Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH:26]([CH3:28])[CH3:27].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([N+:22]([O-:24])=[O:23])=[C:16]([O:21][CH:26]([CH3:28])[CH3:27])[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(OC(C)C)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) was treated with 2-bromo-propane, potassium iodide and potassium carbonate in N,N-dimethylformamide at 80° C. to yield the 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-isopropoxy-2-methyl-5-nitro-pyrimidine as a light yellow solid; m.p. 98-100° C.; MS: [M+H]+=376.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[NH3:17]>CC(C)=O>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13]([NH2:17])(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: N
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25.3 g (0.1 mole) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfonyl chloride are dissolved in a little acetone and the solution is added dropwise slowly, at room temperature, to 100 ml of concentrated ammonia solution. The mixture is stirred for 30 minutes at room temperature and poured into ice water. After acidification with concentrated hydrochloric acid the product is filtered off with suction. It is recrystallized from isopropanol.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:16][N:17]([CH3:21])[C:18](=[O:19])[NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: Br
Product: CN(C)C(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrobromide is treated with dimethyl carbamoyl chloride using a procedure similar to that of Example 5 to form 5-[4-(3,3-dimethylureido)phenyl]-2(1H)-pyrazinone.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:20][CH:16]([CH3:15])[C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: CC#CC(C)O
Reactant: Fc1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(C)Oc1cc(-c2ccc(F)cc2)ncn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 48.5 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 344 mg of 4-chloro-6-(4-fluorophenyl)pyrimidine and 166 mg of 3-pentyn-2-ol, to which 166 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 10 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 205 mg of 4-(4-fluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (174)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:32]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)c(Cl)c1
Yield: 32.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-dichlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and 5-amino-2-[4-(2-hydroxyethyl)piperazin-1-yl]benzonitrile (2.67 g), the title compound (1.2 g) was obtained, melting point: 195–197° C.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[CH2:22][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:8])[N:6]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:2]2[O:3][CH:4]=[C:5]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[CH2:22][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:8])[N:6]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)co2)cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A solution of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (117 mg, 0.277 mmol), p-anisidine (68 mg, 0.554 mmol) and potassium carbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was filtered and concentrated under reduced pressure. The material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient), yielding 35.5 mg (25%) of the title compound as the TFA salt. LC-MS: RT=6.76 min, [M+H]+=510.0.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=3)[S:8][C:7]=2[CH:39]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]([OH:30])[CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:8][C:7]=2[CH:39]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC(O)CN3CCCC(C)C3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CC1CCCN(CC(O)COc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Yield: 65.7 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(2-hydroxy-3-[3-methylpiperidinyl]propoxy)phenyl]methanone (540 mg, 1.0 mmol) was converted to 340 mg of the title compound by the procedure of Example 32 using 360 mg (4.9 mmol) of ethanethiol and aluminum chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])(O)=O.[NH4+].[NH4+].[N+:32]([O-])(OCCC)=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCO[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 40 %

