Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](O)=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[CH2:15][NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][O:75][C:76](=[O:94])[C@@H:77]([NH2:93])[CH2:78][C:79]1[CH:84]=[CH:83][C:82]([C:85]2[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=2)=[CH:81][CH:80]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:23])[NH:93][C@H:77]([C:76]([O:75][CH3:74])=[O:94])[CH2:78][C:79]2[CH:80]=[CH:81][C:82]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=3)=[CH:83][CH:84]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[CH2:15][NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a stirring solution of (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (146 mg), HBTU (95 mg) and DIEA in DMF (5 mL) was added (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (79 mg). After 4 hours, a sufficient amount of water was added and the mixture extracted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated NaHCO3 and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the crude amide. The residue was purified by column chromatography on silica gel (hexanes/ethyl acetate from 80:20 to 60:40) to give the product (169 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH2:25][CH3:26])=[O:13])=[CH:9][CH:10]=1
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(Oc2ccccc2F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(Oc2ccccc2F)cc1

Procedure:
2-[4-(2-Fluorophenoxy)phenyl]propionic acid (2.32 g.) in ethanol (16 ml.) containing concentrated sulfuric acid (0.5 ml.) were refluxed for 5 hours and the alcohol removed. After dilution with water the product was isolated in ether and distilled to give ethyl 2-[4-(2-fluorophenoxy)phenyl]propionate, b.p. 176°-177° C./2.5 mm.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:35])[C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([N:21]3[CH:25]=[C:24]([C:26]4[C:27]5[CH:34]=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH:23]=[N:22]3)[CH2:18][C:19]#[N:20])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:65][N:66](C=O)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[C:19]([CH2:18][CH:17]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[C:4]([F:35])=[CH:3][C:2]([C:65]#[N:66])=[CH:7][N:6]=2)=[O:9])[CH2:11][CH2:12]1)#[N:20]
Reactant: N#CCC(CN1CCN(C(=O)c2ncc(Cl)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#CCC(CN1CCN(C(=O)c2ncc(C#N)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 150 °C

Procedure:
A mixture of 4-{4-[(5-chloro-3-fluoropyridin-2-yl)carbonyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (15 mg, 0.030 mmol, from Example 1), 2-(Dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (3.7 mg, 0.0091 mmol), Tris(dibenzylideneacetone)dipalladium(0) (3.3 mg, 0.0036 mmol) and zinc cyanide (18 mg, 0.15 mmol) in DMF (0.50 mL, 6.4 mmol) and one drop of water was degassed by purging with a stream of nitrogen for 5 minutes, then was heated in the microwave for 15 minutes at 150° C. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (6 mg, 40%). 1H NMR (300 MHz, d6-dmso): δ 12.10 (br s, 1H), 8.93 (t, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.59 (dd, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.65-3.58 (m, 2H), 3.25-3.19 (m, 2H), 3.19-3.13 (m, 2H), 2.92-2.78 (m, 2H), 2.66-2.25 (m, 4H); LCMS (M+H)+: 485.2.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][NH:14]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][N:14]2[CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2)on1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of (S)-Azetidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide; hydrochloride (78.6 mg; 0.303 mol) in DMF (1 mL) is added tetrahydro-4H-pyran-4-one (0.056 mL; 0.606 mmol) and acetic acid (0.069 mL; 1.212 mmol). The reaction is stirred at room temperature for 50 minutes before adding sodium cyanoborohydride (57 mg; 0.909 mmol). The reaction mixture is left stifling at room temperature for 18 hours. After this time, the reaction mixture is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 308 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[Br:10]Br>C(Cl)Cl>[Br:10][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=1
Reactant: Cc1ccnc(C)c1N
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(Br)nc(C)c1N

