Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH2:15])=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[CH:10][C:9]=1[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(N2C(=O)c3ccccc3C2=O)c(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cc(N2C(=O)c3ccccc3C2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Methoxyacetyl chloride (0.65 ml) was added dropwise to a solution of N-(2-chloro-4-fluoro-5-aminophenyl)phthalimide (1.39 g) and triethylamine (1.16 ml) in dry methylene chloride (45 ml) and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulphate, filtered and evaporated to dryness to yield N-[2-chloro-4-fluoro-5-(2-methoxyacetamido)phenyl]phthalimide as a solid (1.72 g, 99%); NMR (CDCl3): 3.53 (s, 3H), 4.04 (s, 2H), 7.37 (d, 1H), 7.81 (m, 2H), 7.98 (m, 2H), 8.57 (d, 1H), 8.62 (broads s, 1H); m/s: [M−H]− 361, 363.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:6][CH:7]([O:11][CH2:12][CH3:13])[CH2:8][CH:9]=[CH2:10])[CH3:5].N#N>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:4]([O:6][CH:7]([O:11][CH2:12][CH3:13])[CH2:8][CH:9]1[CH2:3][CH2:10]1)[CH3:5]
Reactant: C=[N+]=[N-]
Reactant: C=CCC(OCC)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CCOCC
Product: CCOC(CC1CC1)OCC
Temperature: 0 °C

Procedure:
Diazomethane (6.17 g, 147 mmol) was added dropwise to 3.02 g (21 mmol) of 3-butenal diethyl acetal in 10 ml of dry ether with intensive stirring at 0° C. Then 70 mg (0.312 mmol) of palladium (II) acetate in 50 ml of dry ether was added all at once. Then stirring at 0° C. continued until the evolution of N2 ceased (10 min.). The ether was distilled off to the reduced volume of the reaction mixture ca 10 ml. The precipitate was filtered off on a fritted glass funnel and the filtrate evaporated. The crude product (2.57 g) contained 97% of the title compound (GC) and was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([Li])CCC.CCCCCC.[C:33]([Cl:41])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[ClH:41].[C:33]([C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cl
Product: O=C(c1ccccc1)c1ccccc1CCN1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.1 g of 1-(t-butyloxycarbonyl)-4-(2-phenylethyl)piperazine was dissolved in 8 ml of tetrahydrofuran, and 2.8 ml of butyllithium (1.6N, a hexane solution) was added dropwise to the solution at -30° C. followed by stirring for 30 minutes. Next, 0.88 ml of benzoyl chloride was added thereto, and the solution was stirred for 3 hours, poured into ice water, and then extracted with 50 ml of chloroform. The resultant chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated, and the residue was separated through a silica gel column chromatograph (hexane/ethyl acetate=1/1). The resultant oil dissolved in 10 ml of ether, and 4.8 ml of a 4N hydrochloric acid/dioxane solution was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated crystals were collected by filtration, whereby 0.36 g of 1-2-[2-benzoylphenyl]ethyl)piperazine.hydrochloride was obtained.
Reaction SMILES: CS(C)=O.[NH:5]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>O>[NH:5]([C:12]1[S:13][CH:14]=[C:15]([CH:17]=[O:18])[N:16]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OCc1csc(Nc2ccccc2)n1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1csc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A dimethyl sulfoxide solution (120 ml) of 20 g of sulfur trioxide pyridine complex was added dropwise to a mixture comprising 8.3 g of 2-anilinothiazol-4-ylmethanol, 16.5 ml of triethylamine and 120 ml of dimethyl sulfoxide. The resulting mixture was stirred at room temperature for 10 minutes and then poured into water. followed by extraction with ethyl acetate. The extract was washed successively with aqueous acetic acid, aqueous sodium chloride solution and aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The residue afforded by evaporation of the solvent under reduced pressure was recrystallized from a mixture of benzene and acetone. The resulting product was a brown powder having the following physical properties.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)=[C:8]([O:29][CH3:30])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl[C:32]1[C:33]2[N:40]=[CH:39][N:38]([CH2:41][CH3:42])[C:34]=2[N:35]=[N:36][CH:37]=1>>[CH2:41]([N:38]1[C:34]2[N:35]=[N:36][CH:37]=[C:32]([C:14]3[CH:13]=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=4[O:29][CH3:30])[C:17]([O:18][CH3:19])=[CH:16][CH:15]=3)[C:33]=2[N:40]=[CH:39]1)[CH3:42]
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2OC)c(OC)c1
Reactant: CCn1cnc2c(Cl)cnnc21
Product: CCn1cnc2c(-c3ccc(OC)c(-c4ccc(S(=O)(=O)CC)cc4OC)c3)cnnc21
Yield: 13 %