Procedure:
A mixture of 2,4-dibenzyloxybenzaldehyde (1.59 g), diammonium hydrogen phosphate (3.5 g) and n-propyl nitrate (15 mL) in glacial acetic acid (5 mL) is refluxed for 15 hours. The reaction mixture is evaporated to dryness in vacuo and the residue is stirred with water (100 mL). The insoluble material is filtered and dried at 50° C. to yield 2,4-dibenzyloxybenzonitrile as a tan coloured solid (0.6 g, 40%), m.p. 100° C. [Elemental analysis:- C,79.8; H,5.47; N,4.48%. Calculated:- C,80.0; H,5.43; N,4.44%].
Reaction SMILES: CC(OC(=O)[N:7]([CH2:25][CH3:26])[CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14]C2C([CH:21]=1)=CC([N+]([O-])=O)=CC=2)=[O:12])(C)C.F[C:29]1[C:34]([NH:35][C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[CH:44][C:43]([C:47]([NH:49][C:50]2[C:55](F)=[C:54](F)[C:53](F)=[C:52](F)[C:51]=2F)=[O:48])=[CH:42][CH:41]=3)=[O:37])=[C:33](F)[C:32](F)=[C:31](F)[C:30]=1F>CN(C=O)C>[CH2:25]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:31]2[C:32]([CH:21]=1)=[CH:33][C:34]([NH:35][C:36]([C:38]1[NH:39][C:40]3[C:45]([CH:46]=1)=[CH:44][C:43]([C:47]([NH:49][C:50]1[CH:55]=[C:54]4[C:53](=[CH:52][CH:51]=1)[NH:14][C:13]([C:11](=[O:12])[NH:10][CH2:9][CH2:8][NH:7][CH2:25][CH3:26])=[CH:21]4)=[O:48])=[CH:42][CH:41]=3)=[O:37])=[CH:29][CH:30]=2)=[O:12])[CH3:26]
Reactant: O=C(Nc1c(F)c(F)c(F)c(F)c1F)c1ccc2[nH]c(C(=O)Nc3c(F)c(F)c(F)c(F)c3F)cc2c1
Reactant: CCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCNCCNC(=O)c1cc2cc(NC(=O)c3ccc4[nH]c(C(=O)Nc5ccc6[nH]c(C(=O)NCCNCC)cc6c5)cc4c3)ccc2[nH]1
Temperature: 55 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
Compound 78 (127 mg, 0.336 mmol) was reduced to 79 by hydrogenation according to general procedure A in example 10. A mixture of above amine DS13a and 1H-indole-2,5-dicarboxylic acid bis-(pentafluorophenyl-amide) 74 (45 mg, 0.084 mmol) in 2 ml of anhydrous DMF under argon was stirred at 55° C. overnight. The solvent was evaporated to dryness. The residue was dissolved in 5 ml of TFA/anisole (8:2) and the mixture was kept at room temperature for 1 h. The product was precipitated by ether and purified by HPLC described in general procedure B in example 10 to give 76 (22 mg, 40%). ESI MS: 662.27 (M+H+), 331.64 (M/2+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9](OC)=[O:10])=[C:6]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[N:5]=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[CH2:8][C:9](=[O:10])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cc1c(Cl)ncnc1NCc1ccc(OC)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)c(OC)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Combine a solution of methyl 2-(4-chloro-6-(2,4-dimethoxybenzylamino)pyrimidin-5-yl)acetate (1.00 equiv; 2.23 mol; 783 g) in p-toluenesulfonic acid (0.5 equiv; 1.10 mol; 212 g) with Toluene (12 L) and stir at reflux. After 1 h, remove toluene in vacuo and extract with DCM. Wash the organic layer with saturated NaHCO3(aq) and brine, dry over Na2SO4, filter and concentrated in vacuo. Slurry the residue in methanol (2 L) and concentrate in vacuo to approximately 1 L. Cool the slurry to 10° C., filter, wash with cold methanol, and dry to obtain the title compound (1.65 mol; 527 g; 74.05%) as a yellow-orange solid. 1H NMR (400 MHz, CDCl3): 8.59 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.43 (d, J=2.0 Hz, 1H), 6.40 (d, J=8.5 Hz, 1H), 4.92 (d, s, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.60 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:30]#[C:31][CH2:32][O:33][CH3:34])[CH:15]=2)=[CH:9][C:8]=1[Cl:35])C.[OH-].[Na+].Cl>C(O)C>[Cl:35][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:17]=[C:16]([C:30]#[C:31][CH2:32][O:33][CH3:34])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCOC)cc(OCCCN3CCOCC3)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(Cl)c2)c1
Reaction time: 1 h

Procedure:
{2-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 50 mg. HPLC-MS: m/z: 506.0 (M+); Rt: 1.56 min. δH (400 MHz; CDCl3) 2.06-2.15 (m, 2H), 2.82-2.92 (m, 2H), 3.15-3.23 (m, 2H), 3.45 (s, 3H), 3.56 (d, 2H), 3.78 (t, 2H), 3.95-4.03 (m, 4H), 4.30 (s, 2H), 4.89 (s, 2H), 5.91-5.94 (m, 1H), 6.63-6.66 (m, 1H), 6.93 (d, 1H), 7.01-7.03 (m, 1H), 7.40 (dd, 1H), 7.58 (d, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:21]([Si:18]([CH3:20])([CH3:19])[O:1][CH:2]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCC(CCC(O)Cc2ccccc2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Reaction time: 24 h
Yield: 92.7 %

