Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.[CH3:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1[NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1B1OC(C)(C)C(C)(C)O1.Br[C:37]1[N:42]=[C:41]([CH2:43][NH:44][C:45]2[C:50]([CH:51]([CH3:53])[CH3:52])=[CH:49][CH:48]=[CH:47][C:46]=2[CH:54]([CH3:56])[CH3:55])[CH:40]=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.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.CO>[CH:54]([C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([CH:51]([CH3:53])[CH3:52])[C:45]=1[NH:44][CH2:43][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[CH2:12][NH:11][C:10]2[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=2[CH3:8])[N:42]=1)([CH3:56])[CH3:55]
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(CNc2c(C(C)C)cccc2C(C)C)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 27.2 g (95.0 mmol) of Na2CO3×10H2O, 410 ml of water and 120 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 14.2 g (38.0 mmol) of 2-methyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 13.3 g (38.0 mmol) of N-[(6-bromopyridin-2-yl)methyl]-2,6-diisopropylaniline, and 2.19 g (1.90 mmol) of Pd(PPh3)4 in 500 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate-triethylamine=100:20:1, vol.). Yield 10.1 g (52%) of a yellow powder. Anal. calc. for C36H39N3: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.28; H, 7.73; N, 8.09. 1H NMR (CDCl3): δ 7.91 (d, J=8.4 Hz, 1H, 4-H in naphthyl), 7.89 (m, 1H, 8-H in naphthyl), 7.79 (m, 1H, 4-H in Py), 7.66 (d, J=8.4 Hz, 1H, 3-H in naphthyl), 7.47 (m, 1H, 7-H in naphthyl), 7.36-7.42 (m, 4H, 3, 5-H in Py and 5, 6-H in naphthyl), 7.04-7.10 (m, 3H, 3, 5-H in ortho-tolyl and 4-H in 2,6-diisopropylphenyl), 7.01 (m, 2H, 3, 5-H in 2,6-diisopropylphenyl), 6.61 (m, 1H, 4-H in ortho-tolyl), 6.52 (m, 1H, 6-H in ortho-tolyl), 4.22-4.35 (m, 4H, CH2N), 4.02 (br.s, 1H, NH), 3.93 (br.s, 1H, NH), 3.28 (sept, J=6.8 Hz, 2H, CHMe2), 2.09 (s, 3H, Me in ortho-tolyl), 1.16 (d, J=6.8 Hz, 6H, CHMeMe′), 1.14 (d, J=6.8 Hz, 6H, CHMeMe′).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br-:26].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:26])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(N3CCN(C)CC3)cc21
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCc2cc(Br)c(N3CCN(C)CC3)cc21
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A stirred mixture of 1-acetyl-2,3-dihydro-6-(4-methylpiperazin-1-yl)-1H-indole (D11, 2.0 g, 0.0077 mole) and anhydrous potassium carbonate (2.12 g, 0.015 mole) in a mixture of dichloromethane (100 ml) and methanol (50 ml) at -5° C. under argon was treated portionwise over 20 minutes with benzyltrimethylammonium tribromide (3.14 g, 0.0081 mole). The mixture was allowed to warm to room temperature over 1 h, then concentrated in vacuo and the residue dissolved in dichloromethane (150 ml), washed with water (2×100 ml), dried (Na2SO4) and concentrated in vacuo to afford the title compound as a beige solid (2.52 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][N:62]1[CH:66]=[C:65]([CH2:67][C:68](O)=[O:69])[CH:64]=[N:63]1>CN(C)C(=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:68](=[O:69])[CH2:67][C:65]6[CH:64]=[N:63][N:62]([CH3:61])[CH:66]=6)=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: Cn1cc(CC(=O)O)cn1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1C=CC(NC(=O)Cc2cnn(C)c2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Yield: 68 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.165 M and 0.47 M in N,N-dimethylacetamide, respectively, 275 μL, 0.042 mmol Example 23e and 0.13 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.25 M in N,N-dimethylacetamide, 253 μL, 0.063 mmol), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.05 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to give 0.0168 g (68%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.03 (d, J=2.14 Hz, 1H), 7.57 (s, 2H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J=8.54 Hz, 1H), 6.97 (s, 1H), 6.78 (m, 2H), 6.50 (m, 2H), 4.59 (m, 2H), 4.06 (s, 3H), 3.81 (s, 3H), 3.52 (s, 2H). MS (APCI+) m/z 483.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10](I)[CH:11]=[CH:12][CH:13]=1.N1CCCCC1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C1COCC1.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>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=[CH:12][CH:13]=1
