Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O.Br[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1.BrCC1CCCCO1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:45][C:46]1[O:47][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:50]=1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Cl)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 166-169° C.; 1H NMR (300 MHz, CDCl3) δ7.29-7.18 (m, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.89 (d, J=7.82 Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.45-6.34 (m, 2H), 5.11 (d, J=16.2 Hz, 1H), 4.99 (d, J=9.2 Hz, 1H), 4.88 (d, J=9.2 Hz, 1H), 4.81 (d, J=16.2 Hz, 1H), 4.52 (t, J=8.6 Hz, 2H), 2.98 (t, J=8.60 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 162.2, 162.0, 151.6, 143.1, 141.8 (q, J=43.0 Hz), 131.6, 130.0, 128.7, 124.6, 118.8 (q, J=267.1 Hz), 119.7, 118.4, 117.1, 112.7, 109.5, 107.2, 92.9, 77.1, 72.4, 58.2, 37.1, 28.9; MS (ES+) m/z 461.9 (M+1), 463.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1.[CH:14](OCC)(OCC)OCC>O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH:14]=[N:12][C:7]=2[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Reactant: CCOC(OCC)OCC
Solvent: O
Product: COC(=O)Cc1ccc2ocnc2c1
Temperature: 25 °C

Procedure:
Methyl-2-(3-amino-4-hydroxyphenyl)acetate (1.39 g, 7.67 mmol) was combined at RT with triethyl orthoformate (10 ml). The reaction mixture was heated to reflux for 12 h and then cooled to RT. Water (70 mL) was added thereto and the reaction mixture was extracted with EA. The combined organic phases were dried over MgSO4 and filtered. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/EA=2:1).
Reaction SMILES: [CH2:1]([C:3]1([OH:13])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CC(CC(C)C)=O>[C:21]([O:13][C:3]1([CH2:1][CH3:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: CCC1(O)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)Cl
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Temperature: 90 °C
Yield: 60 %

Procedure:
180 g of 2-Ethyl-2-adamantanol, 303 g of triethylamine and 500 g of methylisobutyl ketone were mixed by stirring at 90° C. While stirring, 157 g of methacrylic acid chloride was added dropwise to the mixture. After completion of the dropwise addition, the mixture was further stirred for 72 hours. Then, extraction and distillation were conducted to obtain 2-ethyl-2-adamantyl methacrylate at the yield of 60%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:3]1.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH2:16]1[CH2:17][O:18][C:2]2([CH2:7][CH2:6][CH2:5][C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)([C:8]#[N:9])[CH2:3]2)[O:1]1
Reactant: N#CC1(c2ccccc2)CCCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: N#CC1(c2ccccc2)CCCC2(C1)OCCO2
Temperature: 111 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
The mixture of 3-oxo-1-phenylcyclohexanecarbonitrile (2.62 g), ethylene glycol (3.65 mL) and pyridinium p-toluene sulfonate (1 spatula) in benzene (40 mL) was stirred at 111° C. with Dean-Stark apparatus overnight. After cooling down to room temperature, the mixture was washed with saturated sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted with dichloromethane 3 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified by Flash Chromatography with from 25% ethyl acetate/75% hexane to 30% ethyl acetate/70% hexane over 20 minutes. The title compound was obtained as a white solid (1.66 g, 48% yield in 2 steps). 1H NMR (400 MHz, CDCl3) δ 1.56 (1H, dt, J=4, 16 Hz), 1.70-1.79 (1H, m), 1.89-1.96 (3H, m), 2.06-2.28 (3H, m), 3.89-3.97 (2H, m), 4.03-4.12 (2H, m), 7.28-7.32 (1H, m), 7.36-7.39 (2H, m), 7.48-7.51 (2H, m). HPLC purity (retention time): 95% (1.62 min, method C). MS: 266.37 (M+Na+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][C:6]=1[N+:28]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:28][C:6]1[CH:7]=[C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:9]=[CH:10][C:5]=1[C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccccn2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccccn2)cc1N
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of N-[4-(tert-butyl)-3-nitrophenyl]{2-[(2-pyridylmethyl)amino](3-pyridyl)}carboxamide (100 mg, 0.25 mmol, Example 73), iron powder (69 mg, 1.25 mmol) and NH4Cl (10 mg, 0.17 mmol) in EtOH (0.5 mL) and H2O (0.5 ml) was stirred for 4 h at 80° C. The reaction mixture was filtered, concentrated, and purified through column chromatography to give the product. MS (ES+): 376 M+H); (ES−): 374 (M−H). Calc'd. for C22H25N5O—375.21.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.Br[C:36]1[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][OH:43])[N:37]=1>>[NH2:34][C:10]1[N:11]=[C:12]([N:14]2[CH:23]([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:36]4[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][OH:43])[N:37]=4)=[CH:19][CH:20]=3)[CH2:15]2)[CH:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:9]=1
Reactant: OCCn1ccc(Br)n1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccn(CCO)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 82B, Step 3 starting from 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and 2-(3-bromo-1H-pyrazol-1-yl)ethanol. LCMS (M+H)+: m/z=449.3.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].[OH-].[K+].I[CH:15]([CH3:17])[CH3:16]>C1COCC1.CC(OC)(C)C>[CH:15]([O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10])([CH3:17])[CH3:16]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C=O)cc(C)c1OC(C)C