Procedure:
To a solution of 5-(3-hydroxy-4-phenyl-butyl)-pyrrolidin-2-one (4.3 g, 18.43 mmol) in DMF (86 mL) was added tert-butyldimethylsilyl chloride (3.06 g, 20.3 mmol) followed by imidazole (2.5 g, 37 mmol) and DMAP (225 mg). The reaction mixture was stirred for 24 h and was quenched with saturated aqueous ammonium chloride. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2) to yield 5.94 g of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ 7.26-7.10 (m, 5H), 5.68 (m, 1H), 3.83 (m, 1H), 3.54 (m, 1H), 2.69 (m, 2H), 2.30-2.16 (m, 3H), 1.66-1.35 (m, 5H), 0.82 (s, 9H), −0.06 (d, 3H), −0.2 (d, 3H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(O)CC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-glucose and L-(+)-glutamic acid using Raney nickel or palladium/activated carbon (10%) as a catalyst. The product had a melting point of 94° C. and an RF -value of 0.61 (determined on DC-finished plates of silica gel G (Merck) with a transporting fluid made up of 85 parts by volume of methanol and 15 parts by volume of water).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].Cl[CH2:9][C:10](=O)[CH3:11].C(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>O>[CH3:11][C:10]1[CH:7]=[C:2]2[N:1]([CH:9]=1)[CH:6]=[CH:5][CH:4]=[CH:3]2
Reactant: Cc1ccccn1
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc2ccccn2c1
Temperature: 95 °C
Yield: 79.4 %

Procedure:
A mixture of α-picoline (5 g, 53.8 mmol) and chloroacetone (5 g, 53.8 mmol) was heated at 90-100° C. for 4 h. The reaction mixture was then poured into a chloroform/water mixture (50:50 mL) and subsequently extracted. The aqueous phase was treated with 0.6 g of sodium bicarbonate and then extracted with diethyl ether (3×30 mL) to remove the residual α-picoline. A further 8.1 g (96.4 mmol) of sodium bicarbonate were added to the aqueous phase, and the mixture was concentrated to give a mixture of white precipitate and water. Extracting the mixture with diethyl ether gave 5.6 g of 2-methylindolizine 1 in the form of white crystals; m.p.: 57-58° C. 1H NMR (CDCl3): δ 7.77-7.74 (m, 1H), 7.23 (d, J=8.9 Hz, 1H), 7.06 (s, 1H), 6.58-6.53 (m, 1H), 6.36-6.31 (m, 1H), 6.21 (s, 1H), 2.31 (s, 3H), 13C NMR (CDCl3): δ 132.8, 124.8, 124.6, 118.2, 116.5, 111.1, 109.4, 99.7, 12.4.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]1=[O:18]>ClCCl>[Br:1][C:12]1[S:13][C:7]2[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:5](=[O:18])[N:4]([CH3:3])[C:9](=[O:10])[C:8]=2[CH:11]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reactant: BrBr
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Br)sc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (2.79 ml) in dry dichloromethane (25 ml) was added dropwise to a solution of 3-methyl-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12.0 g, WO 98/54190) in dry dichloromethane (100 ml) and stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sodium metabisulfite solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a cream solid. (15.85 g)
Reaction SMILES: B.C1COCC1.[I:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=1[C:10](O)=[O:11]>C1COCC1>[I:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1I
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1I

Procedure:
Borane-THF (1.0M solution in THF; 94 mL; 94 mmol) was added to a stirred solution of 2-iodo-5-(trifluoromethyl)benzoic acid (Intermediate 9, 2.97 g; 9.4 mmol) in THF (300 mL) at 0° C. under N2. The reaction was heated at reflux for 90 min and then carefully quenched with 6N HCl until no further gas evolution. The reaction was diluted with H2O (250 mL) and extracted with EtOAc (3×250 mL). The combined extracts were washed with brine (300 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (0-25% EtOAc/hexanes gradient) to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid. LCMS=285.0 (M−17)+. 1H NMR (CDCl3, 500 MHz): δ 7.97 (d, J=8.3 Hz, 1H), 7.79 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.75 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:24]2[CH2:26][CH2:25]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:24]2[CH2:26][CH2:25]2)[C:5]2[N:6]=[C:7]([NH:38][C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:40][CH:39]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(Cc3c(F)cccc3C3CC3)c2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CN1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(Cc5c(F)cccc5C5CC5)c4n3)cc2)CC1
Yield: 53.3 %