Reactant: COCCOCOc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COCCOCOc1cccc(C#C[Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
3-(2-Methoxy-ethoxymethoxy)-phenyliodide (12.1 g, 39 mmol, 96) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) and cuprous iodide (0.096 g, 0.5 mmol) are dissolved in THF (120 mL) and to this is added piperidine (12 mL) and (trimethylsilyl)acetylene (8 mL, 57 mmol). This mixture is degassed and is then stirred for 2 hours. The reaction is then diluted with ether and washed twice with water and brine and the organic layer dried over magnesium sulfate. The solvent is removed in vacuo to give the title compound. MS (EI) 206 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(OCCCCl)ccc2[nH]1
Reaction time: 96 h
Yield: 74 %

Procedure:
A mixture of ethyl-5-hydroxyindole-2-carboxylate (purchased at Biosynth, Ref H-6350, 15 g, 1.0 eq.), 1-bromo-3-chloropropane (8.8 mL, 1.2 eq.) and potassium carbonate (12.12 g, 1.2 eq.) in butanone (200 mL) was stirred 4 days at reflux. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, evaporated in vacuo and purified on silica, eluting with a 19:1 to 2:1 gradient of cyclohexane/ethyl acetate to yield 15.3 g (74%) of the desired product as light yellow solid. MS (m/e): 282.5 (MH+, 100%).
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][NH:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O.ClCCl>[CH2:1]([CH:8]([CH2:12][N:13]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:22]=[O:24])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C(CNOCc1ccccc1)Cc1ccccc1
Solvent: O=CO
Solvent: ClCCl
Product: O=CN(CC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 2-(R,S)-benzyl-3-benzyloxyamino-propionic acid (7.8 g, 27.4 mmol) in formic acid (40 mL) was cooled in an ice-water bath and treated dropwise with acetic anhydride (15 mL). The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with dichloromethane (150 mL) and partitioned with water (100 mL). The organic layer was separated, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield 2-(R,S)-benzyl-3-(benzyloxy-formyl-amino)-propionic acid as a colourless oil (7.8 g, 91%). 1H-NMR; δ (CDCl3), 7.87-7.16 (10H, m), 4.924.66 (2H, m), 4.03-3.90 (2H, m), 3.17-2.93 (2H, m), 2.78-2.70 (1H, m).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[CH3:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:22]2[CH:23]=[C:18]([F:17])[C:19]([CH3:26])=[CH:20][C:21]=2[O:24][CH3:25])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1.[NH2:15][C:7]1[C:6]([C:4]([C:20]2[C:21]([O:24][CH3:25])=[CH:22][CH:23]=[C:18]([F:17])[C:19]=2[CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1ccc(F)c(C)c1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2c(OC)ccc(F)c2C)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(F)c(C)cc2OC)c(N)n1

Procedure:
The same procedure as described in Example 170 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-fluoro-3-methylanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone as a white solid, MS (M+H)+, 322 and (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(3-fluoro-6-methoxy-2-methyl-phenyl)-methanone as a white solid, MS (M+H)+, 322
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[S:15])[N:6]([CH2:9][C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:7]=1[NH2:8].[C:17](O)(=O)C.C(N)=N>O>[NH:12]1[CH:13]=[CH:14][C:10]([CH2:9][N:6]2[C:7]3[N:8]=[CH:17][NH:1][C:2]=3[C:3](=[O:16])[NH:4][C:5]2=[S:15])=[N:11]1
Reactant: Nc1c(N)n(Cc2cc[nH]n2)c(=S)[nH]c1=O
Reactant: CC(=O)O
Agent: N=CN
Solvent: O
Product: O=c1[nH]c(=S)n(Cc2cc[nH]n2)c2nc[nH]c12
Temperature: 25 °C
Yield: 30.5 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(d) by using 5,6-diamino-1-(1H-pyrazol-3-ylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.63 g, 2.64 mmol, obtained from Example 13(c)) and formamidine acetate (0.41 g, 3.95 mmol) with the exception that after the reaction mixture had cooled to r.t., water (10 mL) was added. The cloudy solution was maintained at 0° C. for 3 h and the precipitate that formed was collected by filtration, washed with water and methanol and dried in vacuo. The material was further purified by recrystallization from DMSO/water to give the title compound (0.20 g, 31% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[C:15]([OH:22])[C:14]=2[CH2:23][CH2:24][CH3:25])[N:6]=1)=[O:4].[OH-].[Li+]>CO.O>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:14]([CH2:23][CH2:24][CH3:25])[C:15]=1[OH:22])(=[O:21])[CH3:20]