Procedure:
4-Hydroxy-3,5-dimethylbenzaldehyde (2.5 g, 16.6 mmol) in THF (100 mL) was treated with KOH (1.5 eq. of 1 N aq. solution, 25 mL) and 2-iodopropane (2.0 eq.) and heated at reflux for 5 days. The reaction was then cooled, transferred to a separatory funnel, diluted with MTBE, washed with H2O, 1 N NaOH (twice), 0.5 N HCl (aq.), brine, dried over MgSO4 and concentrated. The product was purified over silica gel on an ISCO combiflash to yield 1.99 g (10.34 mmol) 4-isopropoxy-3,5-dimethylbenzaldehyde as a colorless liquid. H1 NMR (300 MHz, CDCl3) 9.89 (s, 1H), 7.55 (s, 2H), 4.41-4.26 (m, 1H), 2.32 (s, 6H), 1.32 (d, J=6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:22][O:23][CH3:24])[C:5]=1[CH3:11]
Reactant: COC(=O)c1cccc(O)c1C
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0° C. under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50% complete by tlc (1:2 ethyl acetate/hexanes, 12) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0° C. and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate/hexanes) affording 0.44 g (69%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[CH:4][N:3]=1.[H-].[Na+].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[O:9][C:17](=[O:18])[NH:8][C:6]=2[N:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(O)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc2oc(=O)[nH]c2n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,4-Diamino-pyrimidin-5-ol (500 mg, 3.97 mmol) [prepared according to the method of Hull. J. Chem. Soc. 1956, 2033-2035] was suspended in DMF (10 mL). To this was added consecutively NaH (86.7 mg, 3.77 mmol) and CDI (707 mg, 4.36 mmol), and the reaction mixture was heated with vigorous stirring at 60° C. for 3 h. The mixture was cooled to ambient temperature, and then quenched with water (25 mL). The solvent and water were removed via rotary evaporation, and the residue was then triturated in water (5 mL). The solid was then collected by filtration and dried, affording 230 mg (38%): 1H NMR (400 MHz, d6-DMSO) δ 11.90 (br s, 1H), 7.72 (br s, 1H), 6.72 (s, 2H); Analysis calc'd for C5H4N4O2.0.2; H2O: C, 38.56; H, 2.85; N, 35.98. Found: C, 39.01; H, 2.71; N, 35.58; [M+H]+ m/z 153.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[Cl:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47](Cl)(=[O:49])=[O:48])[CH:41]=[CH:40]2.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:15]3([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)[CH2:19][CH2:20]3)[C:30](=[O:35])[CH2:31]1)(=[O:49])=[O:48])[CH:41]=[CH:40]2
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Triethylamine (253 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (258 mg) in dichloromethane (15 ml), 6-chloronaphthalene-2-sulfonyl chloride (196 mg) was added thereto at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium carbonate solution, the mixture was extracted with dichloromethane, dried, concentrated, and purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the colorless amorphous title compound (255 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:25]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:26].COC(=O)C(OC)C(C1C=CC=C(OCC2C=CC=CC=2)C=1)O>>[CH2:32]([O:31][C:29](=[O:30])[CH:28]([O:27][CH2:25][CH3:26])[CH:13]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[OH:14])[CH3:33]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOCC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Agent: [Li+]
Product: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared from 4-benzyloxybenzaldehyde, lithium diisopropylamide and ethyl 2-ethoxyacetate via the same procedure used for the preparation of 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy propionic acid methyl ester (example 9, step 1). MS (ES) for C20H24O5 [M+H2O—H]+: 327, [M+Na]+: 367.4.
Reaction SMILES: CI.[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][NH:6][C:5]1=[S:15].[OH-].[Na+].[CH2:18](Cl)Cl>CCO>[CH3:3][N:4]1[C:5]([S:15][CH3:18])=[N:6][N:7]=[C:8]1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClCCl
Reactant: Cn1c(-c2cccnc2)n[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Product: CSc1nnc(-c2cccnc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
MeI (2 mL, 32 mmol) in EtOH (10 mL) was added to a mixture of 4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione in 1 M NaOH (70 mL, 70 mmol). After 1 h stirring at r.t., DCM was added and the layers were separated. The water phase was washed with DCM and the combined organic phases were dried and concentrated to give 6.5 g (98%) of the title compound. 1H NMR: 2.76 (s, 3H) 3.59 (s, 3H) 7.43 (m, 1H) 7.99 (m, 1H) 8.71 (m, 1H) 8.86 (m, 1H)
Reaction SMILES: C([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:15][O:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1>C(O)C.[Pd].[H][H]>[OH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:15][O:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(CO[C@@H]2CCCO[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O[C@@H]1CCCO[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 90.3 %