Procedure:
To a solution of 2,4-dimethylpyridin-3-amine (2.0 g, 16 mmol) in CH2Cl2 (20 mL), was added a solution of bromine (3.16 g; 20 mmol) in CH2Cl2 (5 mL) at 0° C. for 5 min. The reaction was concentrated under vacuum. The reaction was poured into H2O (50 mL), extracted with CH2Cl2, washed with Na2SO3 solution, and dried over MgSO4. The CH2Cl2 was concentrated under vacuum to afford the crude compound. The crude was purified over SiO2 to afford to give 6-bromo-2,4-dimethylpyridin-3-amine. 1HNMR (CDCl3, 400 MHz) δ 2.10 (s, 3H), 2.31 (s, 3H), 4.85-5.10 (b, 2H), 7.05 (s, 1H). Exact mass calculated for C7H9BrN2 201.06. found 202.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][CH:3]=1.Cl[C:9]([O:11][CH3:12])=[O:10]>>[CH3:7][C:5]1[S:4][CH:3]=[C:2]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=1
Reactant: Cc1cc(Br)cs1
Reactant: COC(=O)Cl
Product: COC(=O)c1csc(C)c1

Procedure:
Alternatively, initial lithiation of 3-bromo-5-methylthiophene followed by capture with methyl chloroformate gives methyl 5-methylthiophene-3-carboxylate. Free-radical bromination of the methyl group provides 5-(bromomethyl)thiophene-3-carboxylic acid. ##STR46##
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][C:9]([C:26]#[N:27])([C:11]2[C:19]3[C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[O:16][C:15]=3[C:14]([O:24][CH3:25])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=O)=[O:4].Cl.[C:30]([NH2:33])(=[NH:32])[CH3:31].C[O-].[Na+]>CO>[CH3:25][O:24][C:14]1[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[C:19]=2[C:11]([C:9]2([C:26]#[N:27])[CH2:8][CH2:7][C:6]3[N:32]=[C:30]([CH3:31])[NH:33][C:3](=[O:4])[C:5]=3[CH2:10]2)=[CH:12][CH:13]=1
Reactant: CC(=N)N
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2(C#N)CCc3nc(C)[nH]c(=O)c3C2)c2c1oc1ccccc12
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a mixture of the compound obtained in example 1 (200 mg, 0.53 mol), acetamidine HCl (124.5 mg, 1.32 mmol) and sodium methoxide (98.3 mg, 1.85 mmol) in 7 ml of methanol was stirred at 60-70° C. for 18 hrs under nitrogen atmosphere. Once the reaction is complete, the reaction mass was evaporated under vacuum and the residue was diluted with ethyl acetate and water. The organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to get 200 mg (40% yields) of the solid product. MP-more than 300° C.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.I[C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[CH2:16][OH:17].[CH:23](=[N:25][S:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[CH3:24].[NH4+].[Cl-]>C1COCC1>[C:28]([S:26]([NH:25][CH:23]([C:14]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=1[CH2:16][OH:17])[CH3:24])=[O:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC=NS(=O)C(C)(C)C
Reactant: OCc1cc(Cl)ccc1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(NS(=O)C(C)(C)C)c1ccc(Cl)cc1CO
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of iPr2NH (0.31 mL, 2.24 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added 2.5M n-BuLi in THF solution (0.75 mL, 1.86 mmol). The solution was stirred for 15 min at −78° C. and added to it in one portion was 2-iodo-5-chlorobenzyl alcohol (0.5 g, 1.86 mmol). This solution was stirred for 30 min at −78° C. then was concentrated in vacuo and placed under high vacuum for 1 h. The residue, under nitrogen atmosphere, was dissolved in THF (20 mL), cooled to −78° C., and 2.5M n-BuLi in THF solution (0.75 mL, 1.86 mmol) was added. This solution was stirred for 15 min at −78° C. and added drop wise was N-ethylidene-2-methyl-2-propanesulfinamide from the previous step (0.274 g, 1.86 mmol) dissolved in THF (5 mL). This solution was stirred for 30 min at −78° C. then was allowed to equilibrate to ambient temperature over 1 h. Saturated NH4Cl was added (3 mL), and the mixture was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography eluting with a methanol in dichloromethane gradient (1% to 3% MeOH in 0.5% increments). After concentration of desired fractions in vacuo, the separate isomers of 2-(1-tert-butylsulfinamidylethyl)-5-chlorobenzyl alcohol were obtained as a yellow oils (isomer 1(less polar) 120 mg; HPLC RT=2.93 min, method A; LC-MS m/z=290.1; 1H NMR, 400 MHz, CDCl3, 7.38 ppm (s, 1H), 7.36 ppm (d, 1H), 7.28 ppm (dd, 1H), 4.86 ppm (d, 1H), 4.82 ppm (m, 1H), 4.54 ppm (d, 1H), 4.3 ppm (br s, 1H), 3.94 ppm (d, 1H), 1.54 ppm (d, 3H), 1.2 ppm (s, 9H); isomer 2(more polar) 38 mg; HPLC RT=2.69 min; LC-MS m/z=290.1; 1H NMR, 400 MHz, CDCl3 7.4 ppm (d, 1H), 7.365 ppm (d, 1H), 7.28 ppm (dd, 1H), 4.86 ppm (m, 1H), 4.78 ppm (dd, 1H), 4.64 ppm (dd, 1H), 3.67 ppm (br s, 1H), 3.65 ppm (d, 1H), 1.52 ppm (d, 3H), 1.18 ppm (s, 9H)).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=O)[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)(Cl)(Cl)[Cl:42]>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]([Cl:42])[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)C(Cl)=Nc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of resin-supported triphenylphosphine (3 mmol triphenylphosphine/g resin; 58.6 g) and N-(4-benzyloxy-phenyl)-2,2,2-trifluoro-acetamide in carbon tetrachloride (800 ml) was heated to reflux under nitrogen for 18 h. The mixture was allowed to cool then filtered, washing the resin with dichloromethane (1l) and ether (1l). The organics were concentrated in vacuo to give the title compound as a yellow solid (20.7 g). T.l.c. (Cyclohexanelethyl acetate (9:1)) Rf 0.81
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[OH:17][CH2:18][CH2:19][C:20](=O)[CH3:21].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH:20]([CH3:21])[CH2:19][CH2:18][OH:17])[CH2:10]3)=[CH:7][CH:8]=1
Reactant: CC(=O)CCO
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CCO)N1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a suspension of (1S,5R)-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Preparation 18, 100 mg) in tetrahydrofuran (1.1 mL), 4-hydroxy-2-butanone (0.66 mmol), acetic acid (0.66 mmol) and NaBH(OAc)3 (0.88 mmol) were added. The mixture was stirred at room temperature for 2 h. After addition of NaOH (1M), the solvent was eliminated under vacuo, the residue was dissolved in ethyl acetate and the organic layer was washed with H2O and dried over Na2SO4. This solution was concentrated in vacuo to give 130 mg of the title compound which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH:22]([CH3:21])[CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:7]=2[CH:13]=1
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc2c(c1)N(C(C)CN1CCN(C(=O)OC(C)(C)C)CC1)C(=O)CO2