Procedure:
Prepared according to the method described for Example 45 using 2-(4′-(Ethylsulfonyl)-2′,6-dimethoxy-[1,1′-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 59) and 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8) to afford the title compound as an off white solid in 13% yield, 14.7 mg.
Reaction SMILES: FC(F)(F)C(O)=O.Br[C:9]1[C:10]([NH:16][C:17](=[O:30])[C:18]([CH3:29])([NH:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:19])=[N:11][CH:12]=[C:13]([Br:15])[N:14]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Br:15][C:13]1[N:14]=[C:9]2[N:20]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:18]([CH3:29])([CH3:19])[C:17](=[O:30])[NH:16][C:10]2=[N:11][CH:12]=1
Reactant: CC(C)(NCCC1CCOCC1)C(=O)Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC1(C)C(=O)Nc2ncc(Br)nc2N1CCC1CCOCC1
Temperature: 110 °C
Yield: 70.4 %

Procedure:
N-(3,5-Dibromopyrazin-2-yl)-2-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)propanamide trifluoroacetate (0.856 g, 1.517 mmol), N,N-diisopropylethylamine (1.321 mL, 7.59 mmol) and 1,4-dioxane (25 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen and the resulting mixture was sealed, stirred vigorously and heated at 110° C. for 2.5 h. The reaction mixture was concentrated under reduced pressure and purified using flash chromatography (5-50% ethyl acetate in hexane) to give the desired product (0.394 g, 1.068 mmol, 70% yield) as a white solid. MS (ESI) m/z 369.4 [M]+, 371.3 [M+2]+.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[CH2:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1)[CH3:9].CI>C(OCC)C.O>[CH2:8]([N:10]([CH3:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1)[CH3:9]
Reactant: CCNc1ccccc1-c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CI
Product: CCN(C)c1ccccc1-c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under ice-cooling, 60% sodium hydride (54 mg) was added to an N,N-dimethylformamide (3.0 mL) solution of methyl 4-(2-(ethylamino)phenyl)-2-nitrobenzoate (0.27 g), followed by stirring at the same temperature for 5 minutes and then at room temperature for 15 minutes. Methyl iodide (0.083 mL) was added to the reaction mixture under ice-cooling, followed by stirring at room temperature for 1 hour and then at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and then methyl iodide (0.11 mL) was added thereto, followed by stirring at 40 to 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then water and diethyl ether were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-95% hexane/ethyl acetate] to obtain 0.12 g of methyl 4-(2-((ethyl)(methyl)amino)phenyl)-2-nitrobenzoate as a yellow oily substance.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][NH:13][CH3:14]>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]([CH3:14])[SH:7](=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)[SH](=O)=O
Product: Cc1ccccc1

Procedure:
To a stirring solution comprised of para-toluenesulfonyl chloride in dichloromethane at 0° C. is introduced excess gaseous dimethylamine. The precipitate is removed by filtration and the filtrate is concentrated in vacuo to obtain the product.
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2].[OH:10][C:11]1[N:15]=[C:14]([N:16]([CH3:18])[CH3:17])[S:13][N:12]=1>>[CH2:4]([O:3][P:1]([O:10][C:11]1[N:15]=[C:14]([N:16]([CH3:18])[CH3:17])[S:13][N:12]=1)([O:6][CH2:7][CH3:8])=[S:2])[CH3:5]
Reactant: CCOP(=S)(Cl)OCC
Reactant: CN(C)c1nc(O)ns1
Product: CCOP(=S)(OCC)Oc1nsc(N(C)C)n1

Procedure:
Using the procedure of Example 6, diethyl chlorothiophosphate and 3 -hydroxy-5-dimethylamino-1,2,4-thiadiazole were reacted and after chromatography and elution with an 8-2benzene-ethylacetate mixture, there was obtained 3-(diethoxythiophosphoryloxy)-5-dimethylamino-1,2,4-thiadiazole with a melting point of 48° C and Rf=0.55.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[CH:22]1([C:25](=[O:34])[CH2:26][C:27](=[O:33])[C:28](OCC)=[O:29])[CH2:24][CH2:23]1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[N:12]([C:8]3[CH:9]=[C:10]([CH3:11])[C:5]4[N:6]([C:2]([CH3:1])=[N:3][N:4]=4)[CH:7]=3)[C:28](=[O:29])[C:27]([OH:33])=[C:26]2[C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:34])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)cn2c(C)nnc12
Product: Cc1cc(N2C(=O)C(O)=C(C(=O)C3CC3)C2c2ccc(Cl)cc2)cn2c(C)nnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Step 84.5 using 3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (Step 67.4), 4-chlorobenzaldehyde and ethyl 4-cyclopropyl-2,4-dioxobutanoate. tR: 0.82 min (LC-MS 2); ESI-MS: 483 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.97 (m, 4H) 2.41 (s, 3H) 2.55-2.68 (m, 3H) 2.85-2.93 (m, 1H) 6.12 (s, 1H) 7.11-7.28 (m, 2H) 7.28-7.41 (m, 3H) 8.50 (s, 1H) —OH missing.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][O:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Yield: 89.9 %

Procedure:
A solution of 5-hydroxy-1-(oxan-2-yl)-1H-indazole-3-carbaldehyde (120 mg, 0.49 mmol, 1.00 equiv), Cs2CO3 (180 mg, 0.55 mmol, 2.00 equiv) and 1-bromo-2-methoxyethane (500 mg, 3.60 mmol, 3.00 equiv) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 10 h. The reaction was diluted with 50 mL of ethyl acetate and then washed with 4×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate then concentrated under vacuum to give 134 mg (90%) of (R/S) 5-(2-methoxyethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a yellow oil. LCMS (method D, ESI): RT=1.48 min, m/z=305.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH3:10].[NH2:12][C:13]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:14]=1[C:15](O)=O.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:15]1[C:14]2[C:13](=[CH:21][C:20]([F:22])=[C:19]([F:23])[CH:18]=2)[N:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]=1[CH3:10]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(=O)c1ccccc1F
Product: Cc1c(-c2ccccc2F)nc2cc(F)c(F)cc2c1Cl

Procedure:
Prepared according to Procedure J using 1-(2-fluorophenyl)propan-1-one and 2-amino-4,5-difluorobenzoic acid in phosphorous oxychloride to afford a colorless solid upon purification by chromatography on silica gel. Mass Spectrum (ESI) m/e=308.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:33][CH2:34][CH2:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:22][CH2:23][NH:36][CH2:35][CH2:34][F:33])([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: NCCF
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCNCCF)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using 2-fluoroethylamine in Step 2. LC-MS Method 2 tR=1.183 min, m/z=505.1; 1H NMR (CDCl3) 1.48 (d, 3H), 1.94-2.32 (m, 5H), 2.40 (m, 1H), 2.67-2.85 (m, 3H), 2.86 (m, 1H), 4.34 (t, 1H), 4.45 (t, 1H), 5.62 (m, 1H), 6.88-7.19 (m, 6H), 7.20 (m, 4H), 7.40 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>COCCOC>[C:10]1([C:2]2[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 150 mg (0.161 mmol) of {[(t-Bu)2P(OH)]2PdCl}2 (from Experiment 7), 1.43 g (10.0 mmol) of 3-chloroanisole, 1.83 g (15.0 mmol) of PhB(OH)2 and 4.56 g (30.0 mmol) of CsF in 30.0 mL of DME. The resulting mixture was refluxed for 12 h until the starting material was completely consumed as judged by TLC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of diethyl ether. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the ether and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using 2% EtOAc/hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.73 g (94% yield) of 3-phenylanisole.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH:13]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OC1CCCCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(OC2CCCCC2)cc1
Reaction time: 22 h

Procedure:
822 mg (4.95 mmol) of ethyl 4-hydroxybenzoate was dissolved in 20 ml of tetrahydrofuran. 545 mg (5.45 mmol) of cyclohexanol, 1.56 g (5.94 mmol) of triphenylphosphine and 202 mg (1.50 mmol) of diethyl azodicarboxylate were added to the solution, and they were stirred for 22 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with 1 N sodium hydroxide and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16](B(O)O)[O:15][C:14]=12)=O)(C)(C)C.Br[C:48]1[C:56]2[S:55][N:54]=[N:53][C:52]=2[CH:51]=[C:50]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=2)[CH:49]=1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)[CH:25]=2)=[C:13]2[CH:17]=[C:16]([C:48]3[C:56]4[S:55][N:54]=[N:53][C:52]=4[CH:51]=[C:50]([C:57]4[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=4)[CH:49]=3)[O:15][C:14]=12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(B(O)O)oc12
Reactant: Fc1cccc(-c2cc(Br)c3snnc3c2)c1
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cc(-c4cccc(F)c4)cc4nnsc34)oc12

Procedure:
The title compound was prepared from {7-[bis(tert-butoxycarbonyl)amino]-4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-2-yl}boronic acid and 7-bromo-5-(3-fluorophenyl)-1,2,3-benzothiadiazole by a procedure analogous to Example 368. 1H NMR (400 MHz, CD3OD): δ 1.48-1.57 (m, 2 H), 1.94-2.05 (m, 2 H), 2.11-2.22 (m, 4 H), 3.67-3.75 (m, 1 H), 4.21-4.29 (m, 1 H), 7.19-7.26 (m, 1 H), 7.53-7.63 (m, 2 H), 7.72-7.77 (m, 2 H), 7.89 (s, 2 H), 8.08 (s, 1 H), 8.70 (s, 1 H), 8.90 (s, 1 H); MS (ESI): 527.60 [M+H]+; HPLC tR=1.07 min (TOF: polar—2 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].[Cl:14][C:15]1[N:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1>CC#N.O>[NH2:22][C:17]1[N:16]=[C:15]([Cl:14])[N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[N:18]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Nc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cccc(Nc2nc(N)nc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.4 %

Procedure:
Methyl 3-aminobenzoate (0.69 g, 4.55 mmol) and a 1N NaOH aqueous solution (0.91 mL, 0.91 mmol) were added to a solution of 4,6-dichloro-1,3,5-triazin-2-amine (0.75 g, 4.55 mmol) in a 1:1 MeCN/water mixture (40 mL) at 0 C. The mixture was stirred at 0 C for 1 h and room temperature for 3 days. The acetonitrile was removed under vacuum and the resulting white solid in water was filtered and dried under vacuum to provide the title compound (1.1 g, 87%). Method B HPLC-MS: MH+ requires m/z=280/282 Found: m/z=280/282, Rt=1.69 min (95%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.O1CCOCC1>C1COCC1>[NH2:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:2]=1[CH3:1])[C:9]#[N:10]
Reactant: Cc1ccc(C)c(Oc2ccc(C#N)cc2[N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2N)c1
Yield: 89.1 %

Procedure:
The coupled product 30 (12.00 g, 44.73 mmol) was reduced with sodium hydrosulfite (30.47 g, 175.00 mmol) in a mixture of THF (75 mL), water (100 mL), and dioxane (45 mL). After the reaction is complete, volatile organic solvents were removed in vacuo and the precipitate in the remaining water was collected via vacuum filtration to afford compound 31 as a white solid (9.50 g, 89.0% yield, 99.5% pure). 1H NMR (500 MHz, DMSO-d6): δ 7.19 (d, J=8 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 6.86 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.74 (s, 1H), 6.45 (d, J=8 Hz, 1H), 5.52 (s, 2H), 2.23 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][CH2:12][CH2:11][CH2:10]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)=[O:30]>CC(C)=O.O>[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:33][CH:34]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CN(C)C1CCCNc2ccccc21
Reactant: O=C(Cc1ccccc1Cl)Nc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C1CCCN(C(=O)c2ccc(NC(=O)Cc3ccccc3Cl)cc2)c2ccccc21
Yield: 99.6 %

Procedure:
38.8 g of potassium carbonate was added to a solution of 50 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of acetone and 200 ml of water. To the mixture was added 66.5 g of 4-[2-(2-chloro-phenyl)acetylamino]benzoyl chloride with ice-cooling and stirring. The mixture was stirred overnight at room temperature. The reaction mixture was mixed with water, followed by extraction with dichloromethane. The dichloromethane layer was dried over magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography and then recrystallized from methanol to obtain 99.3 g of 5-dimethylamino-1-{4-[2-(2-chlorophenyl)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22](F)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[N:4]=1)[CH3:2].[OH:33][C@@H:34]1[C@@H:38]([OH:39])[CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1.CC(C)([O-])C.[K+]>C1COCC1.CC(O)(C)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([O:33][C@@H:34]4[C@@H:38]([OH:39])[CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(O[C@H]5CN(C(=O)OC(C)(C)C)C[C@@H]5O)ccn34)c12
Temperature: 100 °C
Yield: 91.5 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (32 mg, 0.075 mmol; prepared as in Example 74, Step A) in THF/t-BuOH (1 mL/1 mL) was added (3S,4S)-tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (61 mg, 0.30 mmol) and potassium tert-butoxide (67 mg, 0.60 mmol). The reaction was heated with microwave at 100° C. for 50 minutes, and then concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH 10:1) gave the crude product (42 mg).