Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:13]([O:15]C(C)(C)C)=[O:14])[CH2:10][CH:9]1[CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>CCOCC.O>[C:1]([O:5][C:6]([C:8]1([C:13]([OH:15])=[O:14])[CH2:10][CH:9]1[CH2:11][CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC1CC1(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCC1CC1(C(=O)O)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 69 %

Procedure:
The product of Step 1 (18.3 g, 67.8 mmol) was added to a suspension of potassium tert-butoxide (33.55 g, 299.0 mmol) in dry ether (500 mL) at 0° C., followed by H2O (1.35 mL, 75.0 mmol) and was vigorously stirred overnight at rt. The reaction mixture was poured in a mixture of ice and water and washed with ether (3×). The aqueous layer was acidified with a 10% aq. citric acid solution at 0° C. and extracted with EtOAc (3×). The combined organic layers were washed with water (2×), brine, dried (MgSO4) and concentrated in vacuo to afford the titled product as a pale yellow oil (10 g, 46.8 mmol, 69% yield).
Reaction SMILES: [Br:1][CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)=[CH:5][C:4]=1[F:14].C(N(C(C)C)CC)(C)C.P([O-])(OCC)OCC>C1COCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)=[CH:5][C:4]=1[F:14]
Reactant: Fc1cc(-c2ncon2)ccc1C(Br)Br
Agent: CCOP([O-])OCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(-c2ncon2)ccc1CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a stirring mixture of 3-(3-fluoro-4-methylphenyl)-1,2,4-oxadiazole (5.34 g, 30 mmol), CCl4 (50 mL) and NBS (11.7 g, 66 mmol) was added AIBN (246 mg, 1.5 mmol). The reaction mixture was heated to 80° C. for 3 hour under nitrogen, cooled to room temperature, and 50 mL of saturated sodium bicarbonate solution was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated on a rotovap to give 3-(4-(dibromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole, (9.34 g, 93%) as a white solid which was used in the next step without further purification. A 200 mL round bottom flask was charged with 3-(4-(dibromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (8.37 g, 25 mmol) and THF (60 mL). The mixture was cooled to 0° C. and diisopropyl ethyl amine (3.48 g, 27 mmol) was added dropwise over 15 minutes, followed by diethyl phosphite (3.7 g, 26.8 mmol). The mixture was stirred at room temperature for 60 minutes and quenched with 40 mL of water. The aqueous layer was extracted with ether (2×80 mL). The combined organic layer was washed with 20 mL of sat aq. NH4Cl and 20 mL of saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated on a rotovap to give a crude solid which was purified by a short silica pad to afford 3-(4-(bromomethyl)-3-fluorophenyl)-1,2,4-oxadiazole (6.03 g, 94%). mp 87.3° C. 1H-NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 7.94 (dd, 1H), 7.87 (dd, 1H), 7.58 (t, 1H), 4.57 (s, 2H); 13C-NMR (CD)Cl3, 400 MHz) δ 166.97, 166.95, 165.45, 162.29, 159.73, 132.34, 132.30, 128.99, 128.90, 128.81, 124.04, 124.01, 115.56, 115.32, 25.22, 25.18; 19F-NMR (CDCl3, 400 MHz) δ −115.81, −115.84, −115.86. Anal. Calcd for C9H6BrFN2O: C, 42.05; H, 2.35; N, 10.90. Found: C, 42.17; H, 2.17; N, 10.63.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([CH3:30])[CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=2)=[C:23]([CH3:30])[CH:22]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2F)n1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CSc1nc(Nc2ccccc2F)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-(4-fluoro-2-methyl-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.28 (s, 3H) 0.59 (s, 3H), 7.01 (m, 2H), 7.18 (m, 3H), 7.24 (m, 1H), 8.42 (m, 1H), 9.63 (s, 1H), 11.30 (br s, 1H). LC MS (m/e)=372 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)[CH:7]=1.C[O:23][C:24](OC)(N(C)C)[CH3:25]>C(OCC)(=O)C>[OH:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][C:3]([N+:19]([O-:21])=[O:20])=[C:2]([CH2:1][C:24](=[O:23])[CH3:25])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(C)(OC)N(C)C
Reactant: Cc1cc(-c2ccc(CO)cc2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CC(=O)Cc1cc(-c2ccc(CO)cc2)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A solution of (5′-methyl-2′,4′-dinitro-biphenyl-4-yl)-methanol (0.6 g) in N,N-dimethylacetamide dimethylacetal (5 mL) was heated at 100° C. for 2 hour. The reaction mixture was then cooled, diluted with ethyl acetate, washed with a diluted aqueous solution of hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (acetone/DCM, 3/97) to afford 1-(4′-hydroxymethyl-4,6-dinitro-biphenyl-3-yl)-propan-2-one.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][CH:37]([F:44])[C:38](N(OC)C)=[O:39]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:38](=[O:39])[CH:37]([F:44])[F:36])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)C(F)F
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)F)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2,2-difluoro-N-methoxy-N-methylacetamide.
Reaction SMILES: C[O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[OH-].[Na+]>CO>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:26])=[O:2])[CH2:15][CH2:14]2
Reactant: COC(=O)/C=C/C1=C(c2ccc(OC)cc2)c2ccc(OC)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2=C(/C=C/C(=O)O)CCc3cc(OC)ccc32)cc1
Yield: 83.3 %

Procedure:
As in Example 112, (E)-3-[3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid methyl ester (2.5 g) in methanol (15 mL) was heated at reflux with 1N sodium hydroxide solution (11 mL) at reflux for 1 hour. The usual work up furnished 2 g of (E)-3-[3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid. Crystallization of a small sample from dichloromethane-ethyl acetate gave the analytical specimen, mp 222°-224° C. Anal. Calcd for C21H20O4 : C, 74.98; H, 5.99 Found: C, 74.89; H, 6.00
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[CH3:11][NH:12][C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([O:28]CCC)=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[CH3:11][N:12]([C:8](=[O:10])[CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1)[C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: Cc1nc(CC(=O)O)cs1
Product: Cc1nc(CC(=O)N(C)[C@@H]2CCc3c(CC(=O)O)c4ccccc4n3C2)cs1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2-methyl-1,3-thiazol-4-yl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 398.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH:4]=[C:5]=[CH:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[CH3:24][N+](C)(C)C>CO>[C:1]([O:22][CH3:24])(=[O:21])[CH2:2][CH2:3][CH:4]=[C:5]=[CH:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C[N+](C)(C)C
Reactant: CCCCCCCCCCC/C=C\CC=C=CCCC(=O)O
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCC/C=C\CC=C=CCCC(=O)OC

Procedure:
A solution of 300 mg of 4,5,8Z-eicosatrienoic acid was treated with 0.52 ml of a 20% solution of tetramethylammonium hydroxide in methanol. After stirring for 5 minutes at room temperature the methanol was evaporated under reduced pressure at 30 C. and 5 ml of dimethyl formamide was then added. The resulting suspension was stirred and treated with 0.25 g of methyl iodide. After 30 minutes at room temperature the reaction mixture was diluted with 30 ml of water and extracted with 100 ml of ether. The ethereal solution was washed with water and brine and then dried over sodium sulfate. Evaporation of the ether gave methyl 4,5,8Z-eicosatrienoate.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(O)(=O)C=C.C([C:13]([CH2:18][OH:19])(CO)CC)O.CC1C(N=C=O)=CC([N:27]=[C:28]=[O:29])=CC=1>COC1C=CC(O)=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:27][C:28]([O:19][CH2:18][CH3:13])=[O:29]
Reactant: CCC(CO)(CO)CO
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: C=CC(=O)O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: CCOC(N)=O
Reaction time: 1 h

Procedure:
In a 1 l glass reactor equipped with a stirrer, a thermometer and a dropping funnel were charged 242 g of trimethylolpropane diacrylate and 0.25 g of hydroquinone monomethyl ether, followed by adding dropwise 85 g of 2,4-tolylene diisocyanate over a period of 1 hour with keeping the temperature at 60° C. The content was stirred for 1 hour at this temperature, followed by adding 0.05 g of dibutyltin diacetate and then reaction was continued for further 2 hours. After completion of the reaction, there was obtained 325 g of polyfunctional urethane acrylate, which contained 0.03 % of isocyanate.
Reaction SMILES: [CH3:1][N:2]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]#[C:23][CH2:24][N:25]([CH3:29])[CH2:26][CH2:27][CH3:28])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[O-].[Na+]>CO>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:1])[C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]#[C:23][CH2:24][N:25]([CH3:29])[CH2:26][CH2:27][CH3:28])[CH2:20][CH2:21]2)(=[O:5])=[O:4])=[CH:11][CH:10]=1
Reactant: CCCN(C)CC#C[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(NC(C)=O)cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCN(C)CC#C[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 70 °C

Procedure:
A solution of 44.3 mg (0.1 mmol) of trans-N-[4-(Methyl-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexyl}-sulfamoyl)-phenyl]-acetamide in 5 ml MeOH was treated with 0.37 ml (2 mmol) of sodium methylate (5.4 M in MeOH) and heated at 70° C. for 30 h. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 97:3) gave 31 mg (82%) of pure trans-4-Amino-N-methyl-N-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexyl}-benzenesulfonamide, MS: 378 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C@H:5]([CH3:10])[CH2:6][C:7](O)=[O:8].CSC.B.O>O1CCCC1>[CH3:10][C@H:5]([CH2:6][CH2:7][OH:8])[CH2:4][C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)C[C@H](C)CC(=O)O
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)C[C@H](C)CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 114 g. of 3-(R)-methylglutaric acid mono methyl ester in 715 ml. of dry tetrahydrofuran cooled to 0° C. was added slowly 391 ml. of 2M solution of borane dimethylsulfide in tetrahydrofuran. After the addition was complete the reaction mixture was stirred overnight at room temperature. The reaction was cooled and 50 ml. of water slowly added. The reaction was extracted (3×100 ml.) with ether and the extracts combined, washed with water, a saturated sodium bicarbonate solution and a brine solution, and dried over magnesium sulfate. Removal of the solvent gave 37 g. of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22]C4CCOC4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([C@@H:30]1[CH2:34][CH2:33][CH2:32][O:31]1)#C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][C@@H:30]4[CH2:34][CH2:33][CH2:32][O:31]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C#C[C@@H]1CCCO1
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1C#CC1CCOC1
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1C#C[C@@H]1CCCO1

Procedure:
Compound 2.3 was prepared with the same procedure as the preparation of Compound 1.2, using (S)-2-ethynyl-tetrahydrofuran (Compound 2.2) instead of (S)-2-ethynyl-tetrahydrofuran (Compound 1.1). MS (ESI) m/z=383 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([NH2:36])[CH:31]=1>>[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([NH:36][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:31]=1
Reactant: Cn1nc(N)cc1Cl
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Product: Cn1nc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)cc1Cl
Yield: 30.6 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21) and 5-chloro-1-methyl-1H-pyrazol-3-ylamine (Intermediate 6) afforded N-(5-chloro-1-methyl-1H-pyrazol-3-yl)-3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (51.7 mg, 30.6%); ES+-HRMS m/e calcd for C23H23N5O3F3Cl [M+H+] 510.1515 found 510.1514. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.84 (m, 9H), 1.93 (m, 1H), 2.23 (m, 1H), 3.70 (s, 3H), 5.44 (dd, J=4.4, J=10.4 Hz, 1H), 5.92 (d, J=3.0 Hz, 1H), 6.48 (s, 1H), 7.49-7.64 (m, 2H), 7.83 (t, J=7.9 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 8.18 (d, J=3.0 Hz, 1H), 10.95 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]([C:17]2[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)=[N:11]1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+].Cl>CN1CCCC1=O.O>[NH:32]1[C:1]([CH:3]=[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]2[N:10]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]([C:17]3[C:18]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=34)=[N:11]2)=[N:2][N:34]=[N:33]1
Reactant: N#CCC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1C1CCCCC1=Cc1nnn[nH]1
Temperature: 145 °C
Yield: 7.7 %

Procedure:
A mixture of 3-[2-(2-cyanomethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (1 g), sodium azide (480 mg) and ammonium chloride (200 mg) in 1-methyl-2-pyrrolidone (10 ml) was heated at 140 to 150° C. for 6 hours with stirring. The reaction mixture was cooled to room temperature, which was poured into water and adjusted to pH 1.0 with 1N-aqueous hydrochloric acid. The resulting solution was extracted three times with ethyl acetate (100 ml). organic layers were combined, washed with brine (50 ml×2) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel eluting in turn with 2%, 3%, 5%, 10% methanol in dichloromethane. Fractions containing desired product were collected. Evaporation of the solvent gave a residue which was recrystallized from ethyl acetate to give 3-[2-{2-(1H-tetrazol-5-yl)methylenecyclohexyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (85 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[OH:22][C:9]1([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[N:7]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2cccc(Cl)n2)CC1
Reactant: Nc1nccs1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2cccc(Nc3nccs3)n2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 50.3 mg of tert-butyl 4((6-chloropyridin-2-yl)methyl)-4-hydroxypiperidine-1-carboxylate, 19.3 mg of 2-aminothiazole, 9.0 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 4.8 mg of bis(dibenzylideneacetone)palladium(0), 25.2 mg of sodium carbonate and 0.77 ml of toluene was stirred at 100° C. overnight and 120° C. overnight. 156.6 mg of cesium carbonate, 94.4 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 47.1 mg of bis(dibenzylideneacetone)palladium(0) were added to the reaction mixture, followed by stirring the reaction mixture at 130° C. overnight. The reaction mixture was cooled to room temperature, and diluted with chloroform. An insoluble matter was filtered off using Celite, and the filtrate was concentrated in vacuo. The resulting residue was purified by a preparative thin-layer chromatography (Kieselgel™ 60F254, Art5744 (Merck), chloroform/methanol=10/1) to give the title compound as a brown oil.
Reaction SMILES: S(=O)(=O)(O)O.OO.[OH-].[Na+].[C:10]([N:23]([CH2:25][C:26]([O-:28])=[O:27])[CH3:24])(=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+].[Co:30]>>[C:10]([N:23]([CH2:25][C:26]([O-:28])=[O:27])[CH3:24])(=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Co+2:30].[C:10]([N:23]([CH2:25][C:26]([O-:28])=[O:27])[CH3:24])(=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [Co]
Agent: CCCCCCCCCCCC(=O)N(C)CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: OO
Product: [Co+2]

Procedure:
1000 ml of the cobalt solution resulting from separation of the organic phase and containing sulfuric acid, residues of hydrogen peroxide and 0.98% by weight of Co are adjusted to a pH of 6.5 by addition of about 130 g of 18% strength by weight sodium hydroxide solution and subsequently freed of hydrogen peroxide by heating to the boiling point. 333 ml of aqueous 1M sodium N-lauroylsarcosinate are subsequently added, forming cobalt N-lauroylsarcosinate in the form of a pale pink precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:43].[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[CH:26]=[CH:27][CH:28]=2)[C:10]1=[O:43]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc(CCCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Reactant: Nc1ccccc1
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 140 °C
Yield: 100 %

Procedure:
A mixture of 190 mg (0.3 mmol) of 2-[3-[3-[3-(2,4-dichlorophenyl)-7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-propyl]-isoindole-1,3-dione and 1 ml of aniline was heated at 140° C. for 35 minutes and then cooled. The mixture was added to 40 ml of 2M aqueous hydrochloric acid and the precipitated product was filtered off, washed with 2M aqueous hydrochloric acid, then with water and finally dried to give 200 mg (100%) of 2-[3-[3-[3-(2,4-dichlorophenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-propyl]-isoindole-1,3-dione as a pale brown solid. [Mass spectrum (ESI) MH+ =649].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([NH2:20])=[S:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.I[CH2:22][CH3:23]>CC(C)=O>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([S:19][CH2:22][CH3:23])=[NH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2c[nH]c3ccc(NC(N)=S)cc23)CC1
Reactant: CCI
Solvent: CC(C)=O
Product: CCSC(=N)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 25.1 %

Procedure:
A solution of compound 65 (0.2 g, 0.698 mmol) in acetone (10 mL) was treated with iodoethane (0.33 mL, 4.189 mmol) at room temperature and the resulting solution was refluxed for 4 h. The reaction was brought to room temperature, and solvent was evaporated. The crude was diluted with sat. NaHCO3 solution (20 mL) and compound was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Evaporation of solvent and purification of crude by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 66 (0.055 g, 25%) as a solid. mp 77-79° C.; 1H NMR (DMSO-d6) δ 1.20-1.30 (m, 3H), 2.28 (s, 3H), 2.50-2.57 (m, 4H), 2.90-2.96 (m, 2H), 3.02-3.06 (m, 2H), 5.98-6.04 (m, 2H), 6.60-6.63 (m, 1H), 7.17-7.35 (m, 4H), 10.90 (s, 1H); ESI-MS m/z (%):: 315 (M+, 66), 311 (78), 249 (100).