Procedure:
6-Methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48, 440 mg, 2.5 mmol) was deprotonated with sodium hydride (125 mg, 60% in oil, 3.2 mmol) and alkylated with tert-butyl 4-{3-[(methylsulfonyl)oxy]propyl}piperazine-1-carboxylate (Intermediate 120, 2.5 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/2-propanol (95:5) gave 1.25 g (quantitative) of the product as a yellow oil.
Reaction SMILES: C([O-])(=O)C.[NH4+].C(O)(=O)C.O[N:11]=[C:12]([CH:18]([CH2:23][C:24](=O)[CH3:25])[CH:19]([CH3:22])[CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O>[CH:19]([C:18]1[CH:23]=[C:24]([CH3:25])[NH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:20][CH3:21])[CH3:22]
Reactant: CCOC(=O)C(=NO)C(CC(C)=O)C(C)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)cc1C(C)CC
Temperature: 100 °C

Procedure:
Ammonium acetate (92.5 g) was added to the acetic acid solution (430 mL) of the compound prepared in Example 16 under argon gas atmosphere. The reaction mixture was stirred at 100° C. for an hour. Water was added to the reaction mixture, and the reaction mixture was stirred for an hour. A precipitate was filtrated. The precipitate which was filtrated was dissolved in methylene chloride again, and the solution was purified by column chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain a title compound (44.1 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][C:28]#[N:29])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (150 mg, 0.55 mmol) was suspended in dimethylformamide (10 ml). To the suspension were added potassium carbonate (81 mg, 0.59 mmol) and chloroacetonitrile (44 mg, 0.59 mmol) in order. The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (1% ammonia, 5% methanol/chloroform) to give the subject compound (58 mg, yield 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[O:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([C:14]3([OH:17])[CH2:15][CH2:16][O:12][CH2:13]3)[O:9][C:8]=12
Reactant: O=C1CCOC1
Reactant: COc1nccc2ccoc12
Product: COc1nccc2cc(C3(O)CCOC3)oc12
Yield: 50.7 %

