Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][O:10]C(=O)C)=[C:6]([CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:5]=[CH:4][N:3]=1.O.[NH2:28][NH2:29]>CCO>[F:26][C:25]1[C:20]([C:16]2[N:15]([CH2:14][C:6]3[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([NH:28][NH2:29])[N:3]=[CH:4][N:5]=3)[CH:19]=[CH:18][N:17]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: NN
Reactant: CC(=O)OCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Solvent: CCO
Solvent: O
Product: NNc1ncnc(Cn2ccnc2-c2ncccc2F)c1CCO
Temperature: 70 °C

Procedure:
A mixture of 163 (1.72 g, 4.6 mmol) and hydrazine monohydrate (0.95 g, 19 mmol) in EtOH (20 mL) is heated at 70° C. overnight. The solvent is removed in vacuo and the residue is triturated with ethyl acetate and ethyl ether. Filtration gives the product (164) as a white solid.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NCC(N1CCC[C@H]1C(O)=O)=O)(OC(C)(C)C)=[O:17]>C1COCC1>[CH:10]1([NH:9][C:8](=[O:17])[NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.75 h

Procedure:
A portion (10.3 g=0.05 mole) of dicyclohexylcarbodiimide (DCC) was added dropwise under stirring at 0° C. to a solution of N-Boc-glycyl-L-proline prepared in accordance with the method described in J. Chem. Soc. (C), 954 (1969) (27.2 g=0.1 mole) in dried THF (100 ml) and the reaction mixture was kept under continuous stirring for 45 minutes. To the filtrate obtained by filtering-off of dicyclohexyl urea precipitated in the mixture, was added at 0° C. a solution of 7-amino-4-methylcoumarin (8.75 g=0.05 mole) in dimethylformamide (DMF) (60 ml). After standing overnight at room temperature, the reaction mixture was concentrated in vacuo to give a residue which was dissolved in ethyl acetate (300ml.). The solution was washed successively with 1 N hydrochloric acid, aqueous 5% sodium bicarbonate and water, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was recrystalized from a binary mixture of ethyl acetate (150ml) and n-hexance (70ml) to give 20.1g (yield, 93.4%) of crystalline 7-(n-BOC-glycyl-L-prolyl)amino-4-methylcoumarin.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][O:32][CH2:33][CH2:34][OH:35])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:36]1[CH:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([CH2:31][O:32][CH2:33][CH2:34][O:35][C:41]([C:38]3[CH:39]=[CH:40][S:36][CH:37]=3)=[O:42])[C:20]=2[O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[Cl:30])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)c(Oc2c(COCCO)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: O=C(O)c1ccsc1
Product: COc1ccc(Cl)c(Oc2c(COCCOC(=O)c3ccsc3)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
By reacting 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy-methyl)-pyrimidin-4-yl]-benzenesuiphonamide with 3-thiophencarboxylic acid there was obtained thiophene-3-carboxylic acid 2-[6-(4-tert-butyl-phenylsulfonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylmethoxy]-ethyl ester. MS: M=631.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][NH:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1.CCN(CC)CC>C(Cl)Cl>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][N:7]([CH3:6])[C:1](=[O:4])[CH:2]=[CH2:3])=[CH:10]1
Reactant: CNCc1c[nH]c2ccccc12
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Acryloyl chloride (0.33 mL, 4.10 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (0.60 g, 3.70 mmole) and Et3N (1.03 mL ,7.40 mmole) in CH2Cl2 (30 mL) at 0° C. The reaction was held at 0° C. for ten minutes, then was stirred overnight at RT. The solution was concentrated in vacuo and the residue was diluted with water. The solution was extracted with ethyl acetate, and the combined organic extracts were washed with brine and dried over Na2SO4. The title compound (0.64 g, 80%) was obtained as a light yellow solid: MS (ES) m/e 215 (M+H)+.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[Cl-].[NH4+]>CC1C=CC=CC=1.O1CCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[OH:18])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1cccnc1
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN1CCC(C(O)(c2ccc(F)cc2)c2cccnc2)CC1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred and cooled Grignard-complex previously prepared starting from a mixture of 134 parts of 4-chloro-1-methylpiperidine, 25 parts of magnesium and 652.5 parts of tetrahydrofuran was added dropwise a solution of 170 parts of (4-fluorophenyl)(3-pyridinyl)methanone in 405 parts of tetrahydrofuran at a temperature between 10°-20° C. Upon completion, stirring was continued for 1 hour at room temperature and for 30 minutes at minutes at reflux. After cooling, the whole was decomposed by pouring onto a mixture of crushed ice and ammonium chloride. 270 Parts of methylbenzene were added. The organic layer was separated, dried, filtered and evaporated. The residue was boiled in acetonitrile with activated charcoal. The latter was filtered off over Hyflo and the filtrate was evaporated, yielding 240 parts (95%) of α-(4-fluorophenyl)-α-(1-methyl-4-piperidinyl)-3-pyridinemethanol as a residue (intermediate 18).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][I:33]>CN(C=O)C>[I-:33].[CH3:32][N+:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:19]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1ccccc1-c1cccc(/C=C/C(=O)Nc2ccc(CN3CCCCC3)cc2)c1
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cccc(/C=C/C(=O)Nc2ccc(C[N+]3(C)CCCCC3)cc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.7 %