Procedure:
3.513 g of (2S, 3R)-3-benzyloxy-2-triphenylmethoxymethyltetrahydropyran (prepared as described in Preparation 23) were dissolved in 120 ml of ethanol and hydrogenated at room temperature for 30 hours in the presence of 1.852 g of 10% w/w palladium on activated carbon in a Paal's apparatus at a hydrogen pressure of 4 atmospheres (about 4 bars). The catalyst was filtered off and the filtrate was freed from the solvent by evaporation under reduced pressure. The residue was subjected to column chromatography through 90 g of silica gel, 2.557 g of the title compound were obtained, as a colorless oil, from those fractions eluted with a 7:1 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[C:11]2[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[C:18]([CH3:21])([CH3:20])[O:19][C:10]=2[CH:9]=[C:8]([CH:22]([CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:23])[CH:7]=1.C(O)(=O)C>O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][CH:22]([C:8]2[CH:7]=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[C:11]3[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][C:17]=4[C:18]([CH3:21])([CH3:20])[O:19][C:10]=3[CH:9]=2)[CH3:23])=[CH:32][CH:31]=1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(CCCc1ccc(F)cc1)c1cc(NC(N)=O)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium cyanate (1.22 g., 0.015 mole) was added to a stirred solution of 1.95 g. (0.005 mole) of 10-amino-8-[5-(4-fluorophenyl)-2-pentyl]-5,5-dimethyl-5H-[1]benzopyrano [4,3-c]pyridine in 20 ml. of glacial acetic acid. The mixture was stirred at room temperature for 18 hours and was diluted with 80 ml. of water. After cooling in an ice bath, the aqueous acetic acid solution was decanted, the residue was triturated with water, cooled, filtered, and recrystallized from acetonitrile, m.p. 179°-181°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.CN1C[CH2:24][CH2:23][C:22]1=O.C(N(CC)CC)C.C([Sn](CCCC)(CCCC)/C=C/C)CCC>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([C@@H:12]([N:8]2[C:6]3=[N:7][C:2](/[CH:22]=[CH:23]/[CH3:24])=[CH:3][N:4]=[C:5]3[N:10]=[C:9]2[OH:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C/C=C/[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C/C=C/c1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 120 °C
Yield: 54 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), and (Ph3P)4Pd (0.12 equiv). The bottle was covered with a sheet of Parafilm and purged with nitrogen for 5 min, and N-methylpyrrolidone (14 volume equivalents), triethyl amine (2.0 equiv), and (E)-tributyl(prop-1-enyl)stannane (3.0 equiv) were added by syringe. The resulting mixture was immediately fitted with a septum and cap and heated to 120° C. in a microwave for 20 min. The reaction was then diluted with EtOAc, washed four times with saturated aq. NaHCO3 and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC provided the title compound (54%) as a foam. LCMS m/z (APCI)=281.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:11].N1C=CC=CC=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>C1(C)C=CC=CC=1>[OH:11][C:5]1[C:6]([NH:10][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=2)=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(C)c2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Thionyl chloride (30 mL) was added to 1 (4.5 g, 33 mmol) and the mixture was stirred at reflux overnight. Thionyl chloride was evaporated under reduced pressure and the residue was dried in vacuum to obtain 3-methylbenzoyl chloride (3.59 g). Methyl-3-amino-2-hydroxybenzoate (3.34 g, 20.0 mmol) and pyridine (2 mL) were added to toluene (10 mL) and the mixture was stirred at room temperature for 30 min. Then 3-methylbenzoyl chloride (1.54 g, 10 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1) to obtain methyl 2-hydroxy-3-(3-methylbenzamido)benzoate as a solid (1.8 g, yield 63%). LC-MS (ESI) m/z 287 [M+1]+.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)/[CH:13]=[CH:14]/[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C.CC(O)=O>[C:17]1([C:15]2[N:1]([C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=3)[C:6]#[N:7])[N:2]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccnc(-n2nccc2-c2ccccc2)c1
Reaction time: 12 h
Yield: 81.2 %

