Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[N:17]=[CH:18][O:19][C:20]=1[C:21](Cl)=[O:22].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[O:19][CH:18]=[N:17][C:16]=1[CH3:15])=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1ncoc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ncoc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 78.1 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0456 g, 0.193 mmol), 4-methyloxazole-5-carbonyl chloride (0.029 g; 0.193 mmol), and triethylamine (0.068 mL; 0.483 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 4 to 30% of ethyl acetate in dichloromethane gave 0.0458 g (78%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-methyloxazole-5-carboxamide as a solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:11])=[C:5]([C:9]#[N:10])[CH:6]=[N:7][CH:8]=1)=[CH2:2].C1C(=O)N(Br)C(=[O:15])C1.[OH-].[Na+]>O>[CH3:11][C:4]1[C:3]([CH:1]2[CH2:2][O:15]2)=[CH:8][N:7]=[CH:6][C:5]=1[C:9]#[N:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1cncc(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C#N)cncc1C1CO1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
A suspension of 5-ethenyl-4-methylpyridine-3-carbonitrile (3.00 g, 20.8 mmol) in 30 mL of ButOH and 60 mL of water was added NBS (4.6 g, 26 mmol) portionwise. The mixture was stirred at 40° C. for 2.5 hour then cooled down to 10° C. NaOH solution (2.5 g in 70 mL of water, 62.4 mmol) was added dropwise and stirred for 15 minutes. The reaction mixture was extracted with EtOAc twice and condensed. The residue was purified by column chromatography (petrol ether: EtOAc=20:1) to afford 4-methyl-5-(oxiran-2-yl)pyridine-3-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[CH:9][CH:8]=1)=[O:5].[C:27](O[K])(C)(C)C.CI>C1COCC1.CC(O)(C)C>[Cl:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[CH:19][C:3]=1[C:4]([N:6]([CH3:27])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Cc1nc(-c2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3Cl)cc2)cs1
Reactant: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)(C)O
Product: Cc1nc(-c2ccc(N(C)C(=O)c3ccc(S(C)(=O)=O)cc3Cl)cc2)cs1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a stirring solution of 2-chloro-4-(methylsulfonyl)-N-(4-(2-methylthiazol-4-yl)phenyl)benzamide (50 mg, 0.123 mmol) in THF (1 mL) under nitrogen atmosphere was added 1M solution of tBuOK in tBuOH (0.14 mL) dropwise. After stirring for 15 min, CH3I (0.009 mL, 0.14 mmol) was added and the reaction mixture was stirred at 60° C. for 1 h, before partitioning between water and EtOAc. The organic layer was isolated, washed with brine, and adsorbed on silica. Purification on silica by flash chromatography using a gradient of 40-100% EtOAc/hexane yielded 40 mg of the titled compound as an off-white solid (77% yield).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[S-:25][C:26]#[N:27].[K+].P(OP(OP(OP(O)(O)=O)(O)=O)(O)=O)(O)(O)=O.Cl(O)(=O)(=O)=O>O1CCCC1.O>[OH:1][C@@H:3]1[C@@H:2]([S:25][C:26]#[N:27])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: N#C[S-]
Agent: O=P(O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](SC#N)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg.) and potassium thiocyanate (2 g.) in dry tetrahydrofuran (40 ml.) were treated with tetraphosphoric acid (about 2 ml.), and the reaction was stirred at room temperature for 2 hours. Perchloric acid (60%, 0.1 ml.) was added, and after a further 30 minutes the solution was diluted with water and extracted with ether. The extract was washed with water, dried over sodium sulphate and evaporated to give a colourless oil which was purified by preparative tlc and recrystallisation from acetone/petrol to give the title compound, as white prisms m.p. 165°-170° [α]D + 78°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[CH2:11][C:12]1[C:20]([OH:21])=[CH:19][C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=1.C(O)C>C(O)(=O)C.O=[Pt]=O.C(OCC)C>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][C:12]1[C:20]([OH:21])=[CH:19][C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: OCc1ccccc1/C=C/Cc1cc2c(cc1O)CCO2
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: OCc1ccccc1CCCc1cc2c(cc1O)CCO2
Reaction time: 0.05 h
Yield: 49.2 %