Procedure:
In DMF (6 ml) was dissolved (E)-N-[4-(piperidinomethyl)phenyl]-3-(2-methylphenyl)cinnamamide (0.62 g), and to the mixture was added methyl iodide (0.64 g). The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was solidified with ethyl acetate to give (E)-1-methyl-1-[4-(3-(2-methylphenyl)cinnamamido)benzyl]-piperidinium iodide (Compound 73) (0.79 g) as pale yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>O1CCOCC1>[Cl:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]2[NH:1][C:14](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Temperature: 42 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. product of Example 1, Step A) (97 g, 520 mmol) stirred in dry dioxane (750 mL) at room temperature, trichloromethyl chloroformate (63 g, 320 mmol) was added dropwise. The reaction mixture exothermically warmed slowly to 42° C., and the solid almost completely dissolved before a thick suspension formed again. After the suspension was stirred at ambient temperature for 2.5 hours, the title compound was isolated by filtration, washed with ethyl ether, and dried to yield the title product compound, obtained as a white solid (98 g).
Reaction SMILES: [CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].N1C=CN=C1.[NH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCCC1>[N:35]1([NH:34][C:17](=[O:18])[O:14][C:11]2[CH:10]=[C:9]3[C:8](=[CH:13][CH:12]=2)[N:7]([CH3:15])[C@H:6]2[N:5]([CH3:16])[CH2:4][CH2:3][C@@:2]32[CH3:1])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NN1CCOCC1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CN1CC[C@@]2(C)c3cc(OC(=O)NN4CCOCC4)ccc3N(C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 12.6 %

Procedure:
Eseroline (3 g) and 1,1'-carbonyldiimidazole (2.3 g) were heated in 150 ml dry tetrahydrofuran (THF) at reflux under nitrogen for one hour. After cooling to +5° C., 0.5 g imidazole was added and a solution of 4-aminomorpholine (3 g) in 30 ml dry THF was dropped into the mixture within 30 minutes. When the addition was complete the mixture was warmed to room temperature and stirred for five hours and thereafter stored in a refrigerator overnight. The THF was evaporated and the oily residue purified by chromatography on neutral alumina with CH2Cl2 /MeOH (95:5). The resulting oil was crystallized from ether/hexane to give a solid (0.6 g) which was combined with 0.5 g obtained from similar experiments and recrystallized from the same solvent mixture. This yielded 1.0 g of crystals, m.p. 115°-117° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: N#Cc1ccc2nc(S)sc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(Sc3ccc([N+](=O)[O-])cc3Cl)sc2c1
Yield: 93.2 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-6-carbonitrile (241) (960 mg, 5.0 mmol), 2-chloro-1-fluoro-4-nitrobenzene (Aldrich, 878 mg, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 261 (1.62 g, 93%) was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH2:25]([O:27][NH2:28])[CH3:26].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH2:25]([O:27][N:28]=[C:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:14][CH2:13][CH:12]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9](=[O:11])[CH3:10])[CH2:17][CH2:16]2)[CH2:19][CH2:20]1)[CH3:26]
Reactant: CCON
Reactant: CC(=O)N(c1ccc(F)cc1)C1CCN(C2CCC(=O)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCON=C1CCC(N2CCC(N(C(C)=O)c3ccc(F)cc3)CC2)CC1
Temperature: 80 °C

