Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)#[CH:20].[I-]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#Cc1ccccn1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Temperature: 70 °C
Yield: 96.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.0 g, 2.79 mmol) and triethylamine (4 mL, 0.02 mmol) in N,N-dimethylformamide (4 mL) was treated with 2-ethynylpyridine (345 mg, 3.34 mmol). The resulting reaction mixture was degassed with argon for 10 min and then treated with cooper iodide (168 mg, 0.88 mmol) and bis(triphenylphosphine)palladium (II) chloride (305 mg, 0.44 mmol). The reaction was then heated at 70° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid methyl ester (900 mg, 97%) as a yellow oil: EI-HRMS m/e calcd for C22H23NO2 (M+) 333.1728, found 333.1724.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][N:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1.Cl[C:18]1[C:19]2[CH:27]=[C:26]([CH:28]3[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]3)[S:25][C:20]=2[N:21]=[C:22]([CH3:24])[N:23]=1.[NH4+].[Cl-]>COCCOC>[CH3:34][C:31]1([CH3:35])[CH2:32][CH2:33][CH:28]([C:26]2[S:25][C:20]3[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([CH:9]([C:8]([N:5]4[CH2:6][CH2:7][S:2](=[O:1])(=[O:16])[CH2:3][CH2:4]4)=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:19]=3[CH:27]=2)[CH2:29][CH2:30]1
Reactant: Cc1nc(Cl)c2cc(C3CCC(C)(C)CC3)sc2n1
Reactant: CCOC(=O)CC(=O)N1CCS(=O)(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)N1CCS(=O)(=O)CC1)c1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
Under an argon atmosphere, to DME (12.5 mL) that had been ice-cooled was added Nall (60% oil, 203 mg), followed by stirring for 10 minutes. To this mixture was added dropwise a solution of ethyl 3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropanoate (1.40 g) in DME (10 mL), followed by stirring at the same temperature for 30 minutes. Then, 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (750 mg) was added thereto, followed by stirring at 60° C. overnight. The reaction mixture was left to be cooled, and then a saturated aqueous NH4Cl solution was added thereto, followed by extraction with EtOAc. The organic layer was washed sequentially with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain ethyl 2-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]-3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropanoate (559 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH:13]=O)[CH:3]=1.[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:19][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1
Reactant: CC(C)CN
Reactant: O=Cc1cc(Cl)c2c(c1)OCCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold mixture of 9-chloro-3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde (2.07 g) and of isobutylamine (7.5 ml 8 eq.) were combined in 1,2-dichloroethane (75 ml) and cooled in ice water bath. Acetic acid (5.68 ml) was then added and followed by sodium triacetoxyborohydride (2.75 g, 1.4 eq.). The mixture was allowed to stir at room temperature overnight. It was partitioned with aqueous K2CO3 (75 mL, 1.5M). The aqueous layer was extracted with of dichloromethane (75 ml×2). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (10-100% ethyl acetate in hexanes) gave the desired amine as a light yellow oil: MS (m+1)=270.2.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=[N:21][CH:22]=1>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=1
Reactant: O=S(=O)(Oc1cncc(F)c1)C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1cncc(C#Cc2ccccc2)c1
Temperature: 60 °C
Yield: 65 %

Procedure:
Add phenylacetylene (0.180 mL, 1.6 mmol), copper (I) iodide (0.015 g, 0.08 mmol) bis(triphenylphosphine)palladium (II) dichloride (0.027 g. 0.04 mmol) and triethylamine (0.85 mL, 6 mmol) to a solution of trifluoromethanesulfonic acid 5-fluoro-pyridin-3-yl ester, (prepared essentially as described in PREPARATION 6), (0.367 g, 1.5 mmol) in degassed ethyl acetate (1.5 mL) and heat at 60° C. for 16 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with dichloromethane, to give the title compound (0.192 g, 65%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:27])[CH:6]([S:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].Br[C:29]1[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([CH:6]([S:11][C:12]1[CH:13]=[CH:14][C:15]([C:29]2[CH:30]=[CH:31][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:42][CH:43]=2)=[CH:16][CH:17]=1)[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:27])#[N:2]
Reactant: CC(C)CC(Sc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)NCC#N
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(Sc1ccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1)C(=O)NCC#N
Temperature: 80 °C

