Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38][C:37]=1OS(C(F)(F)F)(=O)=O.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:37]4[N:38]=[CH:39][C:40]5[C:45]([C:36]=4[CH3:35])=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ncc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)ncc2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (86.3 mg, 0.184 mmol), trifluoromethanesulfonic acid 4-methylisoquinolin-3-yl ester (54.8 mg, 0.188 mmol), and Pd(PPh3)4 (14 mg, 0.012 mmol) in 1,4-dioxane (2.8 mL, 36 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (118 mg, 0.361 mmol) in H2O (0.80 mL, 44 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with DCM, washed with water and brine, and dried over MgSO4. The crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→2.5% MeOH in DCM→3% MeOH in DCM→3.5% MeOH in DCM→4% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, giving the title compound as a glassy solid. 1H NMR (400 MHz, CDCl3): δ=9.22 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.08 (dd, J=0.8, 8.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.81 (ddd, J=1.2, 6.8, 8.3 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.68 (ddd, J=0.8, 7.0, 8.0 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=2.4 Hz, 1H), 4.85 (brs, 2H), 4.42-4.13 (m, 3H), 2.90 (brt, J=11.2 Hz, 2H), 2.62 (s, 3H), 2.15 (brdd, J=2.0, 12.4 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.48 (s, 9H). MS(ES+): m/z=485.14 (100) [MH+], 429.12 (66) [MH+-isobutene]. HPLC: tR=2.62 min (polar—5 min, ZQ3).
Reaction SMILES: [NH2:1]C1C(C(N)=O)=NC=C(C2C(C)=CC=CN=2)C=1.[N:18]1([CH2:23][C:24]2[N:33]=[C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[C:31]3[C:26](=[CH:27][C:28]([C:45]4[C:50]([C:51](F)(F)F)=[CH:49][CH:48]=[CH:47][N:46]=4)=[CH:29]C=3)[N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:51][C:50]1[C:45]([C:28]2[CH:29]=[N:1][C:31]3[C:32]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:44])[F:43])=[CH:39][CH:40]=4)=[N:33][C:24]([CH2:23][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:25][C:26]=3[CH:27]=2)=[N:46][CH:47]=[CH:48][CH:49]=1
Reactant: FC(F)(F)c1ccc(Nc2nc(CN3CCCC3)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Reactant: Cc1cccnc1-c1cnc(C(N)=O)c(N)c1
Product: Cc1cccnc1-c1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(CN3CCCC3)nc2c1

Procedure:
The title compound is prepared from 3-amino-5-(3-methyl(2-pyridyl))pyridine-2-carboxamide in a manner analogous to that used for the preparation of [2-pyrrolidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 2.A, steps 6 to 9).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:16]C)[C:6](=[O:18])[C:5]=2[CH:4]=1.C1(=O)C2C(C3C(C=2)=CC=CC=3)=CC=C1.Br>C(O)(=O)C.C(Cl)Cl>[OH:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[OH:16])[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)c1cccc(OC)c1-2
Agent: Br
Agent: O=C1C=CC=C2C1=Cc1ccccc12
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1c2cc(O)ccc2-c2c(O)cccc21
Temperature: 80 °C

Procedure:
Prepare a solution of 2,5-dimethoxy-fluoren-9-one (7.5 g, 0.031 mmole) in 50 mL glacial acetic acid and warm to 80° C. Once all of the fluorenone goes into solution, add 150 mL hydrogen bromide (48% solution). Continue heating to reflux, redissolving any precipitate formed, and reflux overnight. Cool to room temperature and filter. Wash the filtrate with water. Take-up the solids in ethyl acetate and dissolve by heating in a steam bath. Filter through a short column of silica, eluting with hot ethyl acetate. Condense the ethyl acetate eluent on a rotary evaporatory to obtain a dark red solid. Heat in hot methylene chloride to dissolve undesired solid and filter to obtain 2,5-dihydroxy-fluoren-9-one. m.p. 298-301 dec. (Yield 9.4 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[F:11].O1CCCC1.[CH2:17]([CH2:19][NH2:20])[OH:18]>[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:20][CH2:19][CH2:17][OH:18])=[CH:4][C:3]=1[F:11]
Reactant: NCCO
Reactant: Fc1cc(C2CO2)ccc1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCNCC(O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-(4-Bromo-3-fluoro-phenyl)-oxirane (25.1 g, 109 mmol) was combined with tetrahydrofurane (70 ml) to give a yellow solution. Ethanolamine (66.4 g, 65.1 ml, 1.09 mol) was added. The resulting orange solution was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted twice with ethyl acetate. The organic layers were dried over MgSO4 and concentrated in vacuo to yield a yellow oil (27.9 g, 92%), MS (ISP): 277.9 ([{79Br}M+H]+), 279.9 ([{81Br}M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=1.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[N:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[S:25][CH:26]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Reactant: OCc1csc(C(F)(F)F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)cc21
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a mixture of 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (2-(trifluoromethyl)thiazol-4-yl)methanol (80 mg) and toluene (5 ml) was added potassium tert-butoxide (98 mg) at 100° C., and the mixture was stirred at the same temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (29.0 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH2:9]>[O-2].[Cr+3].[O-2].[O-2].[Cr+3].[Ni]=O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:9]
Reactant: O
Reactant: N#Cc1ccccn1
Agent: O=[Ni]
Agent: [Cr+3]
Agent: [O-2]
Product: NC(=O)c1ccccn1
Temperature: 87.5 °C