Procedure:
N-(4-fluorophenyl)-N-(1-(4-oxocyclohexyl)piperidin-4-yl)acetamide (100 mg; 0.3 mmol; 1 eq.) was dissolved in pyridine (2 mL). O-ethylhydroxylamine (22 mg, 0.36 mmol; 1.2 eq.) was added. The solution was heated to 80° C. for 30 min. Saturated NaHCO3 (10 mL) was added and the solution was extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reversed-phase HPLC (2-99% CH3CN/H2O gradient with 0.05% TFA) to provide the desired product. LC/MS m/z 333.2, Retention time=1.79; 10-99% CH3CN/H2O gradient with 0.05% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH3:21])[CH:12]=1)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/[N:48]=N/C(OC(C)C)=O)=O)C.P(N=[N+]=[N-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C[O:76][C:77](=O)[C:78]1[C:83]([NH:84][C:85]([CH:87]2[CH2:89][CH2:88]2)=[O:86])=[CH:82][CH:81]=[CH:80][C:79]=1[CH2:90]Br.C(N(CC)CC)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][CH:9]([N:48]1[C:77](=[O:76])[C:78]2[C:79](=[CH:80][CH:81]=[CH:82][C:83]=2[NH:84][C:85]([CH:87]2[CH2:89][CH2:88]2)=[O:86])[CH2:90]1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH3:21])[CH:12]=1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Reactant: CCOc1cc(C(O)Cc2c(Cl)cncc2Cl)ccc1OC
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(Cc2c(Cl)cncc2Cl)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.6 %

Procedure:
To a mixture of 2-(3,5-dichloro-pyridin-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)-ethanol (500 mg, 1.5 mmol) and PPh3 (0.60 g, 2.3 mmol), was added DIAD (0.44 mL, 2.2 mmol) at 0° C. After 5 min, (PhO)2PON3 was added to the mixture at 0° C. The mixture was allowed to warm to room temperature overnight. To the mixture was added PPh3 (0.9 g, 3.5 mmol) and water (2 mL). The mixture was heated to reflux for 6 hrs. The mixture was extracted with ether (25 mL) and 1N HCl (2×25 mL). The aqueous layer was basified with 10 N sodium hydroxide until pH=14. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layer was concentrated to give an oil. A mixture of the resulted oil, 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (100 mg, 0.64 mmol) and triethyl amine (0.1 mL, 0.7 mmol) in DMF (5 mL) was heated at 80° C. for 27 hrs. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL). The solvent was removed in vacuo. The residue was purified with Preparative HPLC to give cyclopropanecarboxylic acid {2-[2-(3,5-dichloro-pyridin-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (130 mg, 16% yield): mp, 159–161° C.; 1H NMR (CDCl3) δ 0.81–0.91 (m, 2H, CH2), 1.01–1.09 (m, 2H, CH2), 1.45 (t, J=7 Hz, 3H, CH3), 1.56–1.63 (m, 1H, CH), 3.68 (dd, J=4, 13 Hz 1H, CHH), 3.79 (dd, J=11, 13 Hz, 1H, CHH), 3.89 (s, 3H, CH3), 3.91 (d, J=17 Hz, 1H, NCHH), 4.08 (q, J=7 Hz, 2H, CH2), 4.56 (d, J=17 Hz, 1H, NCHH), 5.94 (dd, J=4, 11 Hz, 1H, NCH), 6.86 (m, 4H, Ar), 7.41 (t, J=8 Hz, 1H, Ar), 8.40 (d, J=8 Hz, 1H, Ar), 8.43 (s, 2H, pyr), 10.28 (s, 1H, NH); 13C NMR (CDCl3) δ 8.27, 14.76, 16.09, 33.22, 46.71, 52.63, 56.00, 64.66, 111.44, 112.69, 116.62, 116.95, 117.67, 119.52, 130.65, 133.11, 133.19, 137.96, 141.40, 142.89, 147.59, 148.75, 149.52, 169.32, 172.75; Anal Calcd for C28H27N3O4Cl2: C, 62.23; H, 5.04; N, 7.78. Found: C, 61.99; H, 5.09; N, 7.43.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F-].[Cs+].[N+](C1C=C(S(O[CH2:26][C@H:27]2[O:29][CH2:28]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[O:29]1[CH2:28][C@H:27]1[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1cccc2[nH]ccc12
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
4-Hydroxyindole (3.0 g) was dissolved in DMF (10 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride (10.12 g) was added thereto and the mixture was stirred for 1 hour. Then (S)-glycidyl m-nitrobenzenesulfonate (5.84 g, 99.3% e.e.) was added thereto and the mixture was stirred for 30 hours at the same temperature. After the reaction, water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/isopropyl alcohol; 20:1) to give 4.01 g of (S)-4-(2,3-epoxypropoxy)indole (yield 94.1%, optical purity 99.2% e.e.) as a colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([OH:43])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([OH:43])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
The compound obtained in Example 5 (10.0 g) is dissolved in chloroform (20 ml), and thereto are added a 4M solution of hydrogen chloride in ethyl acetate (60 ml). The mixture is stirred at room temperature overnight. The resulting suspension is neutralized with 2M aqueous sodium hydroxide solution (120 ml) under ice-cooling, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is dissolved in a small amount of ethyl acetate, and crystallized from diethyl ether to give 2-(4-aminophenyl)-7-hydroxy-6-methoxy-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (5.47 g).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOCC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of N2-butyl-8-(methyloxy)-9-[3-(tetrahydro-2H-pyran-4-yl)propyl]-9H-purine-2,6-diamine (93.13 mg, 0.257 mmol) in methanol (10 ml) was added 4M HCl in dioxane (1.5 ml, 6 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated under a steam of nitrogen and the residue was redissolved in methanol (5 ml) and loaded onto a 5 g aminopropyl SPE cartridge and eluted with methanol. The eluant was evaporated under a stream of nitrogen to give the title compound (64 mg).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][S:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[OH-].[Na+]>C1COCC1.CO.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]([C:9]2[CH:8]=[N:7][C:6]([S:5][CH2:4][C:3]([OH:22])=[O:2])=[N:11][CH:10]=2)=[O:21])=[CH:15][CH:16]=1
Reactant: COC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 86.7 %

