Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:20][C:21]1[N:26]=[C:25]([CH2:27]O)[CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:8]([N:3]1[CH2:4][C:5](=[O:7])[N:6]([CH2:27][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:20])[N:26]=2)[C:2]1=[O:1])[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CC(=O)NC1=O)C(C)(C)C
Reactant: Cc1cccc(CO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(CN2C(=O)CN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
A solution containing the product from Example 46C (0.112 g, 0.413 mmol) in dichloromethane (3 mL) at 0° C. was treated with 6-methyl-2-pyridinemethanol (0.056 g, 0.454 mmol), triphenylphosphine (0.141 g, 0.537 mmol), followed by diethyl azodicarboxylate (0.084 mL, 0.537 mmol), stirred at 25° C. for 16 hours, treated with water (3 mL), stirred for 2 hours at 25° C., and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate/dichloromethane to give the title compound (0.151 g, 97% yield).
Reaction SMILES: CO.[NH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[OH:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[Cl:10][C:8]1[C:7]([CH3:11])=[CH:6][C:5]([OH:12])=[C:4]([NH:3][C:13](=[O:15])[CH3:14])[CH:9]=1
Reactant: Cc1cc(O)c(N)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cc(Cl)c(C)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To 30 ml of methanol, there were added 1.0 g (6.4 mmol) of 2-amino-4-chloro-5-methylphenol and 0.71 g (7.0 mmol) of acetic anhydride and stirred at room temperature for 30 minutes. To this solution, there was added 60 ml of water. The crystals thus precipitated were filtered and recrystallized from methanol. Thus 0.89 g (4.5 mmol) of N-(5-chloro-2-hydroxy-4-methylphenyl)acetamide was obtained as pale brown crystals. The yield was 70%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2/[CH:18]=[C:19]1\[O:20][C:21]2[C:28]([CH2:29][N:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)=[C:27]([OH:43])[CH:26]=[CH:25][C:22]=2[C:23]\1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>C(Cl)Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2/[CH:18]=[C:19]1\[O:20][C:21]2[C:28]([CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:27]([OH:43])[CH:26]=[CH:25][C:22]=2[C:23]\1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c(OCc5ccccc5)cccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3c(OCc4ccccc4)cccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of tert-butyl (Z)-4-[(2-{[7-(benzyloxy)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.025 g, 0.043 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was washed with methylene chloride to obtain (Z)-2-{[7-(benzyloxy)-1H-indol-3-yl]methylene}-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.017 g, 71%).
Reaction SMILES: [Na].[CH3:2]I.[Cl:4][C:5]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:6]=1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[NH:10][CH:9]=1>CN(C)C=O>[Cl:4][C:5]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:6]=1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[N:10]([CH3:2])[CH:9]=1
Reactant: COC(=O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Reactant: CI
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(Cl)cc1Cl)cn2C
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.7 %

Procedure:
60% sodium hydlide (0.07 g) and then methyl iodide (0.18 g) are added in that order to an N,N-dimethylformamide solution of 3-(2,4-dichlorobenzyl)-5-metoxycarbonylindole (0.34 g), and stirred at room temperature for 19 hours. After concentrated under reduced pressure, this is extracted with water and ethyl acetate. The resulting extract is washed with water, dried, concentrated, and purified through silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 7/1) to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonyl-1-methylindole (55) (0.30 g).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](OC(N)C)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:31](=[O:33])[CH3:32])(=O)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:9][CH2:8][CH2:7][NH:21][C:31](=[O:33])[CH3:32])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 141.7 %

Procedure:
To a mixture of [(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine (0.58 g, 1.68 mmol) in DMF (10 mL) is added acetic anhydride (0.17 g, 1.68 mmol) and DMAP (0.01 g, 0.082 mmol). The mixture is heated at 85° C. for 45 min, then partitioned between water and ether. The organic layer is washed twice with water, dried over magnesium sulfate and concentrated. Column chromatography (70 g silica gel) using CH2Cl2/acetone (80/20) as eluent gave 0.46 g (71%) of N-{2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:19]=2)[CH2:14]1)(=[O:11])=[O:10].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:19]=2)[CH2:14]1)(=[O:10])=[O:11]
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1OC)C2
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1S(=O)(=O)NC1Cc2ccc(C(=O)CCC(=O)O)cc2C1

