Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.O.[CH3:19]O>>[CH3:19][O:4][C:3](=[O:5])[CH:2]([Br:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12]
Reactant: O=C(O)C(Br)c1ccccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(Br)c1ccccc1Cl

Procedure:
α-Bromo-2-chlorophenyl acetic acid (350.0 gm) was dissolved in methanol (1.18 Liter) and concentrated sulphuric acid (53.20 gm) was added. The reaction mixture was refluxed for 4 hours. After completion of the reaction, the reaction mixture was distilled out to get a syrupy mass. To the residual mass, water (560 ml) was added and the product was extracted into chloroform (560 ml). The chloroform layer was separated and was treated with 10% aqueous sodium bicarbonate solution (1.12 Litre). The chloroform extract was finally washed with water and chloroform was distilled out to get a syrupy mass to get the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(O)=O>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C/c1c(F)cc(F)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCOC(=O)CCc1c(F)cc(F)cc1F
Temperature: 90 °C
Yield: 89.2 %

Procedure:
Pd/C (0.5 g, 10%, 50% water wet) was added to a solution of ethyl (2E)-3-(2,4,6-trifluorophenyl)-2-propenoate (2.0 g, 8.69 mmol) in ethyl acetate (40 mL) under an argon atmosphere, followed by TEA (2.409 mL, 17.38 mmol) and formic acid (1.666 mL, 43.4 mmol). The reaction mixture was refluxed at 90° C. under argon for 1 h. The reaction mixture was filtered through a celite pad and the filtrate was then washed with water, 5% NaHCO3 solution and brine, before being dried over Na2SO4. Solvent evaporation under reduced pressure yielded the title compound as a pale yellow oil (1.8 g, 89% yield). LCMS: 3.41 min, [M+H+]=232.9
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(C)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1.[H][H]>C1COCC1.CO.[Pt](=O)=O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7][C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)cc2)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)CCc2ccc(OC)cc2)cc1
Yield: 59.5 %

Procedure:
To a solution of commercially available di(4-methoxybenzylidene) acetone (3.5 g, 12 mmol) in THF-MeOH (1:1,100 mL) was added platinum (IV) oxide (90 mg) and the resulting mixture was stirred at room temperature under 4 atmospheres of hydrogen for 19 hours. The catalyst was filtered and washed with THF, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane-ethyl acetate 3:1) to provide 1,5-bis(4-methoxyphenyl)-3-pentanone (2.13 g) and the reduced side product 1,5-bis(4-methoxyphenyl)-3-pentanol (1.0 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13](O)[CH3:14]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:13]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12])=[CH2:14]
Reactant: Cc1c(Br)ccc2c1COC2=O
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1C)COC2=O
Temperature: 140 °C

Procedure:
5-Bromo-4-methyl-2-benzofuran-1(3H)-one (598 mg, 4.47 mmol), potassium vinyl trifluoroborate (507 mg, 2.23 mmol), PdCl2(dppf)-CH2Cl2 Adduct (182 mg, 0.223 mmol), and TEA (0.622 mL, 4.47 mmol) were added to 10 mL ethanol in a 20 mL microwave tube. The tube was sealed and degassed, then heated to 140° C. for 20 min. Analysis by LC-MS showed product peak. The reaction mixture was diluted with ethyl acetate, washed with brine twice, dried and evaporated to dryness. The crude product was purified by MPLC chromatography using a 120 g Redi-sep column and 0-80% ETOAC/Hexane solvent system to yield 5-ethenyl-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, CDCl3): δ ppm 7.76 (d, J=8 Hz, 1H), 7.03 (dd, J=11, 17 Hz, 1H), 5.84 (d, J=17 Hz, 1H), 5.55 (d, J=11 Hz, 1H), 5.29 (s, 2H), 2.34 (s, 3H). LC-MS: M+1=175; tR=2.42 min
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C@@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C@@H:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ccc(CC[C@@H](N)C(C)C)cc2)cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@H](CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)C(C)C

