.2 g, 6.3 mmol), isopropanol (32 mL, 0.2 M), and TFA (1 mL, 13 mmol). The reaction vial was capped, stirred and heated at 78° C. (block temperature) for 20 hr. The volatiles were removed to give a dark residue. Sat. aq. NaHCO3 (40 mL) was added. There was dark gummy solid precipitated out. Ethyl acetate (2×120 mL) and DCM (2×80 mL) were used to extract product. The combined organic layers were dried over Na2SO4 and evaporated to give a dark residue that was purified on silica with a gradient of 100% ethyl acetate to 10% ammonia (7 N in methanol)-90% ethyl acetate to give the title product as a light yellow solid (2.1 g, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1 H) 8.38 (s, 1 H) 7.61 (d, J=8.56 Hz, 2 H) 6.93 (d, J=8.93 Hz, 2 H) 4.71 (dt, J=13.39, 6.63 Hz, 1 H) 3.10 (br. s., 4 H) 2.45 (m, J=4.16 Hz, 4 H) 2.22 (s, 3 H) 1.52 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C19H24ClN7 386.2 (M+H)+ with Cl isotope pattern. The regiochemistry of the product was also confirmed by small molecule X-ray crystallography.
Reaction SMILES: [OH:1][CH:2](/[CH:12]=[CH:13]/[C:14]1[N:15]([CH3:31])[C:16](=[O:30])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+].O>CO>[OH:11][CH:4]([CH2:3][CH:2]([OH:1])/[CH:12]=[CH:13]/[C:14]1[N:15]([CH3:31])[C:16](=[O:30])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A stirred solution of ethyl (E)-5-hydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)-3-oxohept-6-enoate (0.35 g; prepared as described hereinafter in Reference Example 1) in methanol (15 ml) at 0° C. was treated with sodium borohydride (0.02 g). The mixture was stirred for one hour and then a further portion of sodium borohydride (0.05 g) was added and stirring was continued for another period of 30 minutes. The resulting clear yellow solution was poured into water (100 ml), forming a white solid. The mixture was extracted with diethyl ether (3×75 ml) and the combined extracts were dried over magnesium sulphate and evaporated, to give ethyl (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)hept-6-enoate (0.35 g) in the form of a yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:34]([CH3:36])[CH3:35])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C.O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:24][CH2:25][CH2:26][CH2:27]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:34]([CH3:35])[CH3:36])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)N1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacid (2-hydroxyethyl)-isopropylamide (439) (70 mg, 0.143 mmol), in dichloromethane (10 mL), TPP (131 mg, 0.5 mmol) diisopropyl azodicarboxylate (0.084 mL, 0.429 mmol) were added and stirring was continued for 1 h at room temperature while silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.2). After completion of the reaction, water (10 mL) was added and the mixture was extracted with dichloromethane (2×30 mL). The organic part was dried over sodium sulfate, then concentrated and the resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 70-80% ethyl acetate in hexane as gradient polarity mobile phase to get 9-benzyloxy-2-isopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (440) (60.0 mg, 90.2%) as a white sticky liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:7][CH:6]=1.[N:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[N:37]1([C:43]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[CH2:13][CH:12]3[O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:9][CH:10]=2)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)N1CCOCC1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(OCCOc1ccc(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2OCc2ccc3ccccc3c2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.3 %

Procedure:
A solution of 250 mg (0.56 mmol) of 2,2,2-trichloroethyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 20 ml of toluene was treated in succession with 250 ml (2.8 mmol, 5.0 eq.) of morpholine-4-carbonyl chloride, 375 mg (3.08 mmol, 5.5 eq.) of 4-dimethylaminopyridine and 20 gl (0.075 mmol, 0.1 3 eq.) of dibutyltin diacetate. This mixture was boiled under reflux for 64 hours. In the course of the reaction a further 125 ml (1.40 mmol, 5.0 eq.) of morpholine-4-carbonyl chloride and 188 mg (1.56 mmol, 2.3 eq.) of 4-dimethylaminopyridine were added and the mixture was boiled under reflux for a further 24 hours. The reaction mixture, cooled to room temperature, was poured into 100 ml of an ice/water mixture, stirred for 5 minutes and extracted three times with methylene chloride. The organic phases were each washed once with water and saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The crude product (546 mg) was separated on silica gel using a 9:1 mixture of hexane and acetone as the eluent. There were obtained 42 mg (14% of theory) of 2,2,2-trichloro-ethyl (3RS,4RS)-4-[4-[2-(morpholin-4-ylcarbonyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 665.3, 667 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:20]1[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>CN(C=O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:20]2[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)[O:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CC1CCOc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCOc2cccc(Oc3ncc([N+](=O)[O-])cn3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
4-methyl-3,4-dihydro-2Hchromen-5-ol (Intermediate 211, 111 mg, 0.676 mmol) was dissolved in 5.0 mL of DMF. K2CO3 (140 mg, 1.01 mmol) and 2-chloro-5-nitropyrimidine (162 mg, 1.01 mmol) were added and the reaction mixture was stirred for 1 hour at room temperature. DMF was then evaporated under high vacuum and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 1:0 to 7:3 as eluents affording the title compound (192 mg).
Reaction SMILES: Cl.Cl.[C:3]1([C@@H:9]2[CH2:14][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][N:10]2CC=C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C.[OH-].[Na+].C1(C)C=CC=CC=1>O.[Ru](Cl)(Cl)Cl>[C:3]1([C@H:9]2[NH:10][CH2:11][CH2:12][N:13]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCN1CCN(Cc2ccccc2)C[C@H]1c1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CN2CCN[C@H](c3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
In distilled water (3 mL), (R)-2-Phenyl-4-(phenylmethyl)-1-(2-propenyl)hexahydropyrazine dihydrochloride (328 mg, 1.0 mmol) produced in Example 19 was dissolved. To the solution, ruthenium chloride (5 mg, 0.02 equivalent) and activated charcoal (6 mg) were added. The mixture was stirred at 100° C. for 24 hours. To the mixture, 30 wt % aqueous solution of sodium hydroxide (295 mg, 2.2 equivalents) and toluene (3 mL) were added. The formed insolubles were separated by filtration, and washed with toluene (3 mL). After the organic layer and aqueous layer of the filtrate were separated, the organic layer was washed twice with distilled water (6 mL). The organic layer was concentrated and dried under vacuum, to obtain 227 mg of the title compound as pale brown oil (yield: 91%, chemical purity: 94.8 area %). The retention time in the chemical purity analysis method was 2.4 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:6][C:5]2[C:7]([O:20][C:21]3[CH:22]=[C:23]([F:30])[C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=3)=[CH:8][C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[CH:10][C:4]=2[O:3]1.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:27]([C:24]1[C:23]([F:30])=[CH:22][C:21]([O:20][C:7]2[C:5]3[CH2:6][C:2]([CH3:1])([CH3:31])[O:3][C:4]=3[CH:10]=[C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[CH:8]=2)=[CH:26][N:25]=1)=[O:29])[CH3:33]
Reactant: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Reactant: CCN
Product: CCNC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Example 176, from 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid (176a) and ethyl amine (1.0 mL, 2.0 M solution in THF) to give a white solid (203 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1 H) 8.12 (d, J=2.02 Hz, 1 H) 7.65 (t, J=5.43 Hz, 1 H) 7.23-7.32 (m, 1 H) 6.96-7.12 (m, 3 H) 6.78 (d, J=2.02 Hz, 1 H) 3.77 (s, 3 H) 3.40-3.58 (m, 2 H) 2.89 (s, 2 H) 1.50 (s, 6 H) 1.26 (t, J=7.20 Hz, 3 H); LCMS for C23H24FN5O4 m/z 454.20 (M+H+); Anal. Calcd. for C23H24FN5O4.0.10 AcOH: C, 60.65; H, 5.35; N, 15.24; Found: C, 60.62; H, 5.36; N, 15.28.