Procedure:
Prepared analogously to Example 2 from methyl 4-(2-o-methoxybenzenesulphonamido-indan-5-yl)-4-oxobutyrate by hydrolysis with sodium hydroxide.
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[CH2:12]([NH2:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:18][C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[N:5][N:4]=1)[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccco1
Reactant: CSc1nncc2nccn12
Product: c1coc(CNc2nncc3nccn23)c1
Reaction time: 8 h

Procedure:
A 5.0 gm. portion of 5-(methylthio)-imidazo[1,2-d]-as-triazine is combined with 45 ml. of furfurylamine and refluxed for 2 hours. The mixture is allowed to stand at room temperature overnight. The gummy solid is collected and crystallized from 60 ml. of hot methanol, giving 2.75 gm. of the desired product as crystals, m.p. 212°-214° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:51]1[C:63]2[CH:62]([CH2:64][O:65][C:66](=[O:83])[NH:67][C:68]3[CH:73]=[CH:72][C:71]([NH2:74])=[C:70]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)[CH:69]=3)[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1>CN(C=O)C.CCOC(C)=O>[CH:51]1[C:63]2[CH:62]([CH2:64][O:65][C:66](=[O:83])[NH:67][C:68]3[CH:73]=[CH:72][C:71]([NH:74][C:11]([C:10]4[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:17][CH:16]=[CH:15][CH:14]=4)=[O:13])=[C:70]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[CH:69]=3)[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Reactant: O=C(O)c1cccnc1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(NC(=O)c2cccnc2OCc2ccccc2)c(OCc2ccccc2)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
2-Benzyloxy-nicotinic acid (423) (0.157 g, 0.687 mmol) was dissolved in DMF (4 mL), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.273 g, 0.721 mmol) was added followed by iPr2EtN (0.143 mL, 0.824 mmol) and the mixture was shaken in a Teflon septum capped 40 mL vial at room temperature for 25 minutes. (4-Amino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (65) (0.3 g, 0.687 mmol) was added and the mixture was shaken at room temperature for 16 h. LC-MS indicated complete coupling at this point. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), NaHCO3 (aqueous saturated, 15 mL) and brine (15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography (eluding with 15–100% EtOAc/hexane in 30 minutes) gave the desired product (424) as a yellow powder upon concentration (0.436 g, 0.673 mmol, 98% yield). LC-MS (ESI): (exact mass: 647.24) m/e=648.3 [M+1]+ (100%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C(=O)(O)[O-:12].[Na+].ClC1C=C(C=CC=1)C(OO)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3][C:2](=[O:10])[O:12]1
Reactant: O=C([O-])O
Reactant: O=C1Cc2ccccc2C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1Cc2ccccc2CO1
Temperature: 20 °C
Reaction time: 20 h
Yield: 90.4 %

Procedure:
To 6.60 g (0.050 mol) of 2-indanone in 50 mL of dry dichloromethane was added 38.0 g (0.45 mol) of powdered anhydrous sodium bicarbonate, followed by 17.0 g (0.10 mol) of m-chloroperoxybenzoic acid. After stirring at 20° C. for 20 hours, further 3.0 g (0.017 mol) of the peracid was added and stirring continued for 24 hours. After addition of 200 mL of 10% aqueous Na2S2O3 stirring was continued until two clear phases had formed. The organic solution was separated and the aqueous phase was extracted with two 100 mL portions of dichloromethane. The combined organic solutions were dried (MgSO4) and concentrated under vacuum at 30° C. Solution in a mixture of ether and pentane, filtration and concentration under vacuum gave 6.7 g (90%) of 1,4-dihydro-3H-2-benzopyran-3-one, which could be recrystallized from ether or sublimed at 30°-40° C. (0.24 mm); mp 78°-79° C.; TLC Rf 0.36 (SiO2, CH2Cl2, brown-orange with iodine).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: Oc1ccccc1Br
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccccc1OCCOC1CCCCO1
Reaction time: 1 h
Yield: 79.8 %