Reactant: CCCc1c(OCc2cccc(C(=O)OC)n2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(OCc2cccc(C(=O)O)n2)ccc(C(C)=O)c1O
Reaction time: 12 h
Yield: 64.1 %

Procedure:
Dissolve 6-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridine-2-carboxylic acid methyl ester (3.77 g, 10.9 mmol) in MeOH (20 mL) and water (5 mL). Add 2N aqueous lithium hydroxide (10.9 mmol). After 12 hours, concentrate under reduced pressure and dissolve the residue in 4N hydrochloric acid in dioxane. Add water until white precipitate forms and collect by filtration to yield the title compound as a white solid (2.30 g, 6.99 mmol): 1H NMR (d6-DMSO) δ 0.89 (t, 3H), 1.50 (m, 2H), 2.56 (s, 3 H), 2.63 (t, 3H), 5.31 (s, 2H), 6.57 (d, 1H), 7.47 (m, 1H), 7.67 (d, 1H), 7.93 (m, 2H), 12.84 (s, 1H), (acid proton not observed); mass spectrum (m/e): 328 (M−1).
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1.CO>C(OCC)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:11][CH:12]=1)#[N:17]
Reactant: COC(=O)CCCOc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc(OCCCCO)cc1
Yield: 46 %

Procedure:
LiBH4 (1.5 g; 71.1 mmol) was added to a stirred solution of 4-(4-cyanophenoxy)butyric acid methyl ester (9.63 g; 47.4 mmol; from step (b) above), MeOH (2.87 mL; 71.1 mmol) and diethyl ether (158 mL) and the reaction mixture was refluxed overnight. The ether phase was collected and the residue was extracted with diethyl ether (3×50 mL). The combined organic phase was dried, concentrated and purified using column chromatography (EtOAc:hexane; 1:3) to give the sub-title compound (3.82 g; 21.8 mmol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][C@@:36]1([C:52]([F:55])([F:54])[F:53])[CH2:51][N:39]2[C:40](=[O:50])[CH:41]=[C:42]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[N:43]=[C:38]2[NH:37]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:35][C@@:36]1([C:52]([F:55])([F:53])[F:54])[CH2:51][N:39]2[C:40](=[O:50])[CH:41]=[C:42]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)[N:43]=[C:38]2[N:37]1[CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:12][CH:11]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: OCCc1ccc(N2CCOCC2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
135 mg of 2-(4-morpholinophenyl)ethanol and 223 mg of polymer-supported triphenylphosphine (3 mmol/g) are added to a solution of 100 mg of (S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]-pyrimidin-5-one (Example 1j) in 5 ml of tetrahydrofuran. After stirring for five minutes at ambient temperature, 0.12 ml of diethyl azodicarboxylate is added. The resulting reaction mixture is then stirred overnight at ambient temperature. After filtration, the filtrate is evaporated under reduced pressure. The residue obtained is purified by silica column chromatography (eluent: dichloromethane/methanol 97/03), so as to give 40 mg of (S)-2-methyl-7-morpholin-4-yl-1-[2-(4-morpholin-4-yl-phenyl)ethyl]-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, the characteristics of which are the following:
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[C:30]([O:31][CH:32]([CH3:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:21][O:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:24][CH3:25])[C:17]=1[O:22][CH3:23])[C:13]([C:12]1[C:11]2[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:31][CH:32]([CH3:34])[CH3:33])[C:10]=2[O:9][CH:8]=1)=[O:26]
Reactant: COc1cc(C(=O)c2c([Si](C)(C)C(C)(C)C)oc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)c2coc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-7-isopropoxy-benzofuran (0.066 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammoniumfluoride (76.5 μl, 0.076 mmol, 1M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 20 minutes (monitored by tlc), diluted with ethyl acetate (10 mL) and washed with 1M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether; 7:3) to afford the title compound as a light yellow paste (23 mg) that was used directly in the next step; 1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H, C2H), 7.78 (d, 1H, J=8.60 Hz), 7.15 (s, 2H, benzoyl Hs), 7.04 (d, 1H, J=8.61 Hz), 4.73 (m, 1H), 3.93 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.90 (s, 6H, 2×OMe), 1.37 (d, 6H, J=6.14 Hz).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10](=[O:12])[CH3:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1cc2cnccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cc2cnccc2s1
Reaction time: 1 h