Procedure:
N-(cyanomethyl)-4-methyl-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thio}pentanamide (1.64 g, 4.22 mmol) and tert-butyl 4-bromobenzylcarbamate (1.33 g, 4.64 mmol) were mixed in DMF (12 mL). After addition of sodium carbonate (7.4 mL of a 2.0 M solution, 14.8 mmol), the reaction flask was thoroughly degassed with dry nitrogen. PdCl2dppf (103 mg, 0.13 mmol) was added and the reaction mixture was heated at 80° C. for 4 h. Aqueous sat. NaHCO3 was added, the product was extracted with EtOAc (3×), dried over MgSO4, concentrated in vacuo, and purified by flash chromatography (40% EtOAc/hexanes) to afford tert-butyl {4′-[(1-{[(cyanomethyl)amino]carbonyl }-3-methylbutyl)thio]-1,1′-biphenyl-4-yl}methylcarbamate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:16][C:17]1[C:22]([CH2:23]Br)=[C:21]([F:25])[C:20]([F:26])=[C:19]([F:27])[C:18]=1[F:28]>CCO>[F:16][C:17]1[C:22]([CH2:23][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)=[C:21]([F:25])[C:20]([F:26])=[C:19]([F:27])[C:18]=1[F:28]
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Solvent: CCO
Product: Fc1c(F)c(F)c(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)c(F)c1F

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and pentafluorobenzylbromide (0.204 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[F:24][C:25]([F:30])([F:29])[C:26](O)=[O:27]>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:26](=[O:27])[C:25]([F:30])([F:29])[F:24])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Solvent: ClCCl
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(C(=O)C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1.7 g (0.005 mole), anhydrous trifluoroacetic acid 4.2 g (0.02 mole) and dichloromethane 4 ml was stirred at room temperature for 3 hours. The reaction mixture was evaporated under vacuum and the residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 1.8 g (86%) of 1-ethyl-6-chloro-7-(4-trifluoroacetyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless plates. Melting point: 297°-298° C. (decomposition).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:13][CH:14]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCl>[Cl:8][C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:25]([C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[C:22]([F:21])([F:32])[F:33])=[O:26])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Triethylamine (2.0 mL) was added to an ice cold solution of 3-chloro-6-piperazin-1-ylpyridazine (1.00 g, 6.69 mmol) in dichloromethane (10 mL), followed by the addition of 2-trifluoromethylbenzoyl chloride (2.10 g, 10.03 mmol). The mixture was allowed to warm up to room temperature and then stirred for 30 minutes. The solvent was removed in vacuo and the crude mixture was dissolved in ethyl acetate (15 mL), washed with water and dried over anhydrous Na2SO4. [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone was obtained as a thick liquid after purified by column chromatography in 79% yield (1.96 g). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=7.9 Hz, 1H), 7.63-7.50 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 7.21 (t, J=4.4 Hz, 1H), 6.92 (d, J=9.5 Hz, 1H), 4.20-3.92 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.55 (m, 4H), 3.30 (t, J=5.3 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 167.6, 158.7, 147.7, 134.2, 134.2, 132.3, 129.5, 129.1, 127.2, 126.8, 126.8, 115.6, 46.3, 45.2, 44.7, 41.2. MS (ES+) m/z 371.1 and 373.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=O)[NH:7]2.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH:21]=[CH:20][C:18]=1[NH2:19].C(N=C=NCCCN(C)C)C.Cl.ON1C2N=CC=CC=2N=N1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([B:24]3[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:30])([CH3:29])[O:28]3)=[CH:23][C:17]=1[O:16][CH3:15])=[O:14])[NH:7]2
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To 4-methoxy-1H-indole-2-carboxylic acid (0.844 g, 4.42 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.01 mmol) in dichloromethane (20 ml) at 0° C. under a nitrogen atmosphere were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride (0.846 g, 4.42 mmol) and 1-hydroxy-7-azabenzotriazole (0.546 g, 4.01 mmol). The resulting brown solution was stirred at room temperature overnight. The reaction mixture was poured in water, the solids were collected by filtration and washed with some water. The solid was dried in a vacuum oven at 40° C. The solids were suspended in acetonitril (50 ml) and methanol (10 ml) and heated at 60° C. for 1 hour. The solids were collected by filtration and washed with hot acetonitril. Then the solids were stirred over night in dichloromethane. The mixture was filtered over a filter. The filtrate was concentrated in vacuo and gave 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indole-2-carboxamide (1.1 g).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([CH3:26])[C:14]=1[C:15](O)=[O:16]>>[CH3:26][C:18]1[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:13]([CH3:12])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: Cc1cc(C(F)(F)F)cc(C)c1C(=O)O
Product: Cc1cc(C(F)(F)F)cc(C)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light yellow oil, MS: m/e=355.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-dimethyl-4-trifluoromethyl-benzoic acid (intermediate AQ).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC>[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:1][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)=[CH:17][CH:16]=1
Reactant: CSc1ncc(C#N)c(N)n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(CNc2nc(SC)ncc2C#N)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carbonitrile (229a) (200 mg, 1.2 mmol) in DME (10 ml) were added 4-bromomethyl-benzoic acid methyl ester (274 mg, 1.2 mmol) and K2CO3 (663 mg, 4.8 mmol) at room temperature. The reaction mixture was heated at 100° C. for 5 h, overnight at 60° C., cooled, filtered and concentrated in vacuo. The crude product was used in the next reaction without further purification. LRMS: 314.3(calc.); 315.3 (obt.) (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15](=[N:17][O:18][CH2:19][CH3:20])[CH3:16])=[C:11]([Br:21])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15](=[N:17][O:18][CH2:19][CH3:20])[CH3:16])=[C:11]([Br:21])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCON=C(C)COc1c(Br)ccc(C(=O)OCC)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCON=C(C)COc1c(Br)ccc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.820 g (1.90 mmol) of ethyl 2,4-dibromo-3-(2-ethoxyiminopropyloxy)benzoate was dissolved in a mixture of 8 ml of THF and 8 ml of water, and 0.085 g (2.10 mmol) of NaOH was added. The mixture was stirred at RT for 12 h and then evaporated to dryness. The residue was taken up in water, and 6 N HCl was added. The mixture was then extracted with methylene chloride. The organic phase was dried using Na2SO4 and concentrated, giving 2,4-dibromo-3-(2-ethoxyiminopropyloxy)benzoic acid in the form of a colorless viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][CH2:16][OH:17])[C:6](=[O:11])[C:5]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2ccc(Cl)cc21
Reactant: ClCCOC1CCCCO1
Product: CC1(C)C(=O)N(CCO)c2ccc(Cl)cc21