Procedure:
Add 2-bromo-phenol (10 g, 57.80 mmol) to a suspension of sodium hydride (60% dispersion in mineral oil, 2.77 g, 69.36 mmol) in DMF (6 mL). Stir the mixture for 1 h. Add 2-(2-bromo-ethoxy)-tetrahydropyran (13.54 g, 64.74 mmol). Stir the solution at RT overnight. Dilute the mixture with ethyl acetate and water. Wash the organic layer with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (10% ethyl acetate in hexane) to give the title compound (13.9 g, 80%) as a light yellow oil. MS (ES) m/z 323 [M+Na]+.
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:6]([C:8]([O:10]C)=[O:9])[N:7]=1)#[N:2].[OH:20][Li].O>C1COCC1.O>[C:1]([C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1)(=[O:20])[NH2:2]
Reactant: [Li]O
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(C#N)n1
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (3 g, 10.7 mmol) was dissolved in THF (30 ml) and H2O (8 ml). LiOH.H2O (1.1 g, 16.1 mmol) was added to the solution and the mixture was stirred at RT overnight. The reaction mixture was concentrated and acidified to pH 2 using 1 N HCl. The mixture was extracted with EtOAc and the organic layer was concentrated. Yield 2.2 g. 1H-NMR (400 MHz; DMSO-d6): δ −0.06 (s, 9H), 0.85 (t, 2H), 2.57 (s, 3H), 3.52 (t, 2H), 5.79 (s, 2H), 7.66 (s, 1H), 7.96 (s, 1H), 8.09 (s, 1H), 12.68 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:10]2=[O:27])[CH:5]=[CH:4][N:3]=1.Br[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[N:7]=3)[C:10]2=[O:27])=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)n3)C(C)(C)C2=O)cc1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4)n3)C(C)(C)C2=O)cc1
Temperature: 120 °C

Procedure:
To a solution of 0.45 g of 1-[(2-aminopyrimidin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage f) in 15 mL of dioxane are successively added under argon 0.29 g of 3-bromopyridine, 1.51 g of caesium carbonate, 0.085 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 0.027 g of palladium acetate. The reaction medium is heated at 120° C. for 5 hours. After cooling, the reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica, eluting with dichloromethane, to give 76 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[2-(pyridin-3-ylamino)pyrimidin-4-ylmethyl]imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])(=O)=O)=CC=1.O>CC#N.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:11]([CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])[C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CC1(C)Cn2c(nc(Cl)cc2=O)N1
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)OCCN1c2nc(Cl)cc(=O)n2CC1(C)C
Temperature: 65 °C
Yield: 59.4 %

