Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:18][Si:17]([CH3:20])([CH3:19])[N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N1CCCCCC1=O

Procedure:
Caprolactam, commercially available from Maybridge, (10.0 g, 88.0 mmol), Et3N (14.8 mL, 106 mmol) and chlorotrimethylsilane (13.5 mL, 106 mmol) were dissolved in toluene (60 mL) and refluxed under Ar for 3 h. The reaction was filtered and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C@H:25]1[CH2:30][O:29][CH2:28][CH2:27][NH:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C@H:25]1[CH2:30][O:29][CH2:28][CH2:27][N:26]1[C:21]([C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22]
Reactant: C[C@H]1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
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: CN(C)C=O
Product: C[C@H]1COCCN1C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.2 %

Procedure:
A 100-mL round-bottomed flask was charged with (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (2.04 g, 6.17 mmol, ASW MedChem. Inc., New Brunswick, N.J.), (S)-3-methylmorpholine (0.657 g, 6.50 mmol, Synthetech Inc., Albany, Oreg.), HATU (2.83 g, 7.45 mmol, ChemImpex International Inc., Wood Dale, Ill.), DIPEA (2.20 mL, 12.6 mmol) and DMF (12 mL). The reaction mixture was stirred at room temperature for 1 h. After this time, additional HATU (0.475 g) was added and the stirring at room temperature was resumed for 2 days. The reaction mixture was partitioned between water (120 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×40 mL). The combined organic phases were washed with water (50 mL), saturated aqueous NaHCO3 (50 mL), water (50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford di-tert-butyl (2R)-2-(((3S)-3-methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate (2.71 g) as a light-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18]CC4C=CC=CC=4)=[CH:14][CH:13]=3)[CH:10]([CH2:26][CH2:27][Cl:28])[C:9]2=[O:29])=[CH:4][CH:3]=1.C1CCCCC=1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:26][CH2:27][Cl:28])[C:9]2=[O:29])=[CH:6][CH:7]=1
Reactant: O=C1C(CCCl)C(c2ccc(OCc3ccccc3)cc2)N1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1=CCCCC1
Product: O=C1C(CCCl)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
A stirring mixture of 1-(4-fluorophenyl)-3-(2-chloroethyl)-4-[4-(benzyloxy)phenyl]azetidin-2-one (prepared according to Bioorg. Med. Chem. Lett. 1996, 6, 1271-1274; 2.00 g, 4.88 mmol), Pd(OH)2/C (0.500 g, 20%) and cyclohexene (6 ml) in MeOH (60 ml) was heated to 70° C. After 2 hours, the reaction mixture was cooled to room temperature and was filtered through diatomaceous earth. The solvent was removed under reduced pressure to give the title compound (1.57 g; -quantitative yield). No further purification was necessary. NMR (CD3OD, 400 MHz) 2.20-2.40 (m, 2H), 3.20-3.40 (m, 1H), 3.70 (t, 2H), 4.85 (d, 1H), 6.75-6.80 (m, 2H), 6.90-7.00 (m, 2H), 7.15-7.30 (m, 4H); m/z: 320.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[Cl:19][C:20]1[C:29]([CH:30]=O)=[C:28]([Cl:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>CO>[Cl:19][C:20]1[C:29]([C:30]2[NH:1][C:2]3[CH:3]=[C:4]([N:10]4[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]4)[CH:5]=[C:6]([CH3:9])[C:7]=3[N:8]=2)=[C:28]([Cl:32])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: O=Cc1c(Cl)nc2ccccc2c1Cl
Reactant: CC(=O)N1CCN(c2cc(C)c(N)c(N)c2)CC1
Solvent: CO
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)nc5ccccc5c4Cl)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A 3.6 mmol of 1-[4-(3,4-Diamino-5-methyl-phenyl)-piperazin-1-yl]-ethanone was taken in 40 mL of methanol, to which was added 0.921 gm (3.6 mmol) of the 2,4-Dichloro-quinoline-3-carboxaldehyde, and the mixture was stirred for 10 hrs at room temperature, solvent was evaporated to dryness, and the residue was chromatographed to provide the product. LRMS [M+H]+454; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H, J=7.6 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.85 (dd, 1H, J=7.6, 8.4 Hz), 7.78 (dd, 1H, J=7.6, 8.4 Hz), 6.86 (brs, 1H), 6.83(brs, 1H), 3.76 (br, 2H), 3.62 (br, 2H), 3.15 (br, 2H), 3.01 (br, 2H), 2.66 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Yield: 66.7 %

