Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1B(O)O>>[F:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:2][CH3:3]
Reactant: OB(O)c1ccncc1F
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CNc1cnccc1-c1ccncc1F

Procedure:
The title compound was prepared in analogy to example 69, intermediate, from (4-bromo-pyridin-3-yl)-methyl-amine (example 25, intermediate b) and 3-fluoropyridine-4-boronic acid (CAS RN 458532-97-3). Brown solid (92%). MS (ESI): m/z=204.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19]>CO.CCOCC>[ClH:19].[CH3:18][S:15]([N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)(=[O:16])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)N1CCCNCC1
Temperature: 25 °C

Procedure:
Crude 4-Methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10 ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction mixture was stirred at room temperature. After 5 minutes a precipitate formed, addition of anhydrous methanol (5 ml) caused this to dissolve. The reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo to yield 1.06 g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.C(N(C(C)C)CC)(C)C.Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].[O:38]1CCC[CH2:39]1>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:39]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])=[O:38])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C1CCOC1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-1-boc-piperidine (964 mg, 4.8 mmol) in tetrahydrofuran (15 mL) was added to a solution of p-nitrophenylchloroformate (970 mg, 4.8 mmol) and triethylamine (0.67 mL, 4.8 mmol) in tetrahydrofuran (15 mL) at 0° C. After 1 h, additional diisopropylethylamine was added (1.3 mL, 9.6 mmol) along with glycine methyl ester hydrochloride (604 mg, 4.8 mmol). The reaction was warmed to room temperature and stirred overnight. The mixture was filtered, concentrated and redissolved in ethyl acetate. The ethyl acetate layer was washed with 1N sodium hydroxide (3×), saturated sodium bicarbonate solution, water, brine, and dried over sodium sulfate. Purification by silica gel chromatography (100% dichloromethane→8% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (700 mg). MS 400.29 (M+1)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Yield: 59.7 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 6-methyl-2,4-dichloropyrimidine (3.26 g, 20 mmol), 1,2,3,4-tetrahydroisoquinoline(2.6 ml, 20.5 mmol), triethylamine(3.4 ml, 24.4 mmol) and N,N-dimethyl formamide (10 ml) were used as starting materials, 3.1 g of the titled compound was prepared. (Yield: 59.7%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1)#[N:2].[CH3:32][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:32])=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
The reaction was carried out under argon. (4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (5.0 g, 11.7 mmol) was initially charged in absolute THF (500 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (13.5 ml, 13.5 mmol; 1.15 eq.) was added at −78° C. After 30 min of stirring, iodomethane (8.30 g, 58.5 mmol; 5 eq.) in THF was added and the mixture was stirred for 16 h while slowly warming from −78° C. to RT. The reaction mixture was then concentrated under reduced pressure, and initially 1 N hydrochloric acid (14.0 ml) and then MTBE (500 ml) were added. The organic phase was washed successively with water (2×), saturated sodium bicarbonate solution, saturated ammonium chloride solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (4.3 g, 83% of theory).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[N:9]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>CC(O)CC>[CH2:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH2:11][CH2:10]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=c1cc(Cl)nc[nH]1
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(c2cc(=O)[nH]cn2)CC1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A mixture of 6-chloro-3H-pyrimidin-4-one (36984-063-A; 3.90 g, 29.9 mmol), benzyl 1-piperaz-inecarboxylate (Aldrich; 8.81 g, 40.0 mmol), and diisopropylethylamine (7.0 mL, 40.2 mmol) in 2-butanol (100 mL) was heated in a 250 mL round-bottomed flask equipped with a reflux condenser in an oil-bath at about 80° C. (oil-bath temperature) for 8 hours. The heating bath was removed and the reaction mixture was left standing at room temperature overnight. The white solid was filtered off, washed with 2-butanol, and air-dried to give 4-(6-oxo-1,6-dihydro-pyrimidin-4-yl)-piperazine-1-carboxylic acid benzyl ester (7.76 g, 83%) as a white powder, mp 247-249° C. 1H NMR (d6-DMSO) δ 1.39 (s, 9H), 3.45-3.50 (m, 8H), 5.08 (s, 2H), 5.26 (s, 1H), 7.28-7.38 (m, 5H), 7.90 (s, 1H), 11.66 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)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.O>[CH3:27][S:24]([C:20]1[CH:19]=[C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-7-(3-methanesulfonyl-phenyl)-4-morpholin-4-yl-quinazoline (0.15 g, 0.00037 mol), 2-aminopyridine-5-boronic acid pinacol ester (0.122 g, 0.0005568 mol), cesium carbonate (0.243 g, 0.00074 mol), DMF (4 mL) and water (2 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.013 g, 0.000018 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 5% MeOH in chloroform) to yield the title compound (125 mg, 74%). LC-MS (ESI): Calculated mass: 461.2; Observed mass: 462.1 [M+H]+ (RT: 0.17 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:32]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:37]=1>>[CH2:32]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])[CH:14]=2)=[CH:20][CH:21]=1)[CH3:37]
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)cc1

Procedure:
4-[3-(3,5-Dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=463.2 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]12[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=1)[C:13](=[O:19])[NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][C:2]2=[O:20].Cl>CO.O.[Pt](=O)=O>[CH:14]12[NH:18][CH:1]([CH2:17][CH2:16][CH2:15]1)[C:2](=[O:20])[NH:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]2=[O:19]
Reactant: O=C1NCCNCCNCCNC(=O)c2cccc1n2
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NCCNCCNCCNC(=O)C2CCCC1N2
Temperature: 60 °C
Yield: 73 %

Procedure:
3,6,9,12,18-Pentaazabicyclo[12.3.1]octadeca-1(18),14,16-trien-2,13-dione prepared as in Example 38A (1.0 g, 3.6 mmol) was dissolved in methanol (75 ml) and concentrated hydrochloric acid (2.14 g, 21.7 mmol) was added, then the catalyst platinum dioxide hydrate (0.5 g, 2 mmol). The mixture was heated to 60° C. and hydrogenated at 60 psi for 24 h. A white crystalline solid formed during the hydrogenation. The reaction mixture was filtered, and the precipitate was washed with water to dissolve it. The filtrate was concentrated to remove the alcohol and sodium hydroxide (1.0N) was added to raise the pH to 11. This solution was extracted five times with dichloromethane (75 ml each), the solvent was removed under reduced pressure, and the resulting white solid was dried on the vacuum line to give 0.74 g (73% yield) of product: mp 193°-195.5° C. (dec); 1H NMR (CD2Cl2) δ 0.79-1.48 (several m, 5H), 1.88 (m, 2H), 2.01 (m, 2 H) , 2.63-2.88 (several m, 8 H) , 3.10 (m, 2H) , 3.24 (m, 2H), 3.36 (m, 2H), 7.71 (s, 2H).
Reaction SMILES: C[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH:5]([C:12]([OH:14])=O)[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1([CH2:44][CH2:45][CH2:46][CH2:47]C2C=CC(O)=CC=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:38]1([CH2:44][CH2:45][CH2:46][CH2:47][C:17]2[CH:18]=[CH:2][C:3]([O:4][CH:5]3[CH2:6][CH:7]([C:9]([O:11][CH3:19])=[O:10])[NH:8][C:12]3=[O:14])=[CH:15][CH:16]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccccc1OC(C[C@H](N)C(=O)O)C(=O)O
Reactant: Oc1ccc(CCCCc2ccccc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2ccc(CCCCc3ccccc3)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 23 h
Yield: 92.6 %

Procedure:
A mixture of the compound prepared as described in Example 4 (0.434 g), triphenylphosphine (0.8113 g), and 4-(4-phenylbutyl)phenol (0.700 g) in tetrahydrofuran (3.8 ml) was cooled to approximately 1°-2° C., and treated with diethylazodicarboxylate (0.5386 g) over a two minute period. After the addition was complete, the reaction was allowed to warm to room temperature. After about 23 hours, the solution was concentrated in vacuo. The residue was diluted with chloroform (1 ml), the insoluble material removed by filtration, and the filtrate concentrate din vacuo. The residual oil was dissolved in methylene chloride (4 ml) and purified by preparative centrifugal thin-layer chromatography (4 mm plate, flow rate=8 ml/min), eluting with 50% ethyl acetate/hexane until first band elutes then solvent switched to 100% ethyl acetate. The fractions containing the desired compound were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl 3-[4-(4-phenylbutyl)phenoxy]-2-pyrrolidone-5-carboxylate (583 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8][CH2:9][CH2:10][OH:11])[CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:8]([CH2:9][CH2:10][OH:11])=[O:17])[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCCSCc1cccnc1
Solvent: ClCCl
Product: O=S(CCO)Cc1cccnc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A stirred solution of 2-(3-pyridylmethylthio)ethanol (3.38 g, 20 mmol) in dichloromethane (50 ml) at 0° C. was treated dropwise with a solution of m-chloroperoxybenzoic acid in dichloromethane (50 ml). The mixture was stirred at 0° C. for 1 hr and at room temperature for 3 hrs. The mixture was evaporated in vacuo and purified by flash chromatography on silica eluting with 20% methanol in ethyl acetate to give 2-(3-pyridylmethylsulphinyl)ethanol (3.5 g), as colourless crystals, m.p. 84°-86° C.;
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Br:15])(=O)C>>[Br:15][C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: CC(=O)Br
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Product: Cc1cc(Br)cc[n+]1[O-]
Yield: 31.1 %