Procedure:
(R)-1-{2-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]ethyl}-2-methylpropylamine (48.7 mg, 0.148 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 42 mg (77%), M+H+: 371.3.
Reaction SMILES: [CH2:1]([O:3][PH:4](=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[O-]S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=[C:27]2[C:29]([C:31](O)(O)[C:32](=O)[C:26]2=CC=1)=O>O1CCCC1.ClCCl.O.CO>[CH2:1]([O:3][PH:4](=[O:8])[O:5][CH2:6][C:7]1[CH:27]=[CH:29][CH:31]=[CH:32][CH:26]=1)[C:2]1[CH:31]=[CH:32][CH:26]=[CH:27][CH:29]=1
Reactant: CCO[PH](=O)OCC
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=[PH](OCc1ccccc1)OCc1ccccc1
Yield: 90 %

Procedure:
To a solution of phenol 11 (6.45 g, 11.8 mmol) in tetrahydrofuran (161 mL) at room temperature was charged triflate reagent 12 (6.48 g, 15.3 mmol). Cesium carbonate (11.5 g, 35.3 mmol) was added and the mixture was stirred and monitored by TLC assay (SiO2, 5% methanol in dichloromethane as eluent, dibenzyl product Rf=0.26, visualization by UV or ninhydrin stain and heat). Additional Cs2CO3 was added until the reaction was judged complete. To the reaction contents was charged water (160 mL) and the mixture extracted with ethyl acetate (2×160 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated via rotary evaporator to afford a viscous oil. The crude oil was purified by silica gel column chromatography using a gradient of 100% dichloromethane to 1% methanol in dichloromethane to afford product 9 as a white foam (8.68 g, 90% yield). 1H NMR (CDCl3) δ 7.75 (d, 2H), 7.40-7.20 (m, 16H), 6.95 (d, 2H), 5.65 (d, 1H), 5.20-4.90 (m, 6H), 4.25 (d, 2H), 4.00-3.80 (m, 4H), 3.75-3.65 (m, 3H), 3.20-2.75 (m, 7H), 1.90-1.75 (m, 1H), 1.30-1.20 (m, 1H), 0.90 (d, 3H), 0.85 (d, 3H). 31P NMR (CDCl3) δ 19.1.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>C(O)(=O)C>[N+:15]([C:9]1[CH:8]=[CH:7][N:3]2[CH:4]=[CH:5][N:6]=[CH:1][C:2]=12)([O-:17])=[O:16]
Reactant: c1cc2cnccn2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccn2ccncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.5 g of pyrrolo[1,2-a]pyrazine prepared in Preparation Example 1 was dissolved in 10 ml of glacial acetic acid; and to the resulting mixture was added dropwise a mixture of sulfuric acid/nitric acid (15 ml/15 ml) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, poured into 200 ml of ice-water, and then adjusted to pH 10 with sodium hydroxide solution. The resulting solution was extracted with ethyl acetate (100 ml×3), and concentrated to dryness to obtain 4.3 g of title compound.
Reaction SMILES: [Cl-:1].[K+].O=O.[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[C:6]1[CH3:7].CC1CC(=O)OC1=O>O>[Cl:1][CH2:7][CH:6]1[CH2:8][C:9](=[O:10])[O:11][C:5]1=[O:12]
Reactant: [Cl-]
Reactant: CC1=CC(=O)OC1=O
Agent: CC1CC(=O)OC1=O
Agent: O=O
Agent: [K+]
Solvent: O
Product: O=C1CC(CCl)C(=O)O1
Reaction time: 2 h