Procedure:
Prepared from 5-chloro-3,3,dimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol.4, page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O[NH:9][C:10](=[NH:26])[CH2:11][C:12]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=[CH:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>O>[C:5]([O:4][NH:26][C:10](=[NH:9])[CH2:11][C:12]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=[CH:18]2)[CH2:13][CH2:14][CH2:15][CH2:16]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(CC1(n2ccc3cccnc32)CCCC1)NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)ONC(=N)CC1(n2ccc3cccnc32)CCCC1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Acetic anhydride (11.2 mL, 118.61 mmol) was added to N-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamidine (400) (1.8 g, 6.98 mmol) and stirring was continued for 3 h at room temperature (TLC, ethyl acetate, Rf=0.5). Water (50 mL) was added, and the mixture was basified to pH 8 by solid NaHCO3 and extracted with ethyl acetate (3×50 mL). The organic phase was thereafter dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 2-(1-{1H-pyrrolo[2,3-b]pyridin-1-yl}cyclopentyl)ethanimidamido acetate (401) (1.7 g, 81%) as an off-white solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[N:33][CH3:34])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([CH2:32][NH:33][CH3:34])=[CH:30][CH:31]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CN=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 9.8 %

Procedure:
A solution of (E)-1-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methyliminomethylphenyl)propene-1-one (0.46 g, 1.1 mmol), NaBH3CN (0.14 g, 2.3 mmol) and acetic acid (0.11 mL) in 20 mL of MeOH was stirred at rt for one hour. The reaction mixture was quenched with 50 mL of an aqueous saturated solution of NaHCO3. Extraction with 2×30 mL of DCM, washing with brine, drying over Na2SO4 and concentration in vacuo gave a residue that was purified via flash chromatography of silica gel using DCM:MeOH (97.3) as eluting solvent. Recrystallization from DCM:cyclohexane gave the title compound (0.05 g, 10%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([C:18]1[O:22][N:21]=[C:20]([NH2:23])[CH:19]=1)([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:23][C:20]2[CH:19]=[C:18]([C:15]([CH3:17])([CH3:16])[C:14]([F:24])([F:13])[F:25])[O:22][N:21]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)no1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.4 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429 mmol) in DCM (50 mL) was added 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (92 mg, 0.472 mmol), HATU (245 mg, 0.644 mmol) and Et3N (0.179 mL, 1.287 mmol). Then the mixture was stirred at 25° C. for 12 h. The mixture was concentrated and the crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.4) to yield a yellow oil of 2-(4-bromo-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (50 mg, 0.109 mmol, 25.4% yield): 1H NMR (400 MHz, CDCl3) δ: 8.12 (s., 1H) 7.35-7.27 (m, 2H) 7.23-7.18 (m, 1H) 6.95 (s, 1H) 3.72 (s, 2H) 1.55 (s, 6H); ES-LCMS m/z 411 (M+2).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][CH:23]2O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:23]2[C:24]3[C:20](=[C:19]([O:18][CH3:17])[CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: COc1cccc2c1CCC2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CCc3c(OC)cccc32)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 4-methoxy-1-indanol (110 mg, 0.669 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (87 mg, yield: 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1>CO.N1CCCCC1>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)propyl]piperidine-1-carboxylate (0.0330 g, 0.0847 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0124 g, 0.0847 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol). The resulting crude product was further purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperidine-1-carboxylate (0.0313 g, 71%).