Procedure:
6-Bromo-8-(2-cyclopropyl-6-fluorobenzyl)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (9, 385 mg, 0.9 mmol) and 4-(4-methylpiperazino)aniline (169 mg, 0.9 mmol) were stirred at 140° C. for 6 h. The reaction mixture was purified by column chromatography using dichloromethane:methanol (100:1→100:3→100:5) to yield the title compound as a yellow solid (272 mg, 0.48 mmol, 55%). ESMS m/z 563 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)([O-:3])=[O:2].O1CCCC1.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:14](=[O:16])/[CH:13]=[CH:12]/[CH:11]=[CH:10]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)/C=C/C=C/c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)/C=C/C=C/c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (2E,4E)-5-(2-nitrophenyl)penta-2,4-dienoic acid (9a) (0.44 g, 2.0 mmol) in dry tetrahydrofuran (10 ml) 1,1′-carbonyldiimidazole (0.36 g, 2.2 mmol) (Sigma-Aldrich) was added and the mixture was stirred for 1 hour at ambient temperature. To the reaction mixture triethylamine (0.30 g 3.0 mmol) and methyl 6-aminohexanoate hydrochloride (10) (0.40 g, 2.2 mmol) successively were added and the resultant suspension was stirred for 6 hour at ambient temperature. The solvent was evaporated, to the obtained residue water (15 ml) was added and the precipitate was filtered off. The precipitate was washed with an additional amount of water and dried to give the title compound (0.62 g, 89%) as a yellow solid, m.p. 115-117° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.10-1.79 (6H, m, CH2); 2.29 (2H, J=7.0 Hz, CH2); 3.17 (2H, q, J=5.6 Hz, CH2N);3.60 (3H, s); 6.24 (1H, d, J=14.8 Hz, CH); 7.04-8.10 (8H, m, CH—CH═CH, C6H4, NH).
Reaction SMILES: C[C@H:2]1[C@@H:23]([CH2:24]C2OC3C=CC(NC)=C(C(O)=O)C=3N=2)O[C@:5]2(O[C@H:9]([C@@H:11]([C:13]([C:15]3NC=[CH:17][CH:16]=3)=O)C)[C@H:8](C)[CH2:7][C@H:6]2C)[CH2:4][CH2:3]1.[C:39]([OH:51])(=[O:50])[CH2:40][C:41]([CH2:46][C:47]([OH:49])=O)(C(O)=O)O>CS(C)=O>[CH3:17][CH2:16][CH2:15][CH2:13][CH2:11][CH:9]=[CH:8][CH2:7][CH:6]=[CH:5][CH2:4][CH:3]=[CH:2][CH:23]=[CH:24][CH:47]([OH:49])[CH2:46][CH2:41][CH2:40][C:39]([OH:51])=[O:50]
Reactant: CNc1ccc2oc(C[C@H]3O[C@@]4(CC[C@H]3C)O[C@H]([C@H](C)C(=O)c3ccc[nH]3)[C@H](C)C[C@H]4C)nc2c1C(=O)O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Product: CCCCCC=CCC=CCC=CC=CC(O)CCCC(=O)O
Reaction time: 0.08 h

Procedure:
RBL-1 cells (1.57×107 cells/tube) were preincubated for 10 minutes at 37° C. in the presence of the indicated drugs or vehicle (1% DMSO). Following the transfer of the assay tubes to an icebath, the reaction was initiated by the sequential addition of calcium ionophore A23187, an agent which increases the ability of divalent ions such as Ca++ to cross biological membranes (final concentration=1.9 μM) and 55 μM 1-14C-arachidonic acid (New England Nuclear) at a final specific activity of 3000-4000 cpm/nmole. The final volume in each tube was 1 ml. The assay tubes were incubated at 37° C. for 5 minutes, and the reaction was stopped by transferring the tubes to ice and adjusting the pH of the reaction mixture to pH 3.0-3.5 by the addition of 1M citric acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:48])[CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:46][CH3:47])=[C:43](Br)[CH:44]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:48])[CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:46][CH3:47])=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:44]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1cnc(OC)c(Br)c1
Product: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (5-bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 3, Step 6 to provide (5-{2-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester.