Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:65]OC(NC(C1C=CC=CC=1C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=6[CH3:65])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1C
Yield: 31.4 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-o-tolyl-acetic acid (0.072 g, 0.332 mmol) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.047 g, 31.4%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.86 (M+H+).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1COCC1.CCOCC>[CH:1]1([O:7][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: BrCc1ccccc1
Reactant: OC1C=CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1=CC(OCc2ccccc2)CCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of cyclohex-2-en-1-ol (10.0 g, 101.9 mmol) in anhydrous THF (100 mL) was added to a stirred suspension containing sodium hydride (8.0 g, 199.7 mmol) (60% dispersion in oil) and benzyl bromide in anhydrous THF (250 mL) maintained at 50° C. The resulting solution was stirred at 55-60° C. for 18 h. After cooling to ambient temperature, water was added to quench the reaction and the mixture was diluted with ether (500 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo to an oil that was subjected to a short silica plug filtration to provide 16.1 g of desired product 51a that was used directly in the next step without further purification.
Reaction SMILES: [Br:1]C1C=CC=CC=1C=O.[OH:10][CH2:11][C:12]([CH3:16])([CH2:14][OH:15])[CH3:13].[C:17]1([CH3:33])[CH:22]=[CH:21][C:20](S(OC2C=CC=CN=2)(=O)=O)=[CH:19][CH:18]=1.C1C=CC=CC=1>O>[Br:1][C:19]1[CH:18]=[C:17]([CH:33]2[O:15][CH2:14][C:12]([CH3:16])([CH3:13])[CH2:11][O:10]2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccccn2)cc1
Reactant: O=Cc1ccccc1Br
Reactant: CC(C)(CO)CO
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)COC(c2cccc(Br)c2)OC1
Reaction time: 6 h
Yield: 863 %

Procedure:
A solution consisting of o-bromobenzaldehyde (150 mmol), neopentyl glycol (180 mmol), pyridyl p-tolylsulfonate (15 mmol) and benzene (800 ml) was refluxed and azeotropic dewatered for 6 hours. The reaction mixture was cooled and diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated sodium chloride aqueous solution, dried (Na2SO4), filtrated, concentrated and column separated (eluant: n-hexane/ethyl acetate system) to give 35.1 g of a white solid ketal, yield 86%.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.CC1(C)O[C:16](=O)[CH2:15][C:14](=O)O1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][CH2:14][C:3]3[N:4]4[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]4=[N:1][CH:2]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: c1cn2c(n1)CCCCC2
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: Fc1ccc(N2CCN(CCCc3cnc4n3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 91 using 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine, 2,2-dimethyl-1,3-dioxane-4,6-dione and 1-(4-fluorophenyl)piperazine, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5cccc(S(C)(=O)=O)c5)cccn4n3)c2)CC1

Procedure:
[8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow foam (0.050 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.59 (s, 1H), 8.49-8.43 (m, 2H), 8.00 (d, J=7.5 Hz, 1H), 7.75-7.65 (m, 2H), 7.30-7.20 (m, 2H), 7.06 (d, J=7.7 Hz, 1H), 7.00 (t, J=6.6 Hz, 1H), 6.85 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.13 (s, 3H), 2.62-2.57 (m, 4H), 2.37 (s, 3H). MS=463 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:3]=1.[Na].[CH3:14][OH:15]>>[N:8]1([C:4]2[N:3]=[C:2]([O:15][CH3:14])[CH:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1ccnc(-n2ccnc2)n1
Reactant: CO
Agent: [Na]
Product: COc1ccnc(-n2ccnc2)n1

Procedure:
Following the procedure of Example 15, 180 mg of 4-chloro-2-(1-imidazolyl)pyrimidine were reacted with 23 mg of sodium metal and 2 ml of anhydrous methanol was carried out to yield 134 mg of 2-(1-imidazolyl)-4-methoxypyrimidine, having a melting point of 78°-79° C., recrystallized from a mixture of n-hexane and ethyl acetate.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([NH2:30])[N:27]=[C:26]([C@H]3C4C(=CC=CC=4)C[C@@H]3OC)[N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:42][C:43](O)=O.[CH2:46]1[CH2:50][O:49][CH2:48][CH2:47]1>O>[Si:1]([O:8][C@@H:9]1[CH2:10][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([NH:30][C@H:46]3[C:47]4[C:10](=[CH:9][CH:13]=[CH:43][CH:42]=4)[CH2:11][C@H:50]3[O:49][CH3:48])[N:27]=[CH:26][N:25]=2)[CH2:12][C@@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CO[C@H]1Cc2ccccc2[C@@H]1c1nc(N)cc(N[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)n1
Reactant: C1CCOC1
Solvent: O
Product: CO[C@@H]1Cc2ccccc2[C@@H]1Nc1cc(N[C@H]2C[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl (dimethyl)silyl]oxy}methyl)cyclopentyl][(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidine-4,6-diamine (0.188 g, 0.314 mmol) in THF (1.70 mL) and H2O (1.70 mL) was added AcOH (5.08 mL). The solution was stirred overnight then concentrated in vacuo and purified by flash chromatography (0 to 5% MeOH/EtOAc) to obtain the title compound (0.112 g, 74%). LC/MS: Rt=1.46 min, ES+ 485 (Formic Acid).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[C:28]([F:52])=[CH:29][C:30]([Cl:51])=[C:31]([CH:50]=1)[O:32][C:33]1[CH:47]=[CH:46][C:36]2[N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[S:39][C:35]=2[C:34]=1[C:48]#[N:49]>O1CCCC1.C(OCC)(=O)C>[Cl:51][C:30]1[C:31]([O:32][C:33]2[CH:47]=[CH:46][C:36]3[N:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[S:39][C:35]=3[C:34]=2[C:48]#[N:49])=[CH:50][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5]3)[CH:7]=2)=[C:28]([F:52])[CH:29]=1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cc(NC(=O)c3cccc(C4(C#N)CC4)c3)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (74 mg, 0.330 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (105 mg, 83%) as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[CH:17][C:7]2=1)(=[O:3])[CH3:2].CC(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[C:15](=[O:25])[N:14]([CH3:26])[C:8]3[N:9]([CH3:13])[C:10]4[C:6]([C:7]=3[CH:17]=2)=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:32][N:33]([CH3:35])[CH3:34])=[CH:12][CH:11]=4)=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.9C above, with compound B 6-acetyl-3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and Bredereck's reagent.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][O:12][C:13](=[O:18])[C:14]([NH2:17])([CH3:16])[CH3:15].F[C:20]1[C:21]([CH3:40])=[N:22][C:23]2[C:28]([N:29]=1)=[C:27]([C:30]1[NH:38][C:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=3[CH:31]=1)[CH:26]=[CH:25][CH:24]=2>CS(C)=O>[CH3:15][C:14]([NH:17][C:20]1[C:21]([CH3:40])=[N:22][C:23]2[C:28](=[C:27]([C:30]3[NH:38][C:37]4[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=4[CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[N:29]=1)([CH3:16])[C:13]([O:12][CH3:11])=[O:18]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Prepared according to Example 131, using DIPEA (1761 μl, 10.12 mmol), aminoisobutyric acid methyl ester hydrochloride (778 mg, 5.06 mmol, Sigma Aldrich), and 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 500 mg, 1.687 mmol) in DMSO (8437 μl) stirring at 95° C. for 2 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided methyl 2-methyl-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)propanoate (557 mg, 81%). 1H NMR (CDCl3) δ: 11.16-11.25 (m, 1H), 7.96-8.01 (m, 1H), 7.69-7.74 (m, 1H), 7.40-7.46 (m, 1H), 7.08-7.12 (m, 1H), 5.56-5.71 (m, 1H), 5.15-5.20 (m, 1H), 3.66-3.73 (m, 2H), 3.56 (s, 3H), 3.25 (s, 2H), 2.65 (s, 3H), 1.79 (s, 6H). m/z (ESI, +ve) 394.1 (M+H)+.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:6](Cl)=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1>C(OCC)C>[NH2:1][C:3]1[N:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: Fc1nc(OC(F)(F)F)c(Cl)c(C(F)(F)F)n1
Reactant: N
Solvent: CCOCC
Product: Nc1nc(OC(F)(F)F)cc(C(F)(F)F)n1
Reaction time: 2 h

Procedure:
4.7 g (0.278 mol) of gaseous ammonia were passed over the course of 1 hour into a stirred mixture of 38.0 g (0.147 mol) of 2-fluoro(chloro)-4-trifluoromethoxy-6-trifluoromethylpyrimidine and 150 ml of diethyl ether at −75 to −70° C. The mixture was stirred for 2 hours each at −75 and at 25° C. The precipitate was filtered off with suction, and the organic phase was extracted 3× with water, dried and evaporated. Chromatography on silica gel with methyl tert.-butyl ether yielded 20.4 g (56.1% of theory) of the title compound of melting point 47-49° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]([OH:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[C:3]([CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C(C)O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccnc1C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A solution of 1-(3-methyl-pyridin-2-yl)-ethanol (330 mg, 2.41 mmol) (Kawasaki et al. Nippon Kagaku Zasshi 1962, 83, 949) and NEt3 (0.50 mL, 3.6 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. under N2. MsCl (0.22 mL, 2.8 mmol) was added and the reaction was stirred at 0° C. for 15 minutes. The reaction was diluted with saturated aqueous NaHCO3 (10 mL), the layers were separated and the aqueous solution was extracted with CH2Cl2 (10 mL×2). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure, giving the crude methanesulfonic acid 1-(3-methyl-pyridin-2-yl)-ethyl ester as an orange oil (484 mg, 2.25 mmol, 93%). 1H NMR (CDCl3) δ 1.76 (d, 3H, J=6.6 Hz), 2.45 (s, 3H), 2.84 (s, 3H), 6.07 (q, 1H, J=6.6 Hz), 7.20 (dd, 1H, J=7.8, 4.8 Hz), 7.51 (dd, 1H, J=7.8, 0.9 Hz), 8.51 (dd, 1H, J=4.8, 0.9 Hz).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[C:10]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:11](=[O:17])[CH2:12][CH2:13][CH2:14][C:15]2=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCC(=O)C1=CC=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCCC(=O)C1CCCc1ccccc1

Procedure:
A mixture of 6.8 g (30 mmol) of 2-(3-phenylpropenylidene)-1,3-cyclohexanedione from the preceding example, 0.7 g of 10% palladium on carbon, and 150 mL of ethyl acetate was stirred at room temperature, in an atmosphere of hydrogen, until gas uptake ceased. The catalyst was filtered with suction and the filtrate was concentrated in vacuo giving 6.7 g (97%) of the title dione as an off-white solid which was used without further purification.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.[CH2:9]([OH:21])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]#[C:16][CH2:17][CH2:18][C:19]#[CH:20].Cl.[CH3:23][OH:24]>O=O>[CH2:23]([OH:24])[CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:12]#[C:11][CH2:10][CH2:9][C:3]#[C:4][C:20]#[C:19][CH2:18][CH2:17][C:16]#[C:15][C:14]#[C:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:21]
Reactant: CN(C)CCN(C)C
Reactant: CO
Reactant: C#CCCC#CC#CCCCCO
Agent: Cl
Agent: O=O
Product: OCCCCC#CC#CCCC#CC#CCCC#CC#CCCCCO
Reaction time: 1 h

Procedure:
A mixture of 2 parts cuprous chloride, 12 parts methanol, and 4 parts N,N,N',N'-tetramethylethylenediamine was prepared. To this mixture was added 5,7,11-dodecatriyn-1-ol, produced in Example 22, dissolved in 12 parts methanol over a period of 15 minutes while oxygen was moderately bubbled through the reaction contents. After 1 hour, oxygen flow was stopped and the methanol was distilled leaving a semi-viscous residue. To this was added 100 parts of 3 N hydrochloric acid while stirring, causing product to precipitate. It was collected by filtration, washed once with 25 parts 2 N hydrochloric acid and several times with water. The solid was dissolved in 200 parts xylene and the solution was refrigerated at -8° C. Subsequent crystallization and filtration yielded 6.0 parts of fluffy product, CF4 diol, which turns blue in daylight. The melting point of the material was 101.0° to 104.1° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][C:15](Cl)=[N:16][CH:17]=1)=[O:11].[Cl:23][C:24]1[N:25]=[N:26][C:27]([N:32]2[CH2:37][CH2:36][NH:35][C@H:34]([CH3:38])[CH2:33]2)=[C:28]([CH3:31])[C:29]=1[CH3:30]>ClCCl>[CH3:8][O:9][C:10]([C:12]1[C:13]([C:19]([F:22])([F:21])[F:20])=[N:14][C:15]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[N:26]=[N:25][C:24]([Cl:23])=[C:29]([CH3:30])[C:28]=3[CH3:31])[CH2:33][C@H:34]2[CH3:38])=[N:16][CH:17]=1)=[O:11]
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.0 mL, 14.4 mmol, 2.9 eq) is added to a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (1.25 g, 5.0 mmol, 1 eq), 3-chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (1.20 g, 5.0 mmol, 1 eq) in dichloromethane (40 mL) and the resulting solution is stirred at rt for 2 h. The reaction mixture is diluted with dichloromethane (50 mL) and washed with water (25 mL), then brine (25 mL). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The desired compound is isolated by silica gel chromatography (10-75% EtOAc/heptane) as a white solid (1.83 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:24][CH:23]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1-c1c(Cl)cnn1C
Yield: 15 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-trifluoromethylphenyl isocyanate in a similar manner as described in Example 1.53, providing 8 mg (15%) of Compound 80 (Note: Compound 80 did not precipitate out. Therefore, the CH2Cl2 was, removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%)=427 (M+H37Cl, 22), 425 (M+H35Cl, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.48 (s, 1H), 8.24 (s, 1H), 7.56 (d, J=8 Hz, 2H), 7.50 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.28 (d, J=4 Hz, 1H), 7.27 (s, 1H), 6.96 (d, J=12 Hz, 1H), 3.62 (s, 3H), 3.46 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:10][CH3:11])=[N:5]C(C)=[CH:7][CH:8]=1)#[N:2].[Mn]([O-])(=O)(=O)=O.[K+].[CH:18]([OH:21])([CH3:20])C.[OH2:22].Cl>>[C:1]([C:3]1[CH:8]=[CH:7][C:20]([C:18]([OH:21])=[O:22])=[N:5][C:4]=1[O:10][CH3:11])#[N:2]
Reactant: CC(C)O
Reactant: O
Reactant: COc1nc(C)ccc1C#N
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Product: COc1nc(C(=O)O)ccc1C#N

Procedure:
3-Cyano-2-methoxy-6-methylpyridine is oxidised with potassium permanganate in aqueous solution to give 5-cyano-6-methoxypyridine-2-carboxylic acid (m.p. 235°-237° C.), subsequent hydrogenation of which on palladium/charcoal in isopropanol/water/hydrochloric acid gives the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:27])=[C:11]([CH:13]3[C:17](=[O:18])/[C:16](=[CH:19]/[CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)/[CH2:15][C:14]3=[O:26])[N:12]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:27])=[C:11]([CH:13]3[C:17](=[O:18])[CH:16]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH2:15][C:14]3=[O:26])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 23.2 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (130 mg, 0.32 mmol) in ethanol (2 ml) was added 5% palladium on carbon (13 mg), and the reaction stirred under an atmosphere hydrogen at a pressure of 2 bar for 4 hours. The crude reaction mixture was filtered through a pad of Celite and purified by preparative mass-directed HPLC to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-4-(tetrahydro-pyran-4-ylmethyl)-cyclopentane-1,3-dione (30 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>C(Cl)Cl>[CH3:30][S:31]([NH:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]4)=[N:15][CH:16]=3)[S:21][C:22]=2[CH:28]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(NS(C)(=O)=O)cc4s3)cn2)CC1
Yield: 48.8 %

Procedure:
To 4-[5-(6-amino-benzothiazol-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (12.7 mg, 0.031 mmol) in DCM (1 mL) was added methanesulfonyl chloride (3 μL, 0.034 mmol) followed by pyridine (3 μL, 0.034 mmol). The r.m. was stirred o.n. at r.t. The crude mixture was purified by flash column chromatography (heptane:ethyl acetate; 50:50 to 40:60), to give intermediate tert-butyl 4-(5-{6-[(methylsulfonyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)piperazine-1-carboxylate (7.4 mg) as a solid. MS m/z (M+H) 490, (M−H) 488. This intermediate was dissolved in DCM (1 mL) and TFA (300 μL) was added. The reaction mixture was thereafter stirred for three hours at r.t. The solvent was removed in a stream of nitrogen and the residue was dissolved in DMF (400 μL) and purified by prep. HPLC, to give the title compound (3 mg) as a white solid. 1H NMR δ 8.71 (d, 1H) 8.09 (dd, 1H) 7.72-7.86 (m, 2H) 7.27 (dd, 1H) 6.88 (d, 1H) 3.63-3.77 (m, 4H) 2.95-3.08 (m, 4H) 2.90 (s, 3H); MS m/z M+H 390, M−H 388.