Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:38][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CC(C)(C)C(N)=O
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)C(C)(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and 2,2-dimethylpropanamide, the title compound was obtained as crystals, melting at 170°-172° C. (from ethyl acetate).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][N:12]3[C:16](=[O:17])[CH2:15][S:14][C:13]3=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:19](=O)[CH2:20][CH2:21][CH3:22].N1CCCCC1>C(O)C>[CH:19](=[C:15]1[S:14][C:13](=[O:18])[N:12]([CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:16]1=[O:17])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.18 g (4.5 mmol) of 3-[2-(imidazo[1,2-a]pyridin-5-yl)ethyl]thiazolidine-2,4-dione and 0.41 ml (4.5 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/2) to yield 1.15 g (81.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[S:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)(=[O:14])=[O:13].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cn1cc(S(=O)(=O)c2ccc(F)cc2)c2cc(Br)ccc21
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(S(=O)(=O)c2ccc(N3CCNCC3)cc2)c2cc(Br)ccc21
Temperature: 120 °C
Yield: 81.8 %

Procedure:
The 5-Bromo-3-(4-fluoro-benzenesulfonyl)-1-methyl-1H-indole (0.30 g, 0.85 mmol) was mixed with piperazine (0.34 g, 4 mmole) and methyl sulfoxide (3 mL). The mixture was heated at 120° C. in a sealed tube for 3 hours. The mixture was diluted with 10 mL water and the resultant precipitate was collected by filtration, washed with water, and recrystallized from chloroform/benzene to provide 5-Bromo-1-methyl-3-(4-piperazin-1yl-benzenesulfonyl)-1H-indole (0.302 g, 0.695 mmol), M+H 436.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26]Cl)=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)OC(=O)c1ccccc1
Reactant: NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CNCC(F)(F)F)OC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
(R)-3-(7-chloro-4-(chloromethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate (6.80 g, 16.7 mmol) in acetonitrile (70.0 ml, 1340 mmol) was added 2,2,2-trifluoroethylamine (8.27 g, 84 mmol). After 20 min, potassium carbonate (2.308 g, 16.70 mmol) was added and the reaction mixture was refluxed for 2 h. The solvent was evaporated and the crude product was dissolved in a mixture of dichloromethane and chloroform. A thick emulsion formed and addition of methanol provided a clear organic phase. The organic layer was dried (Na2SO4), the solvent was removed and the crude product was used as such for the next step. MS (ESI) 470 (M+H); Rf=1.56.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][C@@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[C:7]=1[F:21])[CH3:2].Cl.[NH2:33][OH:34].C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][C@@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[C:7]=1[F:21])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[NH:30])[NH:33][OH:34])=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a mixture of 8.85 g (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid ethyl ester described in example 3.6 in 515 ml EtOH were added 20.21 g hydroxylamine hydrochloride and 81.1 ml triethylamine. The solution was stirred over night at 50° C., then evaporated. The crude product was isolated by extraction with EtOAc, then purified by chromatography on silica gel (CH2Cl2/MeOH) to yield 7.64 g (RS)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester as a light brown amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Br:25])[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1ccccc1Br)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccccc1Br
Yield: 69.5 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.1 mmol) prepared in example 4b was reacted with 1-(2-bromophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.0 g, 10 mmol) prepared in example 22a, in toluene to give racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.45 g, 69%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)(C)C.C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:12][CH:11]=2)=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#Cc1ccc(Cc2ccc(C#C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In Step III, a suspension of 1.00 g (2.78 mmoles) of bis(4-trimethylsilylethynylphenyl) methane [Compound (4)] in 50 ml anhydrous deaerated methanol was treated with enough anhydrous ethyl ether to dissolve all solid particles at 25° C. Anhydrous potassium carbonate (300 mg) was added and the mixture was stirred at 25° C. under argon for 16 hours. The solvent was removed and the solid residue was dissolved in 50 ml dichloromethane, treated with 5 g of silica gel and evaporated to dryness. The powder was placed on top of a 40-cm (I.D. 30 mm) column of silica gel (EM Labs, 70-230 mesh) and the column was developed with passage of hexane. A crystalline white solid [Compound (6)] was recovered from the the eluate: 0.60 gm (2.78 mmoles, 100%); mp 63°-64° C. After drying at 56° C./0.01 mm Hg inside an Abderhalden apparatus for 2 hours, the mp increased to 65.5°-66.5° C. IR (KBr) 3280 (very strong, sharp, --C≡CH), 2100 (weak, sharp, --C≡C--), and 1500 cm-1 (medium, sharp, C=C); MS (70 eV) m/e 216 (molecular ion); NMR (CDCl3) δ3.03 (s,2H,C≡C--H), 3.95(s,2H,CH2), 7.10 and 7.43 ppm (q,8H, JAB =8.0 Hz, aromatic).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][C:33]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5C(OC(C)(C)C)=O)=[N:32][CH:31]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:11][CH:10]([CH3:12])[C@@H:9]([C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][C:33]([C@@H:35]5[CH2:39][CH2:38][CH2:37][NH:36]5)=[N:32][CH:31]=4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)[NH2:8]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of (S)-tert-butyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonylamino)-2-methylpropyl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.05 g, 3.27 mmol) in CH2Cl2 (20 mL) was added TFA (5 mL, 64.9 mmol) and the solution was allowed to stir for 2 h. The solvents were removed in vacuo, the residue was dissolved in CH2Cl2: MeOH (1:1) (ca. 10 mL) and absorbed onto an MCX cation exchange cartridge (Oasis). The resin was washed with MeOH and the desired material was released by elution with NH3 in MeOH (2M). The solvents were removed in vacuo to afford the title compound (0.622 g, 91%) as a yellow foam which was sufficiently pure for use in subsequent steps. 1HNMR (500 MHz, CD3OD) δ 7.85-7.88 (m, 4H), 7.75 (m, app d, J=8.2 Hz, 4H), 7.70 (app d, J=5.8 Hz, 2H), 4.96 (t, J=8.2 Hz, 1H), 4.30 (d, J=8.5 Hz, 1H), 3.54-3.57 (m, 1H), 3.47-3.52 (m, 1H), 2.55-2.62 (m, 1H), 2.38-2.46 (m, 1H), 2.28-2.36 (m, 1H), 2.15-2.24 (m, 1H), 1.17 (d, J=6.7 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H). LCMS: Anal. Calcd. for C26H30N6: 426; found: 427 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12](Br)[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15].[CH2:21]([N:23]([CH2:26][CH3:27])[C:24]#[N:25])[CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([N:23]([C:24]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:12]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[N:25]=1)[CH2:26][CH3:27])[CH3:22]
Reactant: CCN(C#N)CC
Reactant: FC(F)(F)C(F)(F)C(Br)=NNc1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)c1nc(C(F)(F)C(F)(F)F)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
3.4 g (0.008 mol) of pentafluoropropionyl bromide 2,4,6-trichlorophenylhydrazone and 0.8 g (0.008 mol) of N,N-diethylcyanamide were added to 20 ml of toluene. Then, 0.9 g (0.009 mol) of triethylamine was added thereto under stirring at room temperature. After completion of the dropwise addition, stirring was continued at room temperature for further 1 hour. Then, 20 ml of toluene was added thereto, followed by washing with water. The organic layer was dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 1.9 g (yield: 54.3%) of the desired compound as a brown powder. Melting point: 66°-70° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N+:23]([O-])=O)=[C:11]([CH:26]=[CH:27]N(C)C)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]1[NH:10][C:11]2=[CH:26][CH:27]=[N:23][C:12]2=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=Cc1nc(OCc2ccccc2)nc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: c1ccc(COc2nc(OCc3ccccc3)c3nccc-3[nH]2)cc1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Zinc dust (30 g) was added to a solution of the product from Example 36.2 (20 g) in acetic acid (300 ml) with cooling to control the exotherm. The resulting mixture was then stirred for 2 h, filtered, and the filtrate was concentrated to dryness. The residue was partioned between chloroform and aqueous sodium bicarbonate, the organic layer was dried and then concentrated to dryness to give a solid residue of 2,4-dibenzyloxypyrrolo[3,2-d]pyrimidine (15.2 g)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[CH2:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27](Cl)=[O:28])=[CH:20]2)[CH3:16]>C(Cl)Cl>[CH2:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[O:28])=[CH:20]2)[CH3:16]
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc2nnc(C(=O)NCC(=O)OC)cc2c1
Reaction time: 5 h

Procedure:
A mixture of glycine methyl ester hydrochloride (2.5 g.) and triethylamine (2.6 ml.) in dry methylene chloride (10 ml.) was added to a solution of 6-ethylcinnolin-3-yl carbonyl chloride (1.1 g.) in dry methylene chloride (10 ml.). The resulting solution was kept at room temperature for 5 hours, diluted with methylene chloride (80 ml.) and washed successively with N-hydrochloric acid, water, 10% w/v sodium bicarbonate solution, and water and then dried (MgSO4). The solvent was evaporated and the solid residue was crystallized from aqueous ethanol to give 6-ethyl-N-(methoxycarbonylmethyl)-cinnolin-3-yl carboxamide, m.p. 135°-137° C.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[CH2:7][N:6]([CH3:18])[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@@H:8]2[CH2:7][N:6]([CH3:18])[CH2:5][C@H:4]2[NH2:1])=[CH:11][C:12]=1[F:17]
Reactant: CN1C[C@@H](N=[N+]=[N-])[C@H](Oc2ccc(Cl)c(F)c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CN1C[C@@H](N)[C@H](Oc2ccc(Cl)c(F)c2)C1
Yield: 19.6 %

Procedure:
To a solution of 426 (0.480 g, 1.77 mmol), PPh3 (0.930 g, 3.54 mmol) and THF (10 mL) was added H2O (1.0 mL). The resultant mixture was heated at 55° C. for 3 h. The solvent was removed in vacuo. The residue was purified by SiO2 chromatography eluting with DCM/MeOH (5:1 DCM/MeOH then 1:1) to afford 85 mg (21% over 5 steps) of trans-(±)-4-(4-chloro-3-fluorophenoxy)-1-methylpyrrolidin-3-amine (428): LC-MS (ESI) m/z 245 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1)[CH3:9])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][CH:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of (S)-tert-butyl-1-(5-bromopyridin-2-yl)ethylcarbamate (Method 27; 2.0 g, 6.6 mmol) in DCM (15 ml) was added HCl/dioxane (17 ml, 4 N, 68 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was removed and 10 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether (6×100 ml), dried over sodium sulfate and concentrated to give the title compound (0.98 g, 73%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=1.2 Hz, 1H), 7.76 (dd, J=2.0 and 8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 4.13 (q, J=6.8 Hz, 1H), 1.73 (b, 2H), 1.41 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]1([CH3:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.Cl.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN1C(=O)CCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1[N:36]1[CH2:37][CH2:38][C:33]([CH3:39])([CH3:32])[CH2:34][CH2:35]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)CCNCC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(-c3ccc4c(c3)CCCC4)nn2c(N2CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 29.6 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (40 mg, 0.091 mmol) and 4,4-dimethylpiperidine.HCl (13.55 mg, 0.091 mmol) in NMP (1 mL) was added DIEA (0.047 mL, 0.272 mmol) and the mixture was heated at 50° C. for 2 h. Then, 1N NaOH (0.272 mL, 0.272 mmol) was added to the reaction mixture and the contents were heated at 50° C. for 2 h. The reaction mixture was then filtered and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (13.5 mg, 0.027 mmol, 29.6% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.77-7.71 (m, 2H), 7.19 (s, 1H), 6.95 (s, 1H), 5.80 (s, 1H), 2.91 (s, 2H), 2.84-2.76 (m, 4H), 1.83-1.75 (m, 4H), 1.65-1.58 (m, 2H), 1.56-1.45 (m, 2H), 1.20 (s, 9H), 1.11 (s., 6H). LCMS (M+H)=506.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21](O)C)[CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:9]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][C:12]([Cl:14])=[CH:11][N:10]=2)[CH2:16][CH2:17]1
Reactant: CC(O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CBr)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.7 %

Procedure:
A mixture of 0.170 g (0.431 mmol) of 3-chloro-N-[5′-chloro-4-(1-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide and 0.135 g (0.517 mmol) of triphenylphosphine in methylene chloride (15 mL) is stirred under an atmosphere of nitrogen at 0 C for 5 minutes. To this is added 0.171 g (0.517 mmol) of carbon tetrabromide in several portions. The mixture is stirred at 0 C for 30 minutes and then warmed to room temperature and stirred for 2 days. The mixture is concentrated under reduced pressure and purified by flash silica gel chromatography to give 0.030 g (15%) of N-(4-bromomethyl-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-3-chloro-benzamide as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]1([CH2:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.O>[CH2:18]([NH:19][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol) in DMF (6 mL) were added phenylmethanamine (268 mg, 2.5 mmol) and TEA (345 mg, 3.4 mmol). The reaction mixture was stirred at 120° C. for 30 min under microwave. The reaction solution was diluted with water (40 mL), and the resulting precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was used in next step without further purification. LCMS (m/z): 307.1/308.1 [M+H]+/[M+2H]+
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:13](=[O:17])[C@H:14]([OH:16])[CH2:15][C:4]=2[CH:3]=1.ClCCl.C(N(C(C)C)CC)(C)C.[C:35](Cl)(=[O:46])[O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1>>[C:35](=[O:46])([O:36][C:37]1[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=1)[O:16][C@H:14]1[C:13](=[O:17])[N:12]([CH2:18][C:19]([F:21])([F:20])[F:22])[CH2:11][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:2]([Cl:1])=[CH:3][C:4]=2[CH2:15]1
Reactant: O=C1[C@H](O)Cc2cc(Cl)c3[nH]ncc3c2CN1CC(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reaction time: 48 h
Yield: 55.7 %

Procedure:
(R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino [3,4-e]indazol-8(3H)-one (1.2 g, 3.60 mmol) in dichloromethane (100.0 ml, 1554 mmol) was added diisopropylethyl amine (0.651 g, 5.03 mmol) followed by 4-nitrophenyl carbonochloridate (0.942 g, 4.67 mmol). After 48 h, the reaction mixture was washed with 1.0 M HCl and the crude product was purified by flash chromatography using 75% EtOAc in hexane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-nitrophenyl carbonate (1.0 g, 2.005 mmol, 56% yield). MS (ESI) 499 (M+H); Rf=1.64.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:32]=[CH:33][C:34]=4[C:35](O)=[O:36])[C:20]=3[NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:32]=[CH:33][C:34]=4[C:35]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:36])[C:20]=3[NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)=[O:14])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3cccc4ncccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4ncccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 3.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(4-phenylpiperidine-1-carbonyl)-7-(5-quinolylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.065 g, 0.6 mmol), the title compound (0.002 g, 3%) was obtained.