Procedure:
To 0.200 g of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one suspended in 7 mL of CH3CN, 0.65 g of cesium carbonate and 0.51 g of 2-isopropoxyethyl 4-methylbenzenesulfonate are added. The mixture is heated to 65° C. for 36 h. Water, ethyl acetate are added and then after decantation, the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1). 0.17 g (yield=45%) of 7-chloro-1-(2-isopropoxyethyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a brown powder.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][N:17]3[C:22]=2[C:21]([NH:23][C:24]2[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)[N:28]=[CH:27]4)=[N:20][CH:19]=[N:18]3)[CH2:9][CH2:8]1)=[O:6].Cl>CO.C1COCC1>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][N:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:22]4=[C:14]([CH2:13][N:10]5[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]5)[CH:15]=[CH:16][N:17]4[N:18]=[CH:19][N:20]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: COC(=O)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aqueous NaOH (2.1 mL, 1.0 N) was added to a solution of 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid methyl ester (352 mg, 0.686 mmole) in a mixture of MeOH (0.2 ml) and THF (0.2 ml) at 0° C. After stirring at 0° C. for 1 hour, the reaction mixture was allowed to warm to RT and left stirring overnight. Aqueous HCl (2.1 ml, 1.0 N) was added dropwise and the reaction was extracted with DCM. The organic extracts were dried (Na2SO4) and the solvents were removed to leave 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid, as a solid (329 mg, purity 84% by LCMS) which was used as such. A solution of the crude acid (100 mg, 0.168 mmole) in THF (2 ml) was added dropwise to a solution of 1,1′-carbonyldiimidazole (33 mg, 0.2 mmole) in THF (0.3 ml) and this was heated at reflux for 30 min. After cooling to RT, cyclopropylsulfonamide (82 mg, 0.67 mmole, 4 equiv.) was added followed by a solution of DBU (50 uL, 0.336 mmole, 2 equiv.) in THF (0.2 ml). The reaction was stirred for 18 hr, diluted with EtOAc (120 ml), washed with pH 4.0 buffer (9 mL), brine (5 mL) and dried (Na2SO4). Removal the solvent followed by radial chromatography (2 mm silica gel plate gradient elution with DCM containing 1 to 5% MeOH) afforded the title compound as a solid (58 mg, 57%). 1H NMR (CDCl3) δ 0.98-1.00 (m, 2H), 1.22-1.27 (m, 2H), 1.84-1.92 (m, 4H), 2.03-2.16 (m, 2H), 2.24-2.3 (m, 1H), 2.83-2.92 (m, 1H), 3.08-3.11 (m, 2H), 3.74 (s, 2H), 5.54 (s, 2H), 6.46 (d, 1H, J=2.5 Hz), 6.81-6.97 (m, 3H), 7.20-7.27 (m, 1H), 7.36-7.51 (m, 3H), 7.84 (s, 1H), 8.06 (s, 2H), 11.82 (bs, 1H). MS: 603.7 (M+H+); HPLC Ret Time: 1.21 min (Gradient Time=2 min, Flow Rate=5 ml/min, Xterra 3.0×50 mm S7 C18 column).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[O:14]1[C:18]2[C:19]3[C:20](=O)[CH2:21][CH2:22][C:23]=3[CH:24]=[CH:25][C:17]=2[N:16]=[CH:15]1.[Cl-].[NH4+]>O1CCCC1>[O:14]1[C:18]2[C:19]3[C:20](=[CH:5][C:3]#[N:4])[CH2:21][CH2:22][C:23]=3[CH:24]=[CH:25][C:17]=2[N:16]=[CH:15]1
Reactant: O=C1CCc2ccc3ncoc3c21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CC=C1CCc2ccc3ncoc3c21
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
To a suspension of 60% sodium hydride (73.4 mg, 1.84 mmol) in tetrahydrofuran (8 mL) was added diethyl cyanomethylphosphonate (322 μL, 1.99 mmol) under ice-cooling, and the mixture was stirred for 15 min. Thereto was added a solution of 6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-one (265 mg, 1.53 mmol) in tetrahydrofuran (8 mL), and the mixture was further stirred for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (220 mg, yield 73%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.C([Li])CCC.[Br:16]C(Br)(Br)Br.[Cl-].[NH4+]>O1CCCC1>[Br:16][C:7]1[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][N:8]=1
Reactant: COCCCn1ccnc1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCn1ccnc1Br
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The solution of 1.05 g of 1-(3-methoxypropyl)-1H-imidazole in 14 ml of tetrahydrofuran is cooled to −70° C. and admixed slowly with 4.6 ml of n-butyllithium (1.6M in hexane). The mixture is stirred at −70° C. over 1 hour and subsequently admixed slowly with the solution of 2.54 g of tetrabromomethane in 14 ml of tetrahydrofuran. After a further 30 minutes, the reaction mixture is admixed with 25 ml of saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with brine, (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.51 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=1.78.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[C:11]([CH2:28][N:29]([CH3:31])[CH3:30])=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](S(C1C=CC=CC=1)(=O)=O)[CH:14]=[CH:13]2.[OH-].[Na+]>CCO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[C:11]([CH2:28][N:29]([CH3:30])[CH3:31])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1ccc2[nH]ccc2c1CN(C)C

Procedure:
{[5-Methoxy-1-(phenylsulfonyl)-1H-indol-4-yl]methyl}dimethylamine trifluoroacetate (127 mg, 0.278 mmol) was refluxed in EtOH (2 ml) and 1 M NaOH (2 ml) for 3 h. The mixture was extracted with DCM The product was purified on Gilson HPLC using 20-40% MeCN in 0.1% TFA. Yield: 54.6 mg (62%); colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:17].C(OC(=O)C)(=O)C>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[C:14](=[O:16])[O:15][C:11](=[O:12])[C:9]3=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:17]
Reactant: Cc1nc2cc(C(=O)O)c(C(=O)O)cc2n1C
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cc3c(cc2n1C)C(=O)OC3=O
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A mixture of the 1,2-dimethyl-5,6-benzimidazoledicarboxylic acid (1.25 g, 5.34 mmol) and acetic anhydride is stirred for 2 hours at reflux temperature, cooled to 5° and filtered. The filter cake is dried to give the title product as brown needles (1.04 g, 90.1%), mp 310°-315° C.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[N:6][CH:5]=1.ICC>>[Br:10][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=1
Reactant: COC(=O)c1cncc(Br)c1
Solvent: CCI
Product: COCc1cncc(Br)c1
Yield: 89 %

Procedure:
Prepared in a similar manner to Example 26a starting from (5-bromopyridin-3-yl)methanol (example 26d) and iodoethane. Yield: 89%. 1H NMR (400 MHz, CDCl3): δ 3.43 (s, 3H), 4.46 (s, 2H), 7.85 (s, 1H), 8.47 (s, 1H), 8.61 (s, 1H).