Procedure:
In a four neck round bottom flask fitted with thermo well, agitator and reflux condenser, 2-cyanopyridine (100 g), de-mineralized water (150 g) isopropyl alcohol (10 g) and chromium oxide-nickel oxide catalyst (1 g) prepared in Example 2 is charged. The mixture is heated up to 85-90° C. for 4-6 h. The completion of reaction is monitored by HPLC. After the completion of reaction the crude product is cooled and filtered to separate picolinamide from the catalyst bed. The catalyst bed is washed with de-mineralized water to make catalyst free from hydrolyzed mass of 2-cyanopyridine. The wet catalyst is recycled back for next batch of hydrolysis. The colorless mother liquor is concentrated and dried to get pure picolinamide. The recovered water layer containing 2-cyanopyridine and alcohol is recycled back for next hydrolysis batch.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=O>C(OS([O-])(=O)=O)CCCCCCCCCCC.[Na+]>[C:1]([C:9]1[CH2:14][CH2:13][CH2:12][C:11]2[C:10]=1[O:15][C:16](=[O:20])[C:17]=2[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)O
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1=C2CCCC(C(=O)c3ccccc3)=C2OC1=O
Yield: 25.5 %

Procedure:
A mixture of 10 g of 2-benzoyl-cyclohexanone, 5.8 g of pyruvic acid and 0.2 g of sodium dodecylsulfate is heated at 150° for 15 hours. After cooling, the raw reaction product is extracted with ethyl ether and the ether solution is washed with an aqueous solution of sodium bicarbonate, then with water and then dried. The residue which is obtained after removing the solvent (9 g) is chromatographed on an SiO2 column using as an eluent cyclohexane: ethyl ether 7:3. There are obtained 3.2 g of 7-benzoyl-3-methyl-2,4,5,6-tetrahydro-benzo[b]furan-2-one. After recrystallization from hexane-ethyl acetate m.p. is 79°-81°.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1.Cl[C:42]1[N:47]=[C:46]([O:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)[CH:45]=[C:44]([CH3:56])[N:43]=1.ClCCl>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:55][C:52]1[CH:53]=[CH:54][C:49]([O:48][C:46]2[CH:45]=[C:44]([CH3:56])[N:43]=[C:42]([NH:40][C:30]3[CH:31]=[CH:32][C:33]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:28]([O:27][CH3:26])[CH:29]=3)[N:47]=2)=[CH:50][CH:51]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(Oc2ccc(F)cc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(F)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Palladium acetate (7 mg, 0.03 mmol) and 2-(dicyclohexylphosphino)biphenyl (22 mg, 0.06 mmol) were dissolved in 2.5 mL of dioxane and stirred at 20° C. under argon for 10 minutes. Sodium tert-butylate (57 mg, 0.59 mmol) was added, followed by 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (80 mg, 0.39 mmol) and 2-chloro-4-(4-fluoro-phenoxy)-6-methyl-pyrimidine (115 mg, 0.48 mmol). The resulting mixture was heated in the microwave oven for 20 minutes at 200° C. Dichloromethane was added, insoluble material filtered off and the resulting solution purified by chromatography on silica gel using ethyl acetate as a solvent. The title compound was isolated as a yellow solid (50 mg, 31%). MS ISP (m/e): 406.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.58 (d, 1H), 7.46 (d, 1H), 7.17 (s, 1H), 7.15-7.05 (m, 4H), 7.04 (d, 1H), 6.91 (dxd, 1H), 6.80 (s, 1H), 6.23 (s, 1H), 3.62 (s, 1H), 2.40 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[CH:7][C:6]=1[NH2:14])[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.CO[C:28](=O)[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>C(Cl)Cl>[CH2:2]([N:4]1[C:5]2[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[CH:7][C:6]=2[N:14]=[C:28]1[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)[CH3:3]
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Reactant: CCNc1cc(C(C)C)ncc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(C)C)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of N4-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride (126 mg, 0.582 mmol) in CH2Cl2 (5 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (0.35 mL, 0.728 mmol). The dark solution is then stirred at room temperature for 45 min. Next, a solution of (2-Thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (65 mg, 0.291 mmol) in CH2Cl2 (2 mL) is added via cannula followed by a 1 mL rinse. The reaction mixture is stirred at reflux overnight. After cooling, it is treated with MeOH (˜0.5 mL) and then diluted with 0.5 N NaOH and additional CH2Cl2. The mixture is stirred vigorously for 15 min and then extracted thrice with CH2Cl2 containing some (˜5%) MeOH. The combined extracts are dried over K2CO3 and concentrated to 156 mg of a crude mixture of the desired 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide. This material is then dissolved in AcOH (6 mL), and the resulting solution is stirred at reflux for 5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is dissolved in CH2Cl2 and washed with 0.5 N NaOH. The aqueous layer is reextracted twice with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude material is purified by preparative TLC. Developing with 15:1 CHCl3 yields 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[C:25]1[C:26]2[C:33]([CH3:34])=[CH:32][S:31][C:27]=2[N:28]=[CH:29][N:30]=1>C(O)(C)C>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:13]=2)=[O:11])=[CH:3][C:2]=1[NH:1][C:25]1[C:26]2[C:33]([CH3:34])=[CH:32][S:31][C:27]=2[N:28]=[CH:29][N:30]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ncnc2scc(C)c12
Temperature: 88 °C
Yield: 25.4 %

Procedure:
N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (0.056 g), 4-chloro-5-methylthieno[2,3-d]pyrimidine (Maybridge Chemical Company, Trevillet, Tintagel, Cornwall, PL34 0HW, GB; 0.037 g) and isopropanol (2 ml) and the reaction mixture was stirred and heated to 88° C. for 18 hours. The reaction mixture was cooled to ambient temperature and the precipitate was isolated and washed in turn with isohexane and diethyl ether. There was thus obtained the title compound (0.021 g); Mass: M+H+ 461.
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.[CH3:19][CH:20]([OH:22])[CH3:21]>>[CH:20]([O:22][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)([CH3:21])[CH3:19]
Reactant: CC(C)O
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from propan-2-ol, (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-isopropoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 283 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH2:25])[N:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([NH:40][C@H:41]([C:43](O)=[O:44])[CH3:42])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O=P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH:25][C:43](=[O:44])[CH:41]([NH:40][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:42])[N:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)(c2cc(N)n(C(C)(C)C)n2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)nn1C(C)(C)C
Reaction time: 0.42 h

Procedure:
A solution of 0.68 g (1.7 mmol) of 4-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)-4-phenylpiperidine-1-carboxylic acid tert-butyl ester and 0.39 g (1.7 mmol) of carbobenzyloxy-L-alanine in 9.0 mL of dry pyridine was stirred at −10° C. as 0.18 mL (1.9 mmol) of POCl3 was added. After 25 min, the reaction mixture was poured into 1M HCl and extracted with EtOAc. The organic layer washed with sat. aq. NaHCO3, dried over MgSO4 and concentrated. Purification on silica gel using 50:50 EtOAc-hexanes as eluant afforded 4-[5-(2-benzyloxycarbonylamino-propionylamino)-1-tert-butyl-1H-pyrazol-3-yl]-4-phenylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C@H:2]1[CH2:20][C@@:17]2([CH2:18][CH3:19])[C@@H:13]([CH:14]=[CH:15][C@:16]2([C:22]#[CH:23])[OH:21])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(O)(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:25]([O:21][C@@:16]1([C:22]#[CH:23])[CH:15]=[CH:14][C@H:13]2[C@H:12]3[C@H:3]([C@@H:2]([Cl:1])[CH2:20][C@:17]12[CH2:18][CH3:19])[C@@H:4]1[C:9](=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]1)[CH2:10][CH2:11]3)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3[C@@H](Cl)C[C@@]21CC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3[C@@H](Cl)C[C@@]21CC
Temperature: 0 °C