Procedure:
6-(3-(2-hydroxymethylphenyl)-trans-prop-2-enyl)-5-hydroxy-2,3-dihydrobenzofuran (2.82 g; 0.01 moles) was dissolved in acetic acid (35 ml) and ethyl alcohol (10 ml) and hydrogenated at 40 psi at room temperature using PtO2 (0.30 g) as a catalyst. The reduction was complete in approximately 3 minutes with a slight exotherm. The catalyst was removed via suction filtration through a bed of celite. The bed was washed with ethyl alcohol (2×10 ml) and the filtrate was relieved of solvent in vacuo to afford a crude gum. The gum was dissolved in ethyl ether (50 ml) and was washed sequentially with brine (2×50 ml) and saturated NaHCO3 solution (2×50 m). The organic layer was dried over MgSO4, filtered, and the filtrate evaported in vacuo to yield a crude solid. Recrystallization from ethyl acetate/n-hexane produced 6-(3-(2-hydroxymethyl-phenyl)propyl)-5-hydroxy-2,3-dihydrobenzofuran as white needles (1.4 g, 49%, m.p. 110°-111.5° C.).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)no2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of methyl 4-[3-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl]benzoate (2.10 g), 1 M aqueous sodium hydroxide solution (12 ml), tetrahydrofuran (20 ml) and methanol (20 ml) was stirred at 60° C. for 1 hr. The mixture was acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-[3-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (1.82 g, yield 90%). Recrystallization from hexane-tetrahydrofuran gave colorless crystals. melting point: 293–294° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CN(C=O)C.C1C([CH:47]([OH:50])[CH2:48][NH2:49])=CC(Cl)=C(Cl)C=1.[C:53]1(C)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(N(CC)CC)C>[OH:50][CH2:47][CH2:48][N:49]([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: Cc1ccccc1
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)N(CCO)c1ccccc1

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 and DMF in toluene. Then treatment with triethylamine and phenylethanolamine in toluene.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:35])=[C:20]([CH:34]=1)[C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[C:26]([Cl:33])[CH:25]=1)=[O:22].C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:28]([C:27]3[CH:31]=[CH:32][C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:34]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=4[CH3:35])=[CH:25][C:26]=3[Cl:33])=[O:29])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.391 g of 4-[(5-fluoro-2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature overnight. The mixture is washed with H2O, 1 N HCl, H2O, 1M NAHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is again passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and the solid crystallized from ethyl acetate to give crystals, m.p. 137-140° C.
Reaction SMILES: [OH:1][CH:2]([CH3:23])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)=[O:11])[CH2:6][CH2:5]1.[C:24]([Cl:27])(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+].Cl>ClCCl.CO.C(N(CC)CC)C>[ClH:27].[C:24]([O:1][CH:2]([CH3:23])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3)=[O:11])[CH2:6][CH2:5]1)(=[O:26])[CH3:25]
Reactant: CC(O)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)OC(C)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C

Procedure:
0.5 Gram of 6-[4-(2-hydroxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and 0.3 ml of triethylamine were dissolved in 10 ml of dichloromethane, the mixture was stirred at a room temperature, 0.15 g of acetyl chloride was added slowly thereto and further stirred at a room temperature for 1 hour. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution then dried with anhydrous sodium sulfate. The solvent was removed by distillation under a reduced pressure and the residue obtained was treated by means of a silica gel column chromatography, then the objective product was dissolved in methanol and converted into the hydrochloride by adding a concentrated hydrochloric acid. Recrystallized from water-acetone to obtain 0.22 g of 6-[4-(2-acetoxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril monohydrochloride. Melting point: 239°-241° C. (decomposed).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:13](CC)[CH2:14][CH3:15])[CH3:12].CS(OS(C)(=O)=O)(=O)=O.N1CCCC1.Cl>O1CCCC1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:13]2[CH2:14][CH2:15][CH2:12][CH2:11]2)[CH3:9])[N:7]=1
Reactant: CCN(CC)CC
Reactant: CC(O)c1cccc(Br)n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CC(c1cccc(Br)n1)N1CCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)ethanol (Example 3, Step 1) (0.5 g