Procedure:
Next, the reacted gas was passed through a layer in a Pyrex tube (diameter: 2.5cm) packed with 20cc of an oxychlorinating catalyst comprising silica-alumina carrying 5% by weight of potassium chloride and 5% by weight of cupric chloride, at a temperature of 250°C while introducing oxygen in an amount of 1000cc/hour. The water generated was trapped in a vessel and the chlorine gas recovered was circulated, whereby the reaction was carried out for 2 hours. After completion of the reaction, the product was analyzed using gas chromatography, and it was confirmed that the product contained 7.4g of citraconic acid anhydride and 1.8g of methylsuccinic acid anhydride. In addition, a small amount of chloromethylsuccinic acid anhydride was formed.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.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>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][OH:13])[CH:20]=2)=[CH:6][N:7]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CNC(=O)c1nc(Br)cnc1N
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1nc(-c2cccc(CO)c2)cnc1N
Temperature: 90 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
3-Amino-6-bromo-N-methylpyrazine-2-carboxamide (2.00 g, 8.65 mmol) was dissolved in DMF followed by addition of 3-hydroxymethyl phenyl boronic acid (1.57 g, 10.32 mmol), K2CO3 (3.0 g, 21.7 mmol) and Pd(PPh3)4 (10 mol %, 1.0 g). This mixture was stirred at 90° C. under nitrogen for 12 hours. The reaction mixture was poured into water (150 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were washed with brine (50 mL) then dried over anhydrous sodium sulfate. Filteration, concentration and column chromatography on silica (50% ethylacetate/hexanes) gave a solid which was dried to afforded 2.02 g (92% yield) of the title compound; 1H NMR (400 MHz, d6-DMSO): δ0 8.80 (s, 1H), 8.74 (br, 1H), 8.01(s, 2H), 7.45 (m, 4H), 5.21(t, 1H), 4.60 (d, 2H), 2.81(d, 3H); MS (EI) for C13H14N4O2: 259.38 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)(C)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[N:5]=[CH:4][CH:3]=[C:2]3[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:15][CH:16]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(COc2cccc3c(Cl)ccnc23)cc1
Solvent: CC(C)O
Product: COc1ccc(COc2cccc3c(N4CCNCC4)ccnc23)cc1
Yield: 97.1 %

Procedure:
A mixture of compound 23 (4.70 g, 15.68 mmol) and piperazine (13.63 g, 158.23 mmol) in isopropanol (30 mL) was refluxed for 46 hours with stirring. Isopropanol was evaporated under vacuo and the reaction mixture was made alkaline using saturated NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (3×100 mL), dried over Na2SO4, concentrated under vacuo to afford 5.32 g (97%) of compound 24, which was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.73 (bs, 1H), 2.80-3.44 (m, 8H), 3.80 (s, 3H), 5.36 (s, 2H), 6.82-6.94 (m, 2H), 6.99 (d, 1H, J=8 Hz), 7.23-7.35 (m, 1H), 7.44 (d, 2H, J=8.4 Hz), 7.58 (d, 1H, J=8 Hz), 8.76-8.82 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.BrCC1CCCCO1>>[CH2:22]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:6]3[CH:7]=[C:2]([F:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=3[O:19][CH2:18]2)[C:9]1=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(cc1F)C1(CO2)C(=O)Nc2ccccc21
Reactant: BrCc1ccccc1
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and benzylbromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-benzyl-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (86%) as a colorless solid: mp 160-162° C.; 1H NMR (300 MHz, CDCl3) δ7.39-7.26 (m, 5H), 7.20 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.16-7.09 (m, 1H), 7.06-6.97 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.61 (d, J=6.8 Hz, 1H), 6.43 (d, J=10.1 Hz, 1H), 5.05 (d, J=15.5 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.83 (d, J=15.5 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ182.3, 173.3, 166.3, 165.6, 147.9, 137.5, 133.7, 128.5, 128.0, 126.1, 124.9, 124.6, 114.2, 97.5, 84.9, 77.3, 62.0, 47.6, 33.5; MS (ES+) m/z 376.0 (M+1).
Reaction SMILES: [C:1]([OH:6])(=O)[C@H:2]([CH3:4])[OH:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH2:37]([N:41]1[C:49]([N:50]2[CH2:55][CH2:54][NH:53][C@@H:52]([CH3:56])[CH2:51]2)=[N:48][C:47]2[C:42]1=[N:43][C:44]([C:63]1[CH:64]=[N:65][C:66]([NH2:69])=[N:67][CH:68]=1)=[N:45][C:46]=2[N:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1)[CH:38]([CH3:40])[CH3:39]>C(Cl)Cl.CO.C(Cl)Cl.CN(C)C=O>[NH2:69][C:66]1[N:65]=[CH:64][C:63]([C:44]2[N:43]=[C:42]3[C:47]([N:48]=[C:49]([N:50]4[CH2:55][CH2:54][N:53]([C:1](=[O:6])[C@@H:2]([OH:3])[CH3:4])[C@@H:52]([CH3:56])[CH2:51]4)[N:41]3[CH2:37][CH:38]([CH3:39])[CH3:40])=[C:46]([N:57]3[CH2:62][CH2:61][O:60][CH2:59][CH2:58]3)[N:45]=2)=[CH:68][N:67]=1
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1c(N2CCN(C(=O)[C@H](C)O)[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 24 h
Yield: 53 %