Reaction SMILES: C(O)(C(F)(F)F)=O.O.[Cl:9][C:10]1[S:14][C:13]([C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[C:20](=[O:44])[N:21]([CH2:28][C:29]2[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=2)[CH2:32][NH:33]C(=O)OC(C)(C)C)[C:22]3=[O:27])=[O:16])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[NH2:33][CH2:32][C:31]1[CH:30]=[C:29]([CH:43]=[CH:42][CH:41]=1)[CH2:28][N:21]1[C:20](=[O:44])[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:15]([C:13]2[S:14][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:16])[C:22]1=[O:27]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 ml of a mixture of TFA and water (9:1) are added dropwise to an ice-cooled mixture of 3.95 g (7.5 mmol) of tert-butyl 3-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzylcarbamate in 40 ml of chloroform. Ice-cooling is removed and the solution is stirred at room temperature for 2 h and then concentrated. The residue is taken up in dichloromethane/methanol (98:2) and the mixture is washed with sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated. Yield: 3.22 g (97.8% of theory);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1.[C:19](Cl)(=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Solvent: c1ccncc1
Product: CCCCCCCCCCC(=O)Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
161 mg of (±)-6-fluoro-8-amino-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione were dissolved in 3.5 ml of pyridine and esterified with 135 mg of undecanoyl chloride. After stirring at room temperature for 6 hours, the majority of the pyridine was removed in vacuo, the residue was extracted with three portions of ethyl acetate and two portions of 1N hydrochloric acid, the organic phases were washed neutral with water and with saturated sodium chloride solution, dried with sodium sulfate and concentrated. The residue was chromatographed on silica gel with chloroform/methanol (19:1). With Rf =0.27 there were eluted 182 mg of material in the form of a resin which yielded, from methanol, (±)-6-fluoro-8-undecylamido-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione in the form of colorless crystals of melting point 69°-71° C.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Sc1ncnc2ccccc12
Reactant: CN(C)c1ccccc1CCl
Product: CN(C)c1ccccc1CSc1ncnc2ccccc12
Yield: 24 %

Procedure:
The title compound(1.31 g) was prepared from 4-mercaptoquinazoline(3.0 g) and 2-dimethylamino benzyl chloride(6.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([N:17]1[C:29]2[CH:28]=[CH:27][C:26]([CH2:30][NH2:31])=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]>>[CH2:15]([N:17]1[C:29]2[CH:28]=[CH:27][C:26]([CH2:30][NH:31][C:11](=[O:13])[CH:10]([CH3:14])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CCn1c2ccccc2c2cc(CN)ccc21
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)CNC(=O)OC(C)(C)C)ccc21

Procedure:
Using 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid and (9-ethyl-9H-carbazol-3-yl)methanamine, and by the reaction and purification in the same manner as in the method described in Step 1 of Example 36, tert-butyl (3-(((9-ethyl-9H-carbazol-3-yl)methyl)amino)-2-methyl-3-oxopropyl)carbamate was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1.[CH3:16]O>>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[C:8]([CH3:15])[CH:7]=1
Reactant: CO
Reactant: Cc1cc(O)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To methanol (10 ml) was added dropwise thionyl chloride (1.92 ml, 26.3 mmol) at 0° C., 4-hydroxy-2-methylbenzoic acid (2.00 g, 13.1 mmol) was added, and the mixture was stirred at 60° C. overnight. After completion of the reaction, the solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washed twice with 5% aqueous sodium hydrogen carbonate solution (10 ml), once with 1 mol/l hydrochloric acid (10 ml), and once with water (10 ml), and the solvent was evaporated to give methyl 4-hydroxy-2-methylbenzoate (2.24 g, yield 100%).