Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])([CH3:36])[CH3:35]>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[CH:13]=[CH:14][C:4]([C:1]2[O:3][C:45](=[O:46])[C:44]([S:43][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH:34]([CH3:35])[CH3:36])=[C:48]([OH:49])[CH:2]=2)=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using ethyl 4-acetylbenzoate (2.93 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 201-203° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 1.35 (t, 3H), 3.42 (m, 1H), 4.35 (q, 2H), 6.94 (m, 1H), 7.00 (s, 1H), 7.10 (m, 2H), 7.28 (m, 1H), 7.99 (m, 2H), 8.11 (m, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(=O)([O-])[O-:10].[K+].[K+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>O1CCCC1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:10])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCCN1C(=O)c1ccc(Cl)cc1
Yield: 61.6 %

Procedure:
40.0 g (0.26 mol) of 4-piperidone hydrochloride (× H2O) and 38.6 g of potassium carbonate are suspended in 300 ml of tetrahydrofuran. 45.4 g of 4-chlorobenzoyl chloride are added thereto with stirring and the mixture is reacted for 2 hours at ambient temperature and refluxed for 2 hours. The reaction mixture is evaporated down in vacuo, the residue is neutralized with 2N hydrochloric acid and extracted with dichloromethane. 38 g of a viscous oil are obtained from the organic phase after removal of the extraction agent.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(CC)CC)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:28]#[C:29][C:30]3[CH:40]=[CH:39][C:33]([C:34]([O:36]CC)=[O:35])=[CH:32][CH:31]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:41])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:28]#[C:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:39][CH:40]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(CC)CC)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2cccc(O)c2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 40.0 mg (0.076 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.00 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 7.90 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.4 Hz), 7.35 (2H, s), 7.15-7.07 (2H, m), 6.77-6.69 (3H, m), 5.92 (1H, t, J=4.7 Hz), 2.25 (2H, d, J=4.7 Hz), 1.23 (6H, s).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(Cl)Cl.O>C(Cl)Cl>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-p-tolyloxy-phenylamine (0.87 g, 4.38 mmol) and pyridine (0.52 mL, 6.53 mmol) in dried CH2Cl2 (10 mL) under N2 at 0° C. was added methanesulfonyl chloride (0.41 mL, 5.26 mmol) dropwise. The mixture was stirred at 0° C. for 1 h and was then poured into CH2Cl2/H2O (10 mL/10 mL). The organic layer was washed with 2N HCl (aq) (3 mL), H2O, brine, dried (Na2SO4), and filtered through Celite. After removal of solvent, the crude product was purified by chromatography (silica gel, 45% EtOAc/hexanes) to give the titled compound. MS (EI) 278 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.O>[N:34]([CH2:13][C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH:12]=1)=[N+:35]=[N-:36]
Reactant: Cc1cnn(-c2ccc(I)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1cnn(-c2ccc(I)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A mixture of 1-(4-iodophenyl)-4-methyl-1H-pyrazole (1.70 g, 5.99 mmol), NBS (1.38 g, 7.75 mmol) and AIBN (0.30 g, 1.83 mmol) in CCl4 (25 mL) was heated at reflux for 1 hr. After being cooled to room temperature, the upper clear solution was decanted out and concentrated in vacuo. The residue was dissolved in DMF (10 mL), NaN3 (0.934 g, 14.3 mmol) was added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with hexane, then with 5% EtOAc in hexane to give 4-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (0.70 g).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].[C:15](OC([O-])=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(OCC)(=O)C>[C:18]([O:17][C:15]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Yield: 85.2 %

Procedure:
4-Piperidone monohydrate hydrochloride (5 g, 0.033 mol) was added to 50 mL distilled water and stirred until dissolved. To this solution was added solid sodium bicarbonate (3 g, 0.035 mol) followed by tert-butyl dicarbonate (7.2 g, 0.033 mol), and the resulting clear solution was stirred for 20 hours at room temperature. The slurry was treated with 100 mL of ethyl acetate and stirred until all solids dissolved. The layers were separated, and the organic layer was washed with 30 mL of 1N H3PO4 and 30 mL of 10% NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 5.6 g (86%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 3.75-3.68 (t, 4H), 2.47-2.40 (t, 4H), 1.5 (s, 9H). MS (DCl/NH3) m/e 200 (M+H)+, 217 (M+H+NH3)+.
Reaction SMILES: FC1C(=O)CCN(C2NN=CC=2[N+]([O-])=O)C1.[N:17]([CH:20]1[CH:26]([OH:27])[CH2:25][CH2:24][N:23]([C:28](OC(C)(C)C)=O)[CH2:22][CH2:21]1)=[N+:18]=[N-:19].ClC1[N:40]([CH2:41][CH:42]([F:44])[F:43])[N:39]=[CH:38][C:37]=1[N+:45]([O-:47])=[O:46]>>[N:17]([CH:20]1[CH2:21][CH2:22][N:23]([C:28]2[N:40]([CH2:41][CH:42]([F:44])[F:43])[N:39]=[CH:38][C:37]=2[N+:45]([O-:47])=[O:46])[CH2:24][CH2:25][CH:26]1[OH:27])=[N+:18]=[N-:19]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])CC1
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Agent: O=C1CCN(c2[nH]ncc2[N+](=O)[O-])CC1F
Product: [N-]=[N+]=NC1CCN(c2c([N+](=O)[O-])cnn2CC(F)F)CCC1O

Procedure:
Following the procedure for Intermediate 48 starting from tert-butyl 4-azido-5-hydroxyazepane-1-carboxylate and 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole gave 5-azido-1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a yellow gum (1.16 g, 50% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.14-8.09 (m, 1H), 6.11 (tt, J=27.8, 4.4 Hz, 1H), 4.50-4.39 (m, 2H), 3.83 (tt, J=8.8, 3.1 Hz, 1H), 3.67 (td, J=4.7, 3.6 Hz, 1H), 3.45-3.21 (m, 4H), 2.37 (d, J=2.9 Hz, 1H), 2.25-2.12 (m, 2H), 2.03-1.91 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3Cl)[N:16]=2)=[C:11]([O:25][CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:27].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]3=[O:27])[N:16]=2)=[C:11]([O:25][CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc2ncnc(Cl)c2[nH]1
Reactant: [OH-]
Agent: [K+]
Product: COc1cc(OCc2ccccc2)ccc1C1=NC2=NC=NC(=O)C2=N1

Procedure:
Prepared analogously to Example 16 from 8-(4-benzyloxy-2-methoxy-phenyl)-6-chloro-purine by reaction with 40% potassium hydroxide solution.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3[O:18][CH3:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=5[O:18][CH3:19])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1cccc(-c2cccn3nc(Cl)nc23)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1OC

Procedure:
4-{4-[8-(2,3-Dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2,3-dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.200 g, 0.690 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.229 g, 0.828 mmol) in a manner analogous to Example 311a and 311b to give product (0.264 g, 72%). MP=93-95° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.77 (d, 1H), 7.52 (m, 3H), 7.15 (m, 6H), 4.05 (m, 2H), 3.87 (s, 3H), 3.68 (s, 3H), 2.88 (br m, 2H), 2.60 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H). MS=530 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[Li]CCCC.[C:22](=[O:24])=[O:23]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([C:22]([OH:24])=[O:23])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-morpholinothieno[2,3-d]pyrimidine (500 mg) was cooled to −78° C. in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLi in hexanes. The reaction was stirred at −78° C. for 30 minutes before warming to −40° C. for several minutes to allow for complete formation of the lithium anion. The reaction was then re-cooled to −78° C. and carbon dioxide gas evolved from dry ice was bubbled in via cannula to the reaction solution for 1 hour. The reaction was then slowly warmed to 0° C. over 30 minutes and the THF was concentrated by rotovap. The reaction was then quenched with water and extracted with Ethyl Acetate to remove any 2-chloro-4-morpholinothieno[2,3-d]pyrimidine. The aqueous layer was then brought to pH of 2-3 by adding concentrated HCl. The resultant solid that crashed out of the aqueous layer was then collected by Buchner funnel, rinsed with water and dried overnight under vacuum to yield 494 mg of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1)=[O:19])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:29][C:26]3[CH:27]=[CH:28][C:23]([CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:24][C:25]=3[F:30])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccc(SC2CCCC2)n1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 92.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 27 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.061 g, 89%).
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[OH:1][CH:3]([CH2:4][NH:29][CH:26]([CH3:28])[CH3:27])[CH2:2][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)N
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2c1
Product: COc1ccc2nc(-c3ccc(OCC(O)CNC(C)C)cc3)n(C)c(=O)c2c1

Procedure:
This compound was prepared analogous to Example 1 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one and isopropylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:28](B(CC)CC)[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:28][CH3:29])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:13])([F:14])[F:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2I)OC1C(F)(F)F
Reactant: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(Cl)ccc2c1C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 110 °C

Procedure:
To the mixture of ethyl 6-chloro-5-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.3g, 0.7 mmol), potassium carbonate(109 mg, 2.87 mmol) and tetrakistriphenyl-palladium (0) (81 mg, 0.07 mmol) in 3 mL of anhydrous DMF was added triethylboron (1.0M/THF, 1.05 mL, 1.05 mmol) under nitrogen. The resulting mixture was heated to 110° C. for five hrs. The reaction was cooled to room temperature, and diluted with 100 mL of ethyl acetate. The resulting organic phase was washed with brine. After removing the solvent, the residue was dissolved in 3 mL of THF, followed by addition of a solution of lithium hydroxide hydrate in 3 mL of water. To the resulting mixture was further added 3 mL of ethanol. The resulting solution was then heated to 80° C. for three hrs. The volatiles were then removed. The residue was diluted with water, and acidified in an ice/water bath with dilute hydrochloric acid. The product was extracted with ethyl acetate. The organic extracts were washed with brine, and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on short silica gel with 3:7 EtOAc/hexane+1% HOAc to remove the polar impurities. After concentrating the collected fraction, the residue was further purified on reverse phase HPLC. It gave 75 mg slightly yellow solid. M.P.=171.5-172.5° C. 1H NMR (CDCl3/400 Mz), 8.07(s, 1H), 7.32(d, J=8.8 Hz, 1H), 6.82(d, J=8.8 Hz, 1H), 5.65(q, J=6.8 Hz, 1H), 2.91(m, 2H), 1.18(t, J=7.6 Hz, 3H). 13C NMR(CDCl3/400 MHz) 169.5, 152.8, 141.5, 136.5, 134.1, 127.7, 123.4(q, J=287.7 Hz), 118.6, 116.3, 115.5, 69.8(q, J=33.4 Hz), 23.1, 14.7. 19F NMR(CDCl3/400 Mz) −78.72(d, J=6.8 Hz). MS(ES−)=305.0 (M−H, 100). High resolution MS(ES−), m/e calc. For C13H10ClF3O3: 305.0198 (M−H), found: 305.0157.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:2][C:3]#[C:4][CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC#CCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hexyn-1-ol (880 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1, 2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1.[N:15]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]=[N:10][C:11]([N:18]3[CH2:19][CH2:20][N:15]([C:21](=[O:22])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:30])[F:31])[CH2:16][CH2:17]3)=[CH:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variation's only as required to use 6-chloropyridazine-3-carboxylic acid cyclopropylmethylamide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (31% yield). 1H NMR (500 MHz, CDCl3) δ 8.16-7.88, 7.75, 7.68-7.46, 7.18, 7.00, 4.17-3.64, 3.21-3.12, 1.07-1.00, 0.61-0.44, 0.26-0.20.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.[ClH:16]>O>[ClH:16].[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][NH2:1])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (3.6 g) in water (18 ml) was added dropwise to an ice-salt cooled solution of 4-fluoro-2-nitroaniline 7 g) in conc. hydrochloric acid (45 ml) over a 30 minutes interval. The mixture was stirred at 0° C. for 30 minutes. Then to the mixture was added dropwise a solution of stannous chloride dihydrate (28.6 g) in conc. hydrochloric acid (24 ml) below 5° C. over an hour interval. The precipitates were collected by filtration and washed with ether to give crystals of 4-fluoro-2-nitrophenylhydrazine hydrochloride 4.4 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[C:14]([O:25][CH3:26])[CH:13]=1)P(OCC)(=O)OCC.[CH:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[C:28]1=O)[CH2:34]2.P(=O)([O-])[O-].[Li]CCCC>C1COCC1>[CH3:26][O:25][C:14]1[CH:13]=[C:12]([C:3]([O:2][CH3:1])=[C:28]2[CH:29]3[CH2:35][CH:33]4[CH2:32][CH:31]([CH2:36][CH:27]2[CH2:34]4)[CH2:30]3)[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH:15]=1
Reactant: CCOP(=O)(OCC)C(OC)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Temperature: -68 °C
Reaction time: 0.08 h