Procedure:
L-Lactic acid (29.6 μl, 0.34 mmol), 1-hydroxybenzotriazole monohydrate (43.0 mg, 0.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (80.8 mg, 0.42 mmol), and triethylamine (58.8 μl, 0.42 mmol) were added to an N,N-dimethylformamide solution (3.0 ml) of 5-{9-isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (127.2 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred for 1 day followed by the addition of L-lactic acid (29.6 μl, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (80.8 mg, 0.42 mmol), triethylamine (58.8 μl, 0.42 mmol), and methylene chloride (3.0 ml). The resulting mixture was stirred for 1 day and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (77.9 mg, 53%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[CH2:6]([O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]([C:22]2[N:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)[N:12]=1)=[O:10])C>CO>[CH3:6][O:8][C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]([C:22]2[N:23]=[N:24][C:25]([O:2][CH3:1])=[CH:26][CH:27]=2)[N:12]=1)=[O:10]
Reactant: C[O-]
Reactant: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(Cl)nn2)n1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nn2)n1

Procedure:
28% Sodium methoxide-methanol (3 mL) was added to the above-obtained 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid ethyl ester (1.50 g) in methanol (45 mL), and the resultant mixture was refluxed under heat for 2 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (ethyl acetate-hexane), to thereby give 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester as a solid (480 mg, 34%).
Reaction SMILES: [C:1]([O:5]CC)(=[O:4])[C:2]#[CH:3].N1CCOCC1.C(N(C(C)C)CC)(C)C.C(OC([NH:28][N:29]=[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)[CH:31](Cl)Cl)=O)C.[OH-].[K+]>C(Cl)Cl.C(O)C.O>[F:41][C:40]([F:42])([F:43])[C:36]1[CH:35]=[C:34]([C:30]2[N:29]=[N:28][CH:3]=[C:2]([C:1]([OH:5])=[O:4])[CH:31]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: C#CC(=O)OCC
Reactant: CCOC(=O)NN=C(c1cccc(C(F)(F)F)c1)C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCN1
Product: O=C(O)c1cnnc(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
Ethyl propiolate (130 mL, 1.28 mole) was stirred under N2 in methylene chloride (2.5 L) at RT while morpholine (112 mL, 1.28 mole) was added dropwise over 20 min. External cooling by means of an ice bath was employed. The mixture was then refluxed for 30 min. and then cooled to RT. Diisopropylethylamine (426.4 mL, 2.45 mole) was then added to the mixture followed by [2,2-dichloro-1-[3-(trifluoromethyl)phenyl]ethylidene]hydrazinecarboxylic acid ethyl ester (400 g, 1.17 mole) which was added dropwise as a solution in methylene chloride (800 mL) over 30 min. The mixture was then refluxed for 18 h, cooled, and partitioned 2 times with water. The organic layer was dried (MgSO4), filtered and evaporated in vacuo to give a crude oil. The crude oil was taken up in 3 L of ethanol and then KOH 302 g of 86.6%, 4.66 moles) was added while the solution was stirred. The mixture was then refluxed under N2 for 2 h. Water (500 mL) was then added and most of the ethanol was removed in vacuo. The mixture was then dissolved in 3 L of water and extracted 3×800 mL with methylene chloride which was discarded. The aqueous layer was then made acidic with 12N HCl to precipitate the pyridazine acid (gas is evolved). The acid is then dried in vacuo to give 6-[3-(trifluoromethyl)phenyl]-4pyridazinecarboxylic acid (247 g, 79% yield, Compound No. 2) as a brown solid which was recrystallized from ethyl acetate/methanol.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH:22]3[CH3:27])[N:18]=[C:17](N3CCCC3C)[N:16]=2)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH:22]3[CH3:27])[N:18]=[C:17]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][CH:2]3[CH3:1])[N:16]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1COCCN1
Reactant: CC1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCCC2C)n1
Product: CC1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCOCC2C)n1

