Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH2:12])[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:22][N:21]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:22][N:21]=1)[CH3:1]
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: CN(C)Cc1cccc(CSCCN)c1
Solvent: CCO
Product: Cc1cc(Cc2cnc(NCCSCc3cccc(CN(C)C)c3)[nH]c2=O)cnc1C

Procedure:
Reaction of 2-[3-(dimethylaminomethyl)benzylthio]ethylamine with an equimolar amount of 2-nitroamino-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone by heating under reflux in ethanol for 48 hours gives 2-[2-(3-(dimethylaminomethyl)benzylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1C(=O)O
Product: Cc1nc2ccc(Cl)cc2c(=O)o1

Procedure:
To 15 g of 2-amino-5-chlorobenzoic acid are added 80 ml of acetic anhydride, and the mixture is refluxed for 2 hours. The reaction medium is concentrated and the residue is recrystallized from ethanol. After filtering off and rinsing the precipitate, 10.25 g of the expected product are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:32]3[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=3)[O:14][C:13]3[C:15]4[C:20]([CH:21]=[C:22]([C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[C:17]([N:29]([CH3:31])[CH3:30])[CH:16]=4)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:49](Cl)(=[O:52])[CH2:50][CH3:51]>C(Cl)Cl>[CH3:39][N:38]([CH3:40])[C:35]1[CH:36]=[CH:37][C:32]([C:9]2([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:41])[CH3:1])=[CH:8][CH:7]=3)[O:14][C:13]3[C:15]4[C:20]([CH:21]=[C:22]([C:23]([O:25][CH2:26][CH2:27][O:28][C:49](=[O:52])[CH2:50][CH3:51])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[C:17]([N:29]([CH3:30])[CH3:31])[CH:16]=4)=[CH:33][CH:34]=1
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)C=Cc3c(C(=O)OCCO)cc4ccc(N(C)C)cc4c3O2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCOC(=O)c1cc2ccc(N(C)C)cc2c2c1C=CC(c1ccc(N(C)C)cc1)(c1ccc(N(C)C)cc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2,2-bis(4-dimethylaminophenyl)-5-(2-hydroxyethoxycarbonyl)-9-dimethylamino-[2H]-naphtho[1,2-b]pyran (Example 9, Step 5) (0.045 g, 0.082 mmol) and triethylamine (0.05 ml) in dry DCM (5 ml) was added propionyl chloride in one portion (0.0075 g, 0.082 mmol) and the mixture stirred at RT for 30 minutes. The solvent was then evaporated in vacuo and the crude residue purified by column chromatography (silica gel, DCM/diethyl ether, 10:1), giving the pure product, 2,2-bis(4-dimethylaminophenyl)-5-(2-propionyloxy-ethoxycarbonyl)-9-dimethylamino-[2H]-naphtho[1,2-b]pyran (0.044 g, 89%).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:12][C:9]3[CH:10]=[CH:11][C:5]4[O:4][C:3]([N:2]([CH3:1])[CH2:13][CH:14]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]5)=[N:7][C:6]=4[CH:8]=3)=[O:32])=[CH:29][N:28]=2)=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)nc4)ccc3o2)C1

Procedure:
Combine rac-N2-Methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.034 g, 0.131 mmol), 6-(4-fluoro-phenyl)-nicotinic acid (0.043 g, 0.198 mmol), HATU (0.050 g, 0.131 mmol), polystyrene-bound diisopropylamine (0.327 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (10 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Concentrate the solution in vacuo. Dilute with CH2Cl2, wash with 1.0M NaOH (2×25 mL), dry over Na2SO4, filter, and concentrate in vacuo. Subject the residue to silica gel flash column chromatography (4 g column, eluting with 10% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as an impure mixture. Re-subject the mixture to silica gel flash column chromatography (3×4 g columns, 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white oil (0.030 g, 51%). mass spectrum (m/e): 460.0 (M+1), 458.0 (M−1). 1H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.0, 2.4 Hz, 1H), 8.03-7.97 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.20-7.11 (m, 3H), 3.58-3.46 (m, 2H), 3.16 (s, 3H), 2.72-2.56 (m, 3H), 2.55-2.48 (m, 1H), 2.38-2.32 (m, 1H), 2.33 (s, 3H), 2.04-1.95 (m, 1H), 1.57-1.48 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[C:18](Cl)(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:17][C:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:3][CH2:2][NH:1][C:18](=[O:27])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCNC(=O)CCc1ccccc1
Yield: 37.9 %

Procedure:
Using the method of Example 14, 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine (100 mg, 0.44 mmol) was reacted with hydrocinnamoyl chloride (0.065 mL, 0.44 mmol) to provide 0.06 g of N1-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-3-phenylpropanamide as a white solid, m.p. 254-256° C. 1H NMR (500 MHz, DMSO-d6) δ 8.16 (d, J=8.0 Hz, 1H), 8.07 (t, J=6.0 Hz, 1H), 7.97 (s, 1H), 7.62 (dd, J=8.0, 1.0 Hz, 1H), 7.45 (dt, J=8.0, 1.0 Hz, 1H), 7.26 (m, 3H), 7.16 (m, 3H), 6.6 (broad s, 2H), 4.61 (t, J=7.0 Hz, 2H), 3.54 (q, J=6.0 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H), 2.31 (t, J=7.0 Hz, 2H); MS (EI) m/e 359.1745 (359.1746 calcd for C21H21N5O).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[NH2:15].C(O)(=O)C(C)(C)C>O1CCOCC1>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[CH:5]=[CH:4][N:3]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Clc1nccc(C2CC2)n1
Reactant: Cc1cc(N)cc(Br)c1
Agent: CC(C)(C)C(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2nccc(C3CC3)n2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 2-chloro-4-cyclopropyl-pyrimidine (12.5 g, 81 mmol) and 3-bromo-5-methylaniline (18.1 g, 97 mmol) in 1,4-dioxane (100 mL) was added pivalic acid (9.3 mL, 81 mmol). The resulting mixture was heated to reflux and left stirring for 10 hours. The mixture was allowed to cool to room temperature and hexanes were added (80 mL). The slurry was filtered and the filtrate was washed with MeOH to afford a portion of N-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine. The mother liquors were concentrated, absorbed on silica gel and purified by silica gel column chromatography (EtOAc/Hex) to afford additional N-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine as a white solid. MS ESI calcd. for C14H15BrN3 [M+H]+ 304 and 306. found 304 and 306.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To a solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (0.5 g, 2.2 mmol) in NMP (10 mL) was added 1-Boc-piperazine (0.9 g, 4.8 mmol). The reaction mixture was heated to 110° C. for 12 hours. After cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, 1H), 6.05-5.90 (m, 1H), 3.80-3.30 (m, 9H), 2.84 (m, 1H), 2.20 (m, 1H), 1.49 (s, 9H), 1.29-1.20 (m, 3H). MS (APCI+) [M+H] +377. The resulting mixture of the diastereomers was purified by chiral separation HPLC (Chiralcel ODH column, 250×20 mm, Hexane/EtOH 60:40, 21 mL/min). The first peak (RT=3.73 min) gave the tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.144 g, 24%). The second peak (RT=5.66 min) gave the tert-butyl 4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.172 g, 29%). MS (APCI+) [M+H] +377.
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-])(=O)=O)=CC=1.CC([O-])(C)C.[K+].[CH3:20][Si:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.CO>COCCOC>[CH3:20][Si:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][C:11]#[N:12]
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccnc1CC#N
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Under inert atmosphere, 0.91 g (4.6 mmol) of TOSMIC in solution in anhydrous DME (4 ml) is added to 0.96 g (8.6 mmol) of potassium tert-butylate in suspension in 4 ml of anhydrous DME at −35° C. The reaction mixture is cooled to −50° C. then 1 g (4.4 mmol) of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (Whitten J P, JOC 1986, 51 (10) 1891-1894) in solution in 4 ml of anhydrous DME is added dropwise, keeping the temperature below −45° C. The reaction mixture is stirred at this temperature for 30 min, then 11 ml of methanol is added, and the mixture is heated at 80° C. for 15 minutes. The solvents are concentrated under reduced pressure, and the residue is taken up in a water/acetic acid mixture (13 ml/0.5 ml), the aqueous phase is extracted with dichloromethane (3×100 ml), the organic phases are then washed with a saturated solution of NaHCO3, then dried over Na2SO4. After filtration, the filtrate is concentrated under reduced pressure and the residue is purified by filtration on basic alumina (eluent: A/B=DCM/AcEt 0 to 50% of B), 0.71 g of compound is thus obtained in the form of a yellowish orange oil. Yield=67%. MH+: 238 (Tr: 6.9 min, condition 1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:5]([NH2:12])[CH:6]=[N:7]2.[CH:18](OCC)(OCC)OCC.Cl.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[C:3]2[C:4]3[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:18]=[N:12][C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)CNc1c(N)cnc2cccc(Br)c12
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)Cn1cnc2cnc3cccc(Br)c3c21

Procedure:
A mixture of 5-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine (1.0 g, 3.4 mmol), triethyl orthoformate (0.9 mL, 5 mmol), and pyridine hydrochloride (117 mg, 1.0 mmol) in acetonitrile (17 mL) was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide 9-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a dark oil.
Reaction SMILES: O1C=CC=C1C(Cl)=O.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:16]=[C:17]=[S:18])=[O:15].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:16]=[C:17]=[S:18])=[O:15].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38][C:17]([NH:16][C:14]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[O:15])=[S:18])=[CH:39][CH:40]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccco1
Agent: O=C(N=C=S)c1ccco1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccco4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2-Furancarbonyl isothiocyanate was prepared using commercially available 2-furancarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Furancarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 53%).
Reaction SMILES: [H][H].[C:3](#[N:12])[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1>[Ni]>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH2:3][NH2:12])=[CH:5][CH:6]=1)#[N:9]
Reactant: [H][H]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Ni]
Product: N#Cc1ccc(CN)cc1

Procedure:
194 kg of p-cyanobenzylamine crude product (p-cyanobenzylamine 92% by weight, p-xylylenediamine 8% by weight) obtained by hydrogen reduction of terephthalonitrile in the presence of sponge metal nickel catalyst was mixed with 1,100 kg of water while stirring at 40° C. or less and the mixture was stirred for 3 hours. The crystals which precipitated were separated by centrifugation while washing with water to obtain 197 kg of p-cyanobenzylamine hydrate (water content: 21% by weight).
Reaction SMILES: Cl.[CH:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.C[O:25][C:26](=O)[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>ClCCCl>[NH2:12][C:7]1[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:10]=[CH:9][C:8]=1[NH:11][C:26](=[O:25])[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[S:34][CH:35]=[CH:36][N:37]=1
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Reactant: CC(C)c1cc(N)c(N)cn1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(N)c(NC(=O)Cn2ccnc2-c2nccs2)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 6-isopropyl-pyridine-3,4-diamine hydrochloride (265 mg, 1.41 mmol) in 1,2-dichloroethane (10 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (2.12 mL, 4.24 mmol). The mixture is stirred at room temperature for 45 min and then treated with a solution of (2-thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (252 mg, 1.13 mmol) in 1,2-dichloroethane (2 mL) via cannula, followed by a 1 mL rinse. The reaction mixture is then stirred at reflux for 20 h. After cooling, the reaction mixture is diluted with some MeOH (˜2 mL), followed by some water and then saturated aq NaHCO3. The resulting mixture is stirred vigorously for 15 min. The mixture is then extracted thrice with CHCl3 containing some (˜5) MeOH. The combined extracts are dried over Na2SO4 and concentrated. The crude residue is then triturated with CHCl3, and the resulting mixture filtered. The solid is washed with a small amount of CHCl3 and dried, affording N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide as an off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.52 (s, 1H), 7.86 (s, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.6 Hz, 1H)/, 7.39 (s, 1H), 7.04 (d, J=0.9 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 5.38 (s, 2H), 2.74 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm. The filtrate is concentrated and further purified by flash chromatography on silica gel. Elution with 20:1 CHCl3-MeOH followed by 15:1 CHCl3-MeOH affords 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 44%). 1H NMR (CDCl3, 300 MHz) δ 12.23 (br, 1H), 8.97 (br, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.23 (br, 1H), 7.20 (d, J=0.9 Hz, 1H), 7.04 (s, 1H), 5.82 (s, 2H), 3.14 (sept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br-].[CH2:12]([Zn+])[CH:13]([CH3:15])[CH3:14]>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C[Zn+]
Reactant: Brc1ccc2occc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc2occc2c1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
5-bromobenzofuran (500 mg, 2.56 mmol) was dissolved in THF solution of isobutylzinc(II)bromide (0.5M, 15 mL, 7.40 mmol) in a microwave reaction tube. Pd(PtBu3)2 (65 mg, 0.128 mmol, 0.05 eqv.) was added to this solution. The mixture was purged with N2 gas for 3-5 min and heated at 100° C. for 30 min under microwave irradiation. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with 1N HCl aqueous solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 5% EtOAc in hexanes) to give 0.331 g desired product (74% yield): 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.35 (d, 1H), 7.07 (d, 1H), 6.70(s, 1H), 2.59 (d, 2H), 1.9 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:38]=[N:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O1CCCC1>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:38]=[N:39][C:40]([F:43])=[CH:41][CH:42]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(F)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ccc(F)nc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 59 (39 mg) was dissolved in 1,4-dioxane (4 ml)-tetrahydrofuran (4 ml), and added thereto was 2N sodium hydroxide (2 ml). The mixture was stirred at room temperature for one hour. The mixture was made acidic by addition of an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the desired 1-(β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 60 (34 mg) as colorless powder. APCI-Mass m/Z 463 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.CN1[C:41](=[O:42])[CH2:40][CH2:39]C1.C(Cl)(=O)C=C>C(Cl)Cl>[O:22]([C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH:40]=[CH2:39])[CH:7]=[CH:6][CH:5]=3)[CH:14]=2)[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCCC1=O
Reactant: Nc1cccc(Nc2cc(Nc3cccc(Oc4ccccc4)c3)ncn2)c1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Nc2cc(Nc3cccc(Oc4ccccc4)c3)ncn2)c1
Reaction time: 3 h

Procedure:
To a stirred solution of N4-(3-aminophenyl)-N6-(3-phenoxyphenyl)pyrimidine-4,6-diamine (40 mg, 0.1 mmol), Et3N (0.03 mL, 0.2 mmol) and NMP (0.4 mL) in CH2Cl2 (2 mL), at 0° C., was added acryloyl chloride (6) (29 mg, 0.3 mmol). The reaction mixture was allowed to come to rt and stirred at this temperature for 3 h. It was washed with 10% NaHCO3 solution (2 mL), water (2 mL), brine (2 mL) and dried over Na2SO4. Filtration followed by concentration under reduced pressure offered a residue which was purified by column chromatography (SiO2, 230-400, chloroform/methanol, 9/1) to gave N-(3-(6-(3-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (I-75) as a light brown solid. 1H NMR (DMSO-d6) δ ppm: 5.73 (dd, J=1.72 & 10 Hz, 1H), 6.18 (s, 1H), 6.24 (dd, J=1.92 & 17 Hz, 1H), 6.45 (dd, J=10.04 & 16.88 Hz, 1H), 6.54-6.57 (m, 1H), 7.01-7.05 (m, 2H), 7.11-7.15 (dd, J=0.88 & 7.48 Hz, 1H), 7.19-7.32 (s, 4H), 7.35-7.41 (m, 4H), 7.89 (s, 1H), 8.26 (s, 1H), 9.2 (s, 1H), 9.25 (s, 1H), 10.26 (s, 1H); LCMS: m/e 423.8 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:22](=[O:33])[N:23]([CH2:26][C:27]3[N:28]=[CH:29][NH:30][C:31]=3[CH3:32])[CH2:24][CH2:25][C:14]1=2.C(N(CC)CC)C>ClCCl>[CH3:32][C:31]1[N:30]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH:29]=[N:28][C:27]=1[CH2:26][N:23]1[CH2:24][CH2:25][C:14]2[N:13]([CH3:12])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[C:22]1=[O:33]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCc3c(c4ccccc4n3C)C2=O)ncn1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of benzyl chloroformate (0.28 ml) in dichloromethane (10 ml) was added to a stirred solution of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1one (294 mg) and triethylamine (0.4 ml) in dichloromethane (30 ml) at 20° under nitrogen, and the mixture was stirred overnight. It was then concentrated onto FCC silica and purified by FCC eluting with System A (200:8:1) to give the title compound (62 mg), t.l.c. (System A, 100:8:1) Rf 0.50.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(NCC)C.C(#N)C.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.[Cu]I>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:20]2[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=2)=[CH:11][CH:12]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Brc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCNCC
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(Br)cc2)cc1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
2.8 g (Ph3P)2PdCl2 and 400 mg of CuI are added to a solution of 40.4 g of 4-ethinyl-benzoic acid tert.-butyl ester, 56.6 g of bromoiodobenzene and 1.34 g of Ph3P in 50 ml of diethylamine and 300 ml of absolute acetonitrile and the reaction mixture is stirred for 72 hours at 40° C., suction filtered and dried.