Procedure:
To a solution of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid methyl ester (95.5 mg, 0.3 mmol) in THF (2 mL) and methanol (0.25 mL) was added 1 N NaOH (0.3 mL). After 20 min an additional 0.2 mL of 1 N NaOH was added, and after 40 min an additional 0.1 mL 1 N NaOH was added. After 45 min total reaction time the solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and washed once with water. The aqueous layers were combined and acidified to pH 1 with 3% HCl resulting in the formation of a solid precipitate. The solids were collected by filtration, washed and dried to afford 79.9 mg (88% yield) of the titled acid as a pale beige solid. API-MS m/z 308 (MH+), 306 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[C:6]([CH3:16])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:24]2=[S:25])=[C:6]([CH3:16])[CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cccc(Cl)c1NCCCNC(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(Cl)c1N1CCCN(C(C)C)C1=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To an ice-cold solution of the diamine of Step A (8.2 g) and triethylamine (9.09 mL) in dry chloroform (180 mL) under nitrogen was added thiophosgene (3.92 mL). After 10 minutes in the cold and 30 minutes at ambient temperature, the pH was adjusted to 8 with triethylamine and the reaction was quenched with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate, and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided a white crystalline solid which was triturated with diethyl ether to give the title product (4.5 g, 46%), m.p. 135-136° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25](OCC)=[O:26])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].OC1C=CC=CC=1[NH:37]C1N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[CH2:61]([OH:63])C>[Pd]>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:5]1[N:6]=[C:7]2[C:2]([NH:1][C:61](=[O:63])[N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:3]([C:25]([NH2:37])=[O:26])[N:4]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2O)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(Nc2ccccc2O)nc(Nc2ccccc2OC)c1N
Reactant: CCO
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3O)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Ethyl 5-amino-2-(2-hydroxyphenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl 2-(2-hydroxyphenylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (362 mg, 0.851 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (91 mg, 0.085 mmol) was added. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen overnight. The reaction was then filtered through Celite, solvent was removed under reduced pressure and purified by column chromatography (50% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (272.6 mg, 0.689 mmol, 81% yield). MS (ESI) m/z 396.2 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)[C:4]([O:6][CH3:7])=[O:5].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[CH3:7][O:6][C:4]([C@@H:3]1[CH2:2][O:1][C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])=[N:8]1)=[O:5]
Reactant: COC(=O)[C@H](CO)NC(=O)c1cccc2c1ccn2C(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1COC(c2cccc3c2ccn3C(=O)OC(C)(C)C)=N1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To a solution of tert-butyl 4-({[(1S)-1-(hydroxymethyl)-2-methoxy-2-oxoethyl]amino}carbonyl)-1H-indole-1-carboxylate (2.09 g) in THF (21.0 mL) was added Burgess Reagent (1.44 g) at ambient temperature and the mixture was stirred at 70° C. for 45 minutes. The resulting mixture was diluted with EtOAc (60 mL) and washed successively with saturated NaHCO3 aqueous solution and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=2:1) to afford tert-butyl 4-[(4S)-4-(methoxycarbonyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-indole-1-carboxylate (1.35 g) as a colorless amorphous.