Procedure:
700 mg of 11β-chloro-17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one in 10 ml of pyridine is reacted at room temperature with the addition of 100 mg of 4-dimethylaminopyridine with 6 ml of acetic anhydride. The mixture is introduced, after 4 hours, into ice/water which contains acetic acid. The thus-precipitated product is vacuum-filtered, dissolved in ethyl acetate, and washed with water. The crude product is chromatographed on silica gel with hexane/acetone (0-10%), thus obtaining 510 mg of 17β-acetoxy-11β-chloro-17α-ethynyl-18-methyl-4,15-estradien-3-one as a foam.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:11]=[C:12]([C:16](=[O:18])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>C(OCC)(=O)C>[C:27]([O:25][C:22]1[CH:21]=[CH:20][C:19]([N:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:26])[CH3:1])=[CH:4][CH:5]=3)=[CH:17][C:16](=[O:18])[C:12]([C:13]([OH:15])=[O:14])=[CH:11]2)=[CH:24][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With 1 g of 6-(4-dimethylaminophenyl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid was mixed 10 ml of acetic anhydride and the resulting mixture was subjected to reaction at 130° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and introduced into 150 ml of water. After stirring the mixture for 1 hour, 150 ml of ethyl acetate was added to the mixture, and the organic layer was separated, washed with 100 ml of water and then with 50 ml of a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue was added 20 ml of diethyl ether, and the resulting mixture was filtered to obtain 0.75 g of 1-(4-acetyloxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 128°-131° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[CH2:15]([N:22]1[CH2:27][C@@H:26]([CH3:28])[NH:25][CH2:24][C@@H:23]1[CH3:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([N:22]1[C@@H:23]([CH3:29])[CH2:24][N:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[C@H:26]([CH3:28])[CH2:27]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1c1ccc2nnc(C(F)(F)F)n2n1
Yield: 78.9 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.45 g, 20 mmol), (2S,5R)-1-benzyl-2,5-dimethylpiperazine (4.90 g, 24.00 mmol) and DIPEA (5.14 mL, 30.00 mmol) in DMF (40 mL) was heated at 125° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by MPLC silica chromatography, eluting with 75% EtOAc/isohexane. Pure fractions were evaporated to dryness to afford 6-[(2R,5S)-4-benzyl-2,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (6.16 g, 79%) as a tan gum.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:12].[Na+].Cl>CN1CCN(C)C1=O.O>[F:11][C:9]1[CH:10]=[C:2]([OH:12])[C:3](=[CH:7][CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1ccc(F)cc1O
Temperature: 135 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A solution of 2,4-difluorobenzoic acid (100 g, 0.63 mol) in 1,3-dimethyl-2-imidazolidinone (1,400 mL, 0.45 M) was treated with sodium hydroxide (88 g, 2.2 mol) and heated to 135° C. After stirring for 4 h, the solution was cooled 0° C., disolved in water (100 mL), and transferred to a 5 L Erlenmeyer flask and carefully treated with aq HCl (2,800 mL, 2 N). After filtering off the crude product, the precipitate was disolved in ethyl acetate, dried over sodium sulfate and decolorizing charcol, and filtered. The solution was concentrated under reduced pressure and recrystallized from ethyl acetate and heptane to give 4-fluorosalicylic acid (2 crops, 67 g, 68%) as off-white needles. mp: 188–189° C.; Rf 0.26 (20% methanol in dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:12]=3)[C:4]=2[CH:3]=1.[O:24]1[CH2:27][C:26](=O)[CH2:25]1>ClCCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:23][CH2:22][CH2:21][N:20]([CH:26]5[CH2:27][O:24][CH2:25]5)[CH2:19][CH2:18]4)[N:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C1COC1
Reactant: Clc1cc2c(cn1)cnn2-c1cccc(N2CCCNCC2)n1
Solvent: ClCCCl
Product: Clc1cc2c(cn1)cnn2-c1cccc(N2CCCN(C3COC3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
A mixture of 6-chloro-1-[6-(1,4-diazepan-1-yl)-2-pyridyl]pyrazolo[4,3-c]pyridine (0.4094 mmol; 134.6 mg), oxetan-3-one (0.4912 mmol; 35.40 mg), and Molecular sieve (4A) in 1,2-dichloroethane (12 ml) was stirred at room temperature for 4 hours. STAB (0.6141 mmol; 137.0 mg) was added. The reaction was stirred for 3 days. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford 6-chloro-1-[6-[4-(oxetan-3-yl)-1,4-diazepan-1-yl]-2-pyridyl]pyrazolo[4,3-c]pyridine (99.2 mg, 63%).