Procedure:
To a solution of 1-(thieno[3,2-c]pyridin-2-yl)ethanone (D′-3) (3.5 g, 1 mmol) in anhydrous THF (50 mL) was added LiAlH4 (1.13 g, 1.5 mmol) in portions at 0° C. The suspension was stirred under this temperature for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and filtered. The filtrate was washed with brine, concentrated, and then used for the next step without any further purification.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[C:29]([C:31]3[CH:40]=[C:39]4[C:34]([CH2:35][CH2:36][NH:37][CH2:38]4)=[CH:33][CH:32]=3)[N:28]=[C:27]([NH2:41])[N:26]=2)[CH2:21][CH2:20]1>>[NH2:41][C:27]1[N:28]=[C:29]([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][N:37]([C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([O:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:9][CH:10]=4)=[O:16])[CH2:38]3)=[CH:33][CH:32]=2)[CH:30]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[N:26]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccc(Oc5ccccc5)cc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 4-phenoxyphenyl isocyanate (Aldrich, Cat. #478970) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=536.2.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[F:3][C:4]1[CH:12]=[C:11]([NH:2][CH3:1])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Solvent: O
Product: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylamine (13.5 mL, 40% in water) is added to an ice-cooled mixture of 2,4-difluoro-5-nitro-benzoic acid (10.0 g, 49 mmol) in water (100 mL) and it is stirred for 30 min at rt. The mixture is acidified with 6N aq HCl-solution and the precipitate is filtered, washed with water and dried at 60° C. The crude material is recrystallized from MeOH. The final product is slightly contaminated by its regioisomer 4-fluoro-2-methylamino-5-nitro-benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=C(C3C=C(C=CC=3C)C(O)=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].C1C=C(Cl)C=C(C(OO)=[O:40])C=1.CCOC(C)=O.CCCCCC.[CH2:55]([Cl:57])Cl>>[Cl:57][C:55]1[N:17]=[C:16]([S:29]([CH3:30])=[O:40])[N:15]=[C:14]2[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:10](=[O:31])[NH:11][CH2:12][C:13]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCl
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (1.71 g, 5 mmol) in CH2Cl2 (60 mL) was added m-CPBA (1.17 g, 5.2 mmol). The mixture was stirred at room temperature for 10 minutes, then directly loaded onto a column. Flash chromatography (mobile phase EtOAc/Hexane) afforded the title compound as a white solid 1.58 g (88%). LC-MS m/z 358 (M+H)+.
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[OH:19])([CH3:11])([CH3:10])[CH3:9].[CH3:20][O:21]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[C:8]([C:12]1[C:13]([OH:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH:17]=1)[CH:20]=[O:21])([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1cc(O)c(C(C)(C)C)cc1C=O
Temperature: 5 °C

Procedure:
Chlorobenzene (100 mL) and 2-tert-butyl-5-methylphenol (20.6 gm, 125 mmol) were combined and the mixture stirred and cooled to 5° C. Titanium tetrachloride (27.5 mL) and dichloromethyl methyl ether (19 mL, 210 mmol) were added separately and simultaneously over 45 minutes while holding the reaction temperature between 4 and 7° C. The resulting mixture was stirred at 0-5° C. for 3 hours. Water (100 mL) was cautiously added over 18 minutes to the reaction mixture while holding the temperature below 14° C. The mixture was extracted with ethyl acetate (200 mL) and the resulting organic layer was extracted with 12% hydrochloric acid (2×75 mL). The combined aqueous acid layers were diluted with water (50 mL) and back extracted with ethyl acetate (100 mL). This extract was combined with the first ethyl acetate extract and the whole extracted with 15% KOH (3×100 mL). The KOH extracts were combined and the pH adjusted to 3 with 37% hydrochloric acid (62.8 gm). The resulting mixture was extracted with 1:1 ethyl acetate/toluene (2×150 mL). These organic extracts were combined and back extracted with water (2×50 mL) and the organic solution concentrated to approximately 75 mL. 5-tert-Butyl-4-hydroxy-2-methylbenzaldehyde seed crystals were added and the mixture stirred and cooled to 25° C. The mixture was filtered and the product washed with toluene (30 mL) and vacuum dried at 40° C. to give 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (1): 15 g (78 mmol, 62%): mp: 168-170° C.