Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:29])=[O:28]
Reactant: OCCCCCCOc1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCCOc1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
To a mixture of 10.4 g. of 6-(2-naphthyloxy)-1-hexanol and 8.1 g. of triethylamine in 250 ml. of dichloromethane chilled to -8° C. under nitrogen is added dropwise 5.1 g of methanesulfonyl chloride. After one hour at 0° to -8° C., the mixture is washed with cold water, 10% hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried (magnesium sulfate). The solvent is removed under vacuum to give the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(Cl)c(Cl)c4)ncnc3cn2)cc1
Temperature: 52 °C
Reaction time: 240 h
Yield: 63.6 %

Procedure:
A mixture of compound 204 (2.95 g, 9.55 mmol) and 4-methoxybenzylamine (12.6 mL, 95.5 mmol) in dry DMSO (20 mL) was stirred under a nitrogen atmosphere at 52° C. (bath temperature) for 10 days. The solution was then cooled and petroleum ether (200 mL) was added. It was stirred at room temperature for 10 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (2×200 ml). Water (200 mL) was added and the mixture was stirred at room temperature for 15 min. It was filtered and washed solid with water (5×30 mL), then with petroleum ether (3×30 mL). The sticky yellow/orange solid was stirred with acetone (100 mL) at 35-45° C. (internal temperature) for 10 min. Water (100 mL) was added and stirred at room temperature for 20 min. The solid was collected by suction-filtration, washed with water/acetone (1:1) (5×20 mL), and dried in vacuum over silica-gel/KOH to give pure N4-(3,4-dichlorophenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (213) (2.59 g, 64%) as a yellow/orange solid, mp 209-211° C.; 1H NMR δ [(CD3)2SO] 9.76 (s, 1H), 8.77 (s, 1H), 8.42 (s, 1H), 8.30 (poorly resolved d, J=2.1 Hz, 1H), 7.89 (dd, J=8.8, 2.1 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.38-7.25 (m, 3H), 7.17 (s, 1H), 6.92-6.83 (m, 2H), 4.49 (d, J=6.3 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C21H17Cl2N5O: C, 59.17; H, 4.02; N, 16.43%. Found C, 58.93; H, 4.17; N, 16.12%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH2:21][C:22]([O:24]C)=O)[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[NH3:30]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[NH:30][C:22](=[O:24])[CH2:21][N:9]2[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2
Temperature: 22 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of intermediate 3, 5-benzyloxy-2-methanesulfonyl-1-methoxycarbonylmethyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester, (1.10 g, 2.59 mmol) in acetonitrile (20 ml) was treated with a freshly prepared solution of ammonia in acetonitrile (20 ml) and the resulting mixture stirred at 22° C. for 2 h. The reaction was monitored by LC/MS and rapid formation of the amino intermediate followed by cyclization was observed. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by recrystallization of the solid residue from ethyl acetate/hexane gave 0.770 g (82% yield) of the title ester as white crystals; mp 196° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, t, J=7.2 Hz, CH3), 4.39 (2H, q, J=7.2 Hz, OCH2), 4.57 (2H, s, CH2), 5.24 (2H, s, OCH2), 7.3–7.55 (5H, m, aromatics), 9.6 (1H, broad, NH). Anal. Calcd for C16H15N3O5: C, 58.35; H, 4.59; N, 12.76. Found: C, 57.99; H, 4.27, N, 12.62.
Reaction SMILES: [CH2:1]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[N:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I:18][CH3:19]>>[I-:18].[CH2:1]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N+:9]([CH3:19])=[N:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCCCn1cc(-c2ccccc2)nn1
Product: CCCCCCn1cc(-c2ccccc2)[n+](C)n1
Product: [I-]
Temperature: 40 °C