Procedure:
4-Nitro-2-picoline N-oxide (1.0 g, 6.5 mmol) was treated with acetyl bromide (3.5 mL, 47 mmol) as described in Example 65b to provide the title compound (0.38 g, 31%) as an orange-brown oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)[N:10]=1.S(Cl)([Cl:24])=O>>[Cl:24][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH3:21])=[N:18][CH:17]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethanol (1.87 g) and thionyl chloride (15 ml) was stirred at room temperature for 1-hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (1.41 g, yield 71%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 95–96° C.
Reaction SMILES: [CH:1]([C:11]([O-])=O)([C:7]([O:9]C)=[O:8])[CH2:2][CH2:3][C:4]([O-:6])=O.Br[CH:15]([CH2:20][CH2:21][CH2:22]CC)[C:16](OC)=O>>[CH2:16]([CH:11]1[C:4](=[O:6])[CH2:3][CH2:2][CH:1]1[C:7]([OH:9])=[O:8])[CH2:15][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(Br)C(=O)OC
Reactant: COC(=O)C(CCC(=O)[O-])C(=O)[O-]
Product: CCCCCC1C(=O)CCC1C(=O)O
Yield: 38.4 %

Procedure:
By repeating the procedure described in Example 1 (a) but starting from 195 g of methyl propane-1,1,3-tricarboxylate (F. L. M. Pattison, R. L. Buchanan and F. H. Dean, Can. J. Chem. 43(6), 1700 (1965)) and 176 g of methyl α-bromoheptanoate (H. Reinheckel, Ber. 93, 2222 (1960)), there is obtained 60 g (41%) of 2-n-pentyl-3-oxo-cyclopentanecarboxylic acid, melting at 52° C.
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][NH2:11])[CH2:3][CH2:2]1.[CH:12](OCC)=[O:13]>>[NH:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH2:3][CH2:2]1
Reactant: NCCc1cnn2c1NCC2
Reactant: CCOC=O
Product: O=CNCCc1cnn2c1NCC2

Procedure:
A suspension of 2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylamine (155 mg) in ethyl formate (3 ml) was refluxed for 4.5 hours. After evaporation of the solvent in vacuo, the residue was triturated with ethyl acetate and dried in vacuo to give 2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylformamide (165 mg) as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16](Br)[CH:17]=[N:18][C:9]1=2)=O)(C)(C)C.[CH3:20][N:21]([CH2:26][C:27]1[N:28]([CH3:36])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22](=[O:25])[CH:23]=[CH2:24].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:20][N:21]([CH2:26][C:27]1[N:28]([CH3:36])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22](=[O:25])/[CH:23]=[CH:24]/[C:16]1[CH:17]=[N:18][C:9]2[NH:8][CH2:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cc(Br)cnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)NC(=O)CN2
Temperature: 100 °C
Reaction time: 6 h
Yield: 85.2 %