Procedure:
Starting from 7-methoxyfuro[2,3-c]pyridine (2.5 g) and dihydrofuran-3-one (1.7 g). Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a brown oil (2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([NH:22]C(=O)OC(C)(C)C)[CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:30][CH3:31].C(O)(C(F)(F)F)=O>ClCCl>[NH2:22][C:18]1([C:16]([NH:15][C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:30][CH3:31])[CH:4]=3)=[CH:10][CH:11]=2)=[O:17])[CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc(Oc2ccc(NC(=O)C3(NC(=O)OC(C)(C)C)CCC3)cn2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)C3(N)CCC3)cn2)ccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of 1,1-dimethylethyl (1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}cyclobutyl)carbamate (Intermediate 101, 80 mg) in dry dichloromethane (2 mL) cooled to 0° C. TFA (0.865 mL, 11.23 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours, it was then allowed to reach room temperature. Dichloromethane and the excess of TFA were evaporated. The residue was diluted with dichloromethane (5 mL) and neutralized with a saturated solution of NaHCO3. The organic layer was separated, dried over sodium sulphate, filtered and evaporated to afford the tilte as a white solid (60 mg).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>ClCCl.CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCCCCCO
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCOC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.6 %

Procedure:
Under a nitrogen atmosphere, 4-iodobenzoic acid (1a) (10.6 g, 42.9 mmol) was dissolved in anhydrous dichloromethane (140 mL), and several drops of anhydrous N,N-dimethylformamide were added. Thereafter, oxalyl chloride (4.50 mL, 42.4 mmol) was added at 0° C., and the mixture was stirred at room temperature for 10 hr. The solvent was removed, anhydrous pyridine (70 mL) and n-heptanol (7.0 mL, 49.4 mmol) were added, and the mixture was stirred at 70° C. for 5 hr. The reaction solvent was removed, the residue was diluted with ethyl acetate, washed with distilled water and saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:19) to give heptyl 4-iodobenzoate (2a) (14.5 g, yield 97%) as an oily liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20](O)=[O:21])=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:34][C:35]1([CH2:38][OH:39])[CH2:37][CH2:36]1.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[OH:39][CH2:38][C:35]1([NH:34][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:21])[CH2:37][CH2:36]1
Reactant: NC1(CO)CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(CO)CC5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 8.1 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added (1-aminocyclopropyl)methanol (59 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 25% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(1-(hydroxymethyl)cyclopropyl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 8.1%) as a yellow solid. MS: (M+H)+=363; 1H NMR (300 MHz, DMSO): δ 13.36 (s, 1H), 12.81 (s, 1H), 9.16 (s, 1H), 8.75 (s, 1H), 8.40-8.38 (m, 2H), 7.43 (s, 1H), 7.16 (d, 1H, J=8.7 Hz), 4.89 (brs, 1H), 3.59 (brs, 2H), 2.54 (s, 3H), 0.92-0.83 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH3:13])[CH2:9][CH2:8][CH2:7]2.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](Cl)=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>C1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:12]=2[CH3:13])[CH2:9][CH2:8][CH2:7]3)=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: Cc1cc2c(cc1CCN)CCC2
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)NCCc2cc3c(cc2C)CCC3)cc1OC

Procedure:
5-Aminoethyl-6-methylindan (4.0 g, 0.029 mole) was dissolved in 100 ml of dry benzene, 4 ml of triethylamine was added and a solution of the previously prepared 3,4-dimethoxyphenylacetyl chloride in dry benzene was added to the substituted indan mixture. The reaction mixture was refluxed for several hours and then gently heated overnight at a temperature below reflux. The reaction was then cooled, washed with 3×100 ml of 20% HCl solution, 3×100 ml of 8% NaHCO3 solution and 2×125 ml of water. The benzene layer was then reduced in volume on a rotary evaporator to yield a solid precipitate. The solid was filtered, washed with benzene, air dried to yield a slightly pink powder (3.5 g, mp 144°-145° C.). The crude product was then recrystallized from benzene (large volume), mp 144°-144.5° C.