Procedure:
Phosphonate 30, dissolved in anhydrous THF, is cooled to -68° C. under an argon atmosphere. Similarly, 2-adamantanone (1.1 eq) is dissolved in anhydrous THF and cooled to -68° C. under argon in a separate flask. To the phosphonate solution is added 2.5M nBuLi at -68° C. under argon until the red color of the ylid persists. At this point, 1.2 eq nBuLi is added to complete the ylid formation and the resulting colored solution is stirred at -68° C. for 5 min. While maintaining the low temperature, 2-adamantanone in THF is slowly added to the ylid over an hour. After the final addition of ketone, the reaction mixture is stirred for 2 h while warming to room temperature. The reaction is then heated at reflux for 1 h, cooled and quenched by partitioning with EtOAc and saturated NH4Cl. The organic layer is dried over Na2SO4 and chromatographed with EtOAc/hexanes on a silica gel column to give enol ether 31.
Reaction SMILES: [N:1]1([C:8]2[N:16]3[C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][O:19][C:14]4=[C:15]3[C:10](=[CH:11][CH:12]=[C:13]4[C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])[N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl.CO>[C:40]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[N:16]3[C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:18][O:19][C:14]4=[C:15]3[C:10](=[CH:11][CH:12]=[C:13]4[C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])[N:9]=2)[CH2:2][CH2:3]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCCN(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)CC1
Reaction time: 0.08 h
Yield: 61.7 %

Procedure:
To a solution of (4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (5.0 mg, 0.012 mmol) in methylene chloride (0.44 mL), triethylamine (8.1 μL, 0.058 mmol) was added followed by acetyl chloride (1.6 μL, 0.023 mmol) and the mixture was stirred for 5 min. The mixture was then diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (3.5 mg, 64%). LCMS calc. for C26H29N6O3 (M+H)+: m/z=473.2. found: 473.3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:33][C:29]1[CH:28]=[C:27]([C:19]2[C:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:6]5[O:1][CH2:2][CH2:3][O:4][C:5]=5[CH:10]=4)[N:17]=3)=[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]3[N:20]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a solution of N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-[2-(3-nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (1.09 g, 2.3 mmol) in ethanol (2 mL) was added sodium sulfide nonhydrate (2.76 g, 11.5 mmol) in H2O (2 mL). The mixture was heated at 80° C. for 16 h, allowed to cool to rt and filtered. The filtrate was concentrated to afford the product (1 g) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) 69.29 (s, 1H), 8.76 (d, 1H, J=7.2), 8.51 (d, 1H, J=8.8), 8.15 (d, 1H, J=5.2), 7.39-7.43 (m, 1H), 7.35 (m, 1H), 7.04-7.12 (m, 3H), 6.76-6.72 (m, 2H), 6.65-6.62 (m, 2H), 6.43 (d, 1H, J=5.2), 5.21 (s, 2H), 4.16-4.20 (m, 4H).