Procedure:
A solution of 7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b]pyrazine-4-carboxylic acid tert-butyl ester (494 mg, 1.5 mmol) in propionitrile (12 mL) was treated with N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)-acrylamide (685 mg, 3 mmol) and diisopropylethylamine (788 μL, 4.5 mmol) and purged with Argon for 10 min. Pd(OAc)2 (34 mg, 0.15 mmol) and P(o-Tol)3 (92 mg, 0.3 mmol) was added and the Argon purge was repeated. The mixture was heated to 100° C. and stirred for 6 hours under Argon. Upon cooling, solvent was removed and the residue was purified by Flash chromatography (silica, 1-3% MeOH in CH2Cl2) to afford the title compound (480 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 10.81 and 10.73 (rotamers, 2s, br, 1H), 8.46 and 8.41 (rotamers, 2s, 1H), 7.58 (d, J=15.4 Hz, 1H), 7.51 (m, 3H), 7.23 (d, J=15.4 Hz, 1H), 7.11 (m, 1H), 7.03 (m, 1H), 6.45 and 6.20 (rotamers, 2s, 1H), 5.06 and 4.87 (rotamers, 2s, 2H), 4.32 and 4.28 (rotamers, 2s, 2H), 3.74 and 3.71 (rotamers, 2s, 3H), 3.16 and 3.05 (rotamers, 2s, 3H), 1.44 and 1.42 (rotamers, 2s, 9H). MS (ESI) in/e: 476.2 (M+H)+, 420.2 (M-tert-Bu)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[CH:4][C:3]=1[OH:18].C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].C(OC=CC)=CC>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC.CC(=O)CC>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[C:4]([CH:25]=[CH:26][CH3:27])[C:3]=1[OH:18]
Reactant: O=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Reactant: C=CCBr
Agent: CC=COC=CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCC(C)=O
Product: CC=Cc1cc(C(=O)c2ccccc2F)c(Cl)c(Cl)c1O

Procedure:
A mixture of 2,3-dichloro-4-(2-fluorobenzoyl)phenol (98 g., 0.343 mole), K2CO3 (94 g., 0.68 mole), allyl bromide (37 ml., 0.425 ml.) and 750 ml. of 2-butanone was heated at reflux for 4 hours. After cooling the 2-butanone was partially evaporated and the residue distributed between methylene chloride and aqueous NaCl. The organic layer was dried and evaporated to give 105 g. of the intermediate propenyl ether as a liquid. This material was dissolved in an equal volume of diphenyl ether and heated at 250° for 3.5 hours. The cooled reaction mixture was diluted with hexane and washed several times with 1N aqueous KOH. The combined aqueous washes were acidified with 6N HCl and the resulting mixture extracted with methylene chloride. The methylene chloride solution was dried (MgSO4) and evaporated to a residue. Trituration with hexane gave 73 g. of solid product, m.p. 83°-84° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[OH2:16].CN([CH:20]=[O:21])C>>[CH:10]1[C:11]2[N:12]([CH2:4][C@H:5]([CH3:6])[CH2:13][O:16][CH:10]3[CH2:9][CH2:8][CH2:7][CH2:20][O:21]3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C[C@H](COC1CCCCO1)Cn1c2ccccc2c2ccccc21
Reaction time: 18 h
Yield: 21 %

Procedure:
Carbazole (1.42 g, 0.0085 mol) was dissolved in dry DMF (40 mL) and NaH (60% dispersion in oil) (0.443 g, 0.0111 mol) was added. After stirring at ambient temperature for 45 min compound 8 (2.02 g, 0.0085 mol) was added and stirring continued at room temperature for 18 h. Water (20 mL) was added. Extraction with CH2Cl2 (3×20 ml), drying of the organic phases (MgSO4) and evaporation of the solvents in vacuo afforded an oil. Purification of the crude product twice on a silica gel column (1: Eluent: ethyl acetate/n-heptane(1:8), and 2: Eluent: ethyl acetate/toluene (1:9)) gave the title compound 0.59 g (21%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:37]3[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: O=C1CNCCN1
Solvent: COCCO
Solvent: ClCCl
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCNC(=O)C4)c(OC)cc23)c2c1OCO2
Temperature: 110 °C
Yield: 71.7 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.200 g) was dissolved in 2-methoxyethanol (6 ml) and piperazine-2-one (0.821 g) was then added and the mixture heated to 110° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. There was thus obtained the title compound (0.162 g) as a white powder, NMR Spectrum: (d6-DMSO) 2.10 (quin, 2H), 2.66 (m, 4H), 3.12 (s, 2H), 3.33 (m, 2H), 3.44 (s, 3H), 4.01 (s, 3H), 4.24 (t, 2H), 4.34 (s, 2H), 6.09 (s, 2H), 7.04 (, 1H), 7.06 (s, 1H), 7.19 (s, 1H), 7.77 (s, 1H), 8.46 (s, 1H), 9.04 (s, 1H); Mass Spectrum: M+H+ 554/556.