Procedure:
1-hexyl-4-phenyl-1H-1,2,3-triazole (0.58 g, 2.53 mmol) and iodomethane (2 ml, 32.0 mmol) were added to a 20 mL vial. The reaction was heated at 40° C. for 3 days. The iodomethane was allowed to evaporate in the hood. The following structure was confirmed:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH:8]([CH3:10])[CH3:9])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=1.[CH3:15][Si:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19]>>[CH:8]([N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[C:3]1[CH2:2][CH2:19][C:18]#[C:17][Si:16]([CH3:21])([CH3:20])[CH3:15])([CH3:10])[CH3:9]
Reactant: CC(C)n1c(CCl)nc2ccccc21
Reactant: CC#C[Si](C)(C)C
Product: CC(C)n1c(CCC#C[Si](C)(C)C)nc2ccccc21
Yield: 99.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from of 2-(chloromethyl)-1-isopropyl-1H-benzo[d]imidazole (500 mg, 2.4 mmol) and trimethyl(prop-1-ynyl)silane (323 mg, 2.88 mmol). 1-isopropyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (680 mg, Yield: 100%) was obtained as a brown oil which was used in the next step without any purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO>[F:12][C:10]1[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=[C:2]([CH:13]=[CH2:14])[CH:11]=1
Reactant: O=C1OCc2cc(Br)cc(F)c21
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Product: C=Cc1cc(F)c2c(c1)COC2=O

Procedure:
A mixture of 5-bromo-7-fluoro-2-benzofuran-1(3H)-one (4.6 g, 20.0 mmol), potassium vinyltrifluoroborate (2.9 g, 22 mmol) and Pd (dppf)2Cl2 (0.5 g) in 40 mL of EtOH and 40 mL of TEA was refluxed under Ar for 4 hours. After concentration, the residue was purified by column chromatography (PE:EtOAc=20:1) to afford 7-fluoro-5-vinyl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.23 (s, 1H), 7.17 (d, J=10.0 Hz, 1H), 6.70-6.77 (m, 1H), 5.89 (d, J=17.2 Hz, 1H), 5.51 (d, J=11.2 Hz, 1H), 5.28 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.ClCCl.Cl[Si](C)(C)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[O:28]>C(N(CC)CC)C>[O:30]=[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)[C:27](=[O:28])[CH3:29]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 44 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 500 ml of dichloromethane, 21.0 ml (150 ml) of triethylamine, 20 ml (158 mmol) of chlorotrimethylsilane, and 8.0 g (75 mmol) of pyruvic acid chloride, [J. Org. Chem., 35, 3972 (1970)] gives 6.6 g of 6-[4(1,2-dioxopropylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid after recrystallization from N,N-dimethylacetamide; mp>280°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=O)[O:33]C4C=CC=CC=4)[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14])[CH2:10][CH3:11])[CH3:8].C(C(NC(N1C2C(=CC(OC3C=CN=C(NC(N4CCC(N5CCCC5)CC4)=O)C=3)=CC=2)C=C1)=O)CC)C>CN(C)C=O>[CH2:7]([CH:9]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:33])[CH:26]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=[O:14])[CH2:10][CH3:11])[CH3:8]
Reactant: C1COCCN1
Reactant: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Agent: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCOCC4)c3)ccc21
Reaction time: 2 h
Yield: 29.7 %

Procedure:
N,N-dimethylformamide (3 ml) and morpholine (0.22 ml, 2.5 mmol) were added to a mixture (0.324 g) of phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate synthesized in Example 96; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield the title compound as white crystals (95 mg, 0.21 mmol).
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>C(Cl)Cl>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:38])[CH:30]=2)=[O:37])=[CH:15][CH:14]=1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and N,N-diisopropylethylamine (0.109 mL, 0.63 mmol) in 3.0 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.047 mL, 0.377 mmol) and the reaction stirred at rt for 2 hours. The reaction was quenched with 1.0 mL MeOH, stirred for 15 min and then evaporated. The sample was partitioned between EtOAc and H2O/brine mixture, the EtOAc layer washed with aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4, and evaporated to a tan solid. The solid was chromatographed eluting with CH2Cl2, EtOAc, then 3% MeOH/EtOAc to give the title compound as a white solid (79 mg, 88%). 1H NMR (DMSO-d6) δ: 8.45 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.29-7.35 (m, 2H), 7.28 (s, 1H), 7.16-7.23 (m, 2H), 7.10-7.16 (m, 1H), 6.96-7.02 (m, 2H), 6.76 (d, J=7.0 Hz, 1H), 4.33 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.7 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([O:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:11][CH2:10]3)=[C:5]([CH2:20][CH3:21])[CH:4]=2)=[CH:30][CH:31]=1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 107.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 110.0 mg, 0.39 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc—hexanes) afforded 130.0 mg (79%) of the title compound as a pale-yellow oil.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].[S:12]([O:17]C)([O:15][CH3:16])(=[O:14])=[O:13]>>[CH3:16][O:15][S:12]([O-:17])(=[O:14])=[O:13].[CH3:16][N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc2ccccc2n1
Product: COS(=O)(=O)[O-]
Product: Cc1ccc2ccccc2[n+]1C
Temperature: 100 °C
Yield: 181.9 %

Procedure:
(Method C) (Quinaldinium methyl sulphate salts) Quinaldine (6 g, 41.9 mmol) and dimethyl sulphate (5.28 g, 41.9 mmol, 1 eq) were mixed and heated on a 100° C. oil bath for 5 mins giving a yellow solid. The crude product was recrystallised by dissolving in the minimum amount of methanol at reflux, allowing to cool slightly, precipitating with diethyl ether, cooling, filtering and drying to give the title compound (10.27 g, 38.1 mmol, 91%).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]COC)[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][NH2:34]>C1COCC1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:34][CH3:33])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: COCOCCn1cc(-c2cc3c(C)nc(S(C)(=O)=O)nc3n(C3CCCC3)c2=O)cn1
Solvent: C1CCOC1
Product: CNc1nc(C)c2cc(-c3cnn(CCO)c3)c(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 70 %

Procedure:
8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.17 mmol) was dissolved into 3 ml methylamine in THF (1.0 M). The reaction mixture was then heated to 100° C. in microwave for 30 minutes. The solvent was removed via rot vap and the residue was re-dissolved in 5 ml methanol. A few drops of concentrated HCl was added the mixture was heated to 50° C. for 5 hours. The reaction mixture was cooled down to room temperature. Solvent was removed via rot vap and the residue was triturated with ethylacetate/hexane to give the title compound (45 mg, 70% yield).
Reaction SMILES: S([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[C:12]1[C:20]([O:22][CH2:23]C)=[O:21])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C1COCC1>[NH:11]1[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)c1cc2cnccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2cccnc2[nH]1
Temperature: 15 °C
Reaction time: 12 h

Procedure:
A mixture of compound 6-c (6 g, 17.4 mmol) and Cs2CO3 (CAS 534-17-8) (17 g, 52.2 mmol) in methanol (70 mL) and THF (140 mL) was stirred at 15° C. for 12 h. The solvent was removed under vacuum. H2O (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum to yield product 6-d as a white powder (1.39 g, 46%).
Reaction SMILES: O.[OH-].[Li+].O.C[O:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH3:27])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:10]=1)=[O:8]>O1CCCC1>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH3:27])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:10]=1)([OH:8])=[O:6]
Reactant: COC(=O)c1cn(-c2ncnc3c2ccn3C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2c(-n3cc(C(=O)O)c4ccccc43)ncnc21
Temperature: 20 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
0.629 g (15 mmol) of lithium hydroxide monohydrate and 20 cm3 of water are added to 1.35 g (4.41 mmol) of 3-methoxycarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole dissolved in 20 cm3 of tetrahydrofuran at a temperature in the region of 20° C. After stirring for 4 hours at the reflux temperature of the solvent and for 24 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 30 cm3 of water (pH=12) and extracted with 100 cm3 of ethyl acetate. The pH is then adjusted to 6 by adding 1 N hydrochloric acid solution. The precipitate obtained is filtered off and dried at a temperature in the region of 50° C. under reduced pressure (2.7 kPa), giving 1.0 g of 3-carboxy-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 292 (M+) (base peak).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].BrC1C=CC(O)=C[C:14]=1[CH:20]1OC[CH2:22][O:21]1.[OH-].[Na+].[C:27](#[N:29])C>>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([N:29]([CH2:14][CH2:20][O:21][CH3:22])[CH3:27])[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CC#N
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Agent: [Na+]
Agent: [OH-]
Product: COCCN(C)c1nc(Cl)ccc1C(N)=O
Temperature: 60 °C
Yield: 91 %

Procedure:
To a solution of 2,6-dichloro-nicotinamide (1) (10 g, 52.9 mmol) in acetonitrile (anhydrous, 200 mL) was added (2-methoxy-ethyl)-methyl-amine (2) (18.8 g, 212 mmol). The reaction was heated at 60° C. for 1.5 hours. 5% NaOH solution (1000 mL) was slowly added. The solution was then extracted with EtOAc (3×250 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-30% EtOAc/hexanes gradient, to afford 11.66 g (91% yield) of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.07 (d, J=8.6 Hz, 1H), 7.76 (br. s., 1 H), 6.93 (d, J=8.2 Hz, 1 H), 5.66 (br. s., 1 H), 3.66-3.51 (m, 4 H), 3.32 (s, 3 H), 2.93 (s, 3 H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[C:6]2[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:7]2=[N:8][CH:9]=1.C([O-])=O.[NH4+].C(Cl)Cl.CO>CO.[Pd]>[CH3:19][Si:17]([CH3:18])([CH3:20])[CH2:16][CH2:15][O:14][CH2:13][N:10]1[C:7]2=[N:8][CH:9]=[C:4]([CH2:2][CH2:3][OH:1])[CH:5]=[C:6]2[N:12]=[CH:11]1
Reactant: C[Si](C)(C)CCOCn1cnc2cc(C3CO3)cnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)CCOCn1cnc2cc(CCO)cnc21
Temperature: 70 °C
Yield: 51.9 %

Procedure:
6-Oxiranyl-3-(2-trimethylsilylethoxymethyl)-3H-imidazo-[4,5-b]pyridine (918 mg, 3.15 mmol) was combined with 10% Pd/C (400 mg) and ammonium formate (993 mg, 15.75 mmol) and the mixture was suspended in methanol (25 mL). The reaction mixture was heated to 70° C. for 2.5 h. After cooling to ambient temperature, the mixture was filtered through celite®, eluted with methanol, concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel using 75% ethyl acetate/hexanes then 95.5 CH2Cl2 /MeOH as the eluents, which provided 480 mg of the title compound (43% yield for 3 steps).
Reaction SMILES: N[C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][N:3]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22].C([N:26](CC)CC)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:14]=[C:12]1[NH:11][C:10](=[O:15])[C:9](=[CH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:19]3[CH:18]=[C:17]([C:21]([NH2:26])=[O:22])[O:16][CH:20]=3)[N:7]=2)[S:13]1
Reactant: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Reactant: O=C(Cl)c1ccco1
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: NC(=O)c1cc(-c2nccc(C=C3SC(=O)NC3=O)n2)co1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(Z)—N-(4-(((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)furan-2-carboxamide was prepared as follows. A 2-dram vial charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (30.4 mg, 0.137 mmol), Pyridine (1.1 mL), furan-2-carbonyl chloride (107 mg, 0.821 mmol, 6 equiv.), triethylamine (83 mg, 0.821 mmol, 6 equiv.), and shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (14 mg, 43.3 mg theoretical, 32.4%). LC-MS m/z 317.3 (M+1).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([C:9]1[N:10]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]([C:16]#[N:17])=[C:12]([C:14]#N)[N:13]=1)[CH2:6][CH2:7][CH3:8].[Cl-].[NH4+].C(OCC)(=[O:41])C>C(OCC)C.O1CCCC1>[CH2:5]([C:9]1[N:10]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:11]([C:16]#[N:17])=[C:12]([C:14](=[O:41])[CH2:1][CH3:2])[N:13]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1nc(C#N)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[Mg]Br
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(C(=O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
14 ml of a 3M solution of ethylmagnesium bromide in diethyl ether were added dropwise at 10° C. under an atmosphere of nitrogen to a solution of 8.33 g of 2-butyl-1-tritylimidazole-4,5-dicarbonitrile [prepared as described in Preparation 5(i)] in 83 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, a mixture of a saturated aqueous solution of ammonium chloride and ethyl acetate was added to the reaction mixture, whilst ice-cooling. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The crystalline product thus obtained was washed with diisopropyl ether, to give 4.56 g of the title compound, melting at 140°-143° C. (softening at 83° C.).
Reaction SMILES: [Br:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].C1C=CC=CC=1.[CH3:16][C:17]([NH2:25])([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:16][C:17]([NH:25][C:3](=[O:4])[CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[Br:1])([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)C(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(NC(=O)C(Br)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
Into a 200 ml four-necked flask, there were charged α-bromo-tert-butylacetic acid (9.8 g) and benzene (50 ml), and pyridine (50 ml) and α,α-dimethylbenzylamine (6.9 g) were dropwise added thereto while stirring at room temperature. Dicyclohexylcarbodiimide (10.8 g) was further added thereto, and the reaction was continued at 60°-70° C. for 6 hours, followed by cooling. The solvent was distilled off under reduced pressure, and the residue was extracted with hot benzene. The benzene extract was concentrated by distillation, and the residue was recrystallized from ethanol to give N-(α,α-dimethylbenzyl)-α-bromo-tert-butylacetamide (10.8 g).