Procedure:
To a solution of 2-hydrazinylisonicotinonitrile (100 mg, 0.75 mmol, 1.0 eq., PREPARATION 2) and (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (132 mg, 0.75 mmol, 1.0 eq.) in ethanol (10 mL) was added 2-5 drops of AcOH. The reaction mixture was under reflux conditions for 12 h. After reaction completion, volatiles were removed under reduced pressure, and the resultant crude material was purified by flash column chromatography (20% EtOAc/hexane) to obtain the title compound as a yellow oil (150 mg, 81% yield). [M+H] Calc'd for C15H10N4, 247.09. Found 247.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[CH:15]=3)[N:10]([C:24](=[O:32])[NH:25][C:26]3[S:27][C:28]([Cl:31])=[CH:29][N:30]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[CH3:34][NH2:35]>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][C:21]([NH:35][CH3:34])=[O:22])[CH:15]=3)[N:10]([C:24]([NH:25][C:26]3[S:27][C:28]([Cl:31])=[CH:29][N:30]=3)=[O:32])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(OCCCC(=O)O)cc12
Agent: Cl
Product: CNC(=O)CCCOc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)Nc1ncc(Cl)s1

Procedure:
4-((1′-Acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)oxy)butanoic acid and methylamine hydrochloride
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.S(Cl)([Cl:14])=O>>[Cl:14][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Chloro-5-nitro-2-hydroxy-pyridine (20 g) was added in small portions to thionylchloride (200 mL) under vigorous stirring. The suspension was heated to 100° C. within 1 hour, stirred at 100° C. for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water (3×200 mL) and the organic layer was dried over MgSO4. The solvent was removed under reduced pressure to give 2,3-dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([F:16])=[C:7]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([F:16])=[C:7]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:8]([Cl:19])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1c(F)c(F)cc(C(=O)O)c1F
Solvent: c1ccccc1
Product: CC(=O)Oc1c(F)c(F)cc(C(=O)Cl)c1F
Reaction time: 4 h

Procedure:
In 200 ml of benzene was dissolved 6.10 g (0.026 mole) of 3-acetoxy-2,4,5-trifluorobenzoic acid (V), and to the solution was added 15 ml of thionyl chloride and stirred for 4 hours under reflux. After completion of the reaction, benzene and excess thionyl chloride were completely distilled off under reduced pressure to give 3-acetoxy-2,4,5-trifluorobenzoyl chloride (VI).