Procedure:
This compound is prepared using (R)-3-methylmorpholine (WO 02/064096) in a procedure analogous to that used for the preparation of 4-(4-fluoro-phenyl)-6-(2-methyl-piperazin-1-yl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine in Example 2F step 3.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][CH:7]2[CH2:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]=12.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:16]=[C:4]2[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[CH2:15][CH:7]3[CH2:6][S:5]2)[CH:18]=1
Reactant: CSC1=[N+]2c3ccccc3CC2CS1
Reactant: Nc1cccnc1
Agent: [I-]
Solvent: c1ccncc1
Product: c1cncc(N=C2SCC3Cc4ccccc4N23)c1
Reaction time: 24 h
Yield: 76.5 %

Procedure:
(RS)-3-Methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (14.0 g) is added to a solution of 3-aminopyridine (4.5 g) in pyridine (150 cc). The suspension gradually passes into solution. After 24 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm Hg) at 50° C. The residue is dissolved in a mixture of methylene chloride (500 cc) and 2 N aqueous sodium hydroxide solution (150 cc). The organic phase is decanted, washed with water (200 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. The residue obtained is recrystallised from absolute ethanol (40 cc). (RS)-3-(Pyrid-3-ylimino)-9,9a-dihydrothiazolo[3,4-a]indole (8.2 g), melting at 131° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13]C)[CH:9]=2)[CH:4]=1.[Na].Cl.O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: COc1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Yield: 125.5 %

Procedure:
A suspension of 2,6-dimethoxynaphthalene (20.0 g, Aldrich) in 200 mL of anhydrous EtOH was heated to reflux under a stream of nitrogen. Sodium spheres (18 g, Aldrich) were added gradually to the hot suspension over a period of 2 hours. Additional ETOH (50 ml) was added and the reaction was heated until all of the sodium had dissolved. The solution was cooled to room temperature and placed in an ice bath. The addition of 6 N HCl brought the solution to pH 6, and additional HCl (10 mL) was added. The solution was heated to reflux for 0.5 h. The golden mixture was cooled to room temperature, H2O (200 mL) was added, and the solution was extracted with ET2O. The combined ET2O extracts were dried (Na2SO4), filtered, and concentrated to afford 6-methoxy-2-tetra-lone as a red oil (23.5 g). Triethyl phosphono-acetate (29 mL, Aldrich) was added dropwise to a suspension of hexane-washed sodium hydride (5.8 g of 60% dispersion) in benzene (80 mL) cooled in an ice bath. The phos-phonate solution was stirred at room temperature for 0.5 h, and the ice bath was replaced. A solution of 6-methoxy-2-tetralone (23.5 g) in benzene (20 mL) was added to the phosphonate solution over 10 minutes, and the reaction was allowed to stir at room temperature overnight. The reaction was poured into H2O and extracted with EtOAc (3×150 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to afford a brown oil which was purified using silica gel chromatography. Elution with 10% EtOAc/hexane afforded the title compound (27 g) as a yellow oil. NMR (300 MHz, CDCl3) δ6.98 (d, J=9.03 Hz, 1 H), 6.79-6.70 (m, 2H), 6.35 (s, 1H), 3.94 (q, J=7.11 Hz, 2H), 3.58 (s, 3H), 2.99 (s, 2H), 2.61 (t, J 8.11 Hz, 2H), 2.14 (t, J=8.07 Hz, 2H), 1.08 (t, J 7.14 Hz, 3H).