Procedure:
A mixture of 3 g of 2,4-dihydroxy-3-propylacetophenone, 2.5 g of ethyl bromoacetate, 2.3 g of anhydrous potassium carbonate, and 30 ml of methyl ethyl ketone was refluxed for 5 hours. Then, the solvent was removed under reduced pressure and after addition of 50 ml of toluene, the mixture was washed with water, a diluted aqueous solution of sodium hydroxide, and water successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus formed was recrystallized from a mixture of toluene and n-hexane to provide 2.8 g of ethyl (4-acetyl-3-hydroxy-2-propylphenoxy)acetate (melting point: 66° to 66.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[C:37](O)([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:12])=[CH:5]2
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 40 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
5.52 g of 5-chloro-2-indolecarboxylic acid are dissolved in 40 ml of DMF, 4.57 g of carbonyldiimidazole are added at RT, under nitrogen, the mixture is then heated to 40° C and 4.3 g of DBU and 4.17 g of tertbutanol are added. Heating is continued at 40° C. for 3 hours, the precipitate formed is then filtered off and the filtrate is concentrated under vacuum. The residue is taken up in EtOAc, washed with 10% Na2CO3 solution, with saturated aqueous NaCl, with sulphate buffer and then dried over Na2SO4 and concentrated. The residue is chromatographed on silica, eluting with DCM, to give 0.45 g of the expected compound: m.p.=140-142° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[I:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14]C(=O)O[C:11](=[O:16])[C:10]=2[CH:17]=1>N1C=CC=CC=1>[NH2:14][C:9]1[CH:8]=[CH:7][C:6]([I:5])=[CH:17][C:10]=1[C:11]([NH:4][CH2:1][CH2:2][CH3:3])=[O:16]
Reactant: CCCN
Reactant: O=c1[nH]c2ccc(I)cc2c(=O)o1
Solvent: c1ccncc1
Product: CCCNC(=O)c1cc(I)ccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Propylamine (1.2 g, 20.3 mmol) and 6-iodo-2H-3,1-benzoxazine-2,4(1H)-dione (5.0 g, 17.3 mmol) were combined in pyridine (85 mL) and stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200 mL) and 5% hydrochloric acid (200 mL). The phases were separated and the organic phase was washed with 1N sodium hydroxide, water, and brine. Drying over anhydrous sodium sulfate and evaporation under reduced pressure afforded 3.9 g of the title compound, 1H NMR (300 MHz, CDCl3): δ0.99 (t,3H1); 1.63 (m,2H); 3.35 (m,2H); 5.52 (br s,2H); 5.95 (br s,1H); 6.47 (d, 1H); 7.42 (dd,1H); 7.55(d,1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=5)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]6)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:46][C:47]([CH3:49])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]5[CH2:29][C:30]6([CH2:36][CH2:37][C:38]=5[C:39]5[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=5)[CH2:31][CH2:32][N:33]([CH:47]([CH3:49])[CH3:46])[CH2:34][CH2:35]6)[CH2:25][CH2:26]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCNCC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(CCN(C(C)C)CC4)C3)CC2)cc1Oc1cnc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265H (320 mg) in dichloromethane (5 mL) was added acetone (143 mg) and sodium triacetoxyborohydride (157 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with 2N aqueous NaOH, water and brine. After drying over Na2SO4, the mixture was filtered and the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10](Cl)[C:9]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:9]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:8]=3[S:7][C:6]=2[CH:18]=1
Reactant: Fc1ccc2c(c1)Sc1cc(Cl)ccc1CC2Cl
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C1OCCN1CCN1CCN(C2Cc3ccc(Cl)cc3Sc3cc(F)ccc32)CC1

Procedure:
17 G. of 3,10-dichloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin are treated with 45.5 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and stirred at 120°-130°C. (internal temperature) for 8 minutes. The mixture is treated with 2N sodium hydroxide and extracted with ether. The ether solution is washed to neutrality and shaken out with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and extracted with methylene chloride. The organic solution is washed with water and dried over magnesium sulfate. The residue is recrystallized from acetone, whereby there is obtained 3-{2-[4-(3-chloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone (melting point 168°-170°C.) which is converted into the dimethanesulfonate (melting point 191°-193°C.) by reaction with methanesulfonic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][C:10]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](I)[N:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)=[O:6].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:1][CH:2]([CH3:26])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][C:10]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)=[O:6]
Reactant: Nc1ccccc1
Reactant: CC(C)COC(=O)Nc1nc(-c2ccccc2)c(-c2ccnc(I)n2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(C)COC(=O)Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1

Procedure:
The 4-[2-(2,2-dimethylethoxycarbonyl-amino)-4-phenyl-thiazol-5-yl]-2-iodo-pyrimidine (0.082 g, 0.17 mmol) is heated to reflux with aniline (0.032 g, 0.34 mmol) and dry p-toluene sulfonic acid (0.026 g, 0.136 mmol) in dry dioxane for five hours.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:19](=[O:21])[CH3:20])=[CH:23][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-acetyl-phenylboronic acid to give 1-{4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 343(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]([O:17][CH2:18][CH3:19])=[CH2:16])CCC.[F-].[K+].C(OCC)C>CN(C)C=O.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>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[N:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1ncnc(Cl)c1C
Temperature: 80 °C
Yield: 61.1 %

Procedure:
4,6-Dichloro-5-methylpyrimidine (2.0 g, 12.27 mmol), bis(triphenylphosphine)palladium(II) chloride (0.172 g, 0.245 mmol) and tributyl[1-(ethyloxy)ethenyl]stannane (4.48 ml, 13.25 mmol) were added together in N,N-dimethylformamide (DMF) (45.8 ml) and the resulting mixture was heated at 80° C. under argon for 18 hours. The reaction mixture was allowed to cool to room temperature and poured into an aqueous solution of potassium fluoride (10.4 g in 104 ml water). Diethyl ether (146 ml) was added and the solid was filtered, washed with diethyl ether (×2) and discarded. The filtrate was separated and the organic layer was washed with water, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (1.49 g);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:25])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=2[OH:22])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:33][CH2:34][S:35][C:36](Cl)=[O:37]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:25])=[C:7]([C:15]([C:17]2[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=2[O:22][C:36]([S:35][CH2:34][CH3:33])=[O:37])=[O:16])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])=[O:4]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)c1O
Reactant: CCSC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)cnn1CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
5-Hydroxy-1-ethylpyrazol-4-yl 3-(methoxycarbonyl)-2-methyl-4-(methylsulfonyl)phenyl ketone (510 mg, 1.39 mmol) was dissolved in dry tetrahydrofuran (20 mL), and triethylamine (281 mg, 2.78 mmol) was added thereto. A solution (4 mL) of 96% S-ethyl chlorothiolformate (217 mg) dissolved in dry tetrahydrofuran was added thereto little by little under cooling with ice water. The reaction mixture was stirred for 90 minutes while the reaction temperature was allowed to warm to room temperature. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:4) to obtain the desired product as an oil (417 mg, 0.92 mmol) (yield: 66%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@H:30]([CH3:33])[CH2:31][OH:32]>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@@H](N)CO
Reactant: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Solvent: C1CCOC1
Product: C[C@H](CO)Nc1ncc2cc(Oc3ccc(F)cc3F)c(=O)n(C[C@@H](C)O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((R)2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (400 mg, 1 mmol) was added (R)-2-amino-1-propanol (0.38 mL, 5 mmol) and stirred overnight at room temperature. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 350 mg 6-(2,4-difluoro-phenoxy)-2-((R)-2-hydroxy-1-methyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=181.5-184.4° C.).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.Cl.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[C:22](=[O:23])[C:21]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)=[CH:20][NH:19]2)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:11].[ClH:1].[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:12]2[N:17]=[CH:16][N:15]=[C:14]([N:18]3[C:22](=[O:23])[C:21]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)=[CH:20][NH:19]3)[CH:13]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CN(c2cc(-n3[nH]cc(-n4ccnn4)c3=O)ncn2)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
271 mg (1.5 mmol) of N,N-dimethylazetidine-3-amine dihydrochloride, 400 mg (1.5 mmol) of the compound from Example 12A and 847 mg (6.1 mmol) of potassium carbonate are suspended in 8 ml of N,N-dimethylformamide and stirred at 100° C. for 16 h. The reaction mixture is concentrated under reduced pressure and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength trifluoroacetic acid). Further purification is carried out by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength formic acid). 2 ml of 1 N hydrochloric acid is added to the product-containing fractions, and the mixture is stirred at RT for 1 h. The solid is filtered off and dried under high vacuum. Yield: 62 mg (17% of theory)
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.Br[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Br>>[O:1]([C:8]1[CH:9]=[C:10]([N:11]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCNCCBr
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: Br
Product: c1ccc(Oc2cccc(N3CCNCC3)c2)cc1

Procedure:
In the manner described in example 1 starting from 49 parts of meta-phenoxyaniline and 83.3 parts of bis-(β-bromoethyl)amine dihydrobromide there was obtained a clear solution. After evaporation of the solvent in vacuo, the residue was treated with 700 part of water, rendered alkaline with 60 parts of concentrated NaOH and extracted twice with 200 parts of ether. Th solution was dried. Upon distillation, there were obtained 26 parts of 1-(3-phenoxyphenyl)-piperazine, B.P./0.5 mm Hg: 180°-190° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH2:11](O)[CH:12]=C>C1(C)C=CC=CC=1.[Zn]>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: C=CCO
Reactant: COC(=O)C1CCCC1=O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1CCCC1=O
Temperature: 25 °C
Yield: 99.3 %

Procedure:
To a stirred solution of methyl 2-oxocyclopentanecarboxylate (4.26 g, 30 mmol) and allyl alcohol (10.2 mL, 150 mmol) in anhydrous toluene (25 mL) was added powdered zinc (0.40 g, 6 mmol). After refluxing the mixture for 48 h, it was cooled to room temperature and the suspension was filtered. The filter cake was rinsed with toluene and the combined filtrate was concentrated to afford allyl 2-oxocyclopentanecarboxylate (5.01 g, 99%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 5.89 (ddt, J1=15.9 Hz, J2=10.5 Hz, J3=4.8 Hz, 1 H), 5.33 (dtd, J1=15.9 Hz, J2=2.7 Hz, J3=1.4 Hz, 1 H), 5.23 (dtd, J1=10.5 Hz, J2=2.7 Hz, J3=1.4 Hz, 1 H), 4.83-4.75 (m, 1 H), 3.18 (t, J=9.0 Hz, 1 H), 2.41-2.23 (m, 4 H), 2.22-2.07 (m, 1 H), 1.94-1.80 (m, 1 H); MS (+CI): m/z for C9H12O3: expected 168.1; found 169.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1([CH3:35])[CH2:34][O:33][CH2:32][CH2:31][NH:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:28][C:29]1([CH3:35])[CH2:34][O:33][CH2:32][CH2:31][N:30]1[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:15][N:14]=1)=[O:18]
Reactant: O=C(O)c1ccc(C#Cc2cccc(F)c2)cn1
Reactant: CC1(C)COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)COCCN1C(=O)c1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
(50 mg, 0.21 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 1, step 2) was dissolved in DMF (0.5 ml) and Hunig's Base (44 μl, 0.31 mmol, 1.2 equiv.), 3,3-dimethylmorpholine (36 mg, 0.25 mmol, 1.5 equiv.) and TBTU (73 mg, 0.23 mmol, 1.1 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired (3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone (61 mg, 87% yield) was obtained as a light yellow oil, MS: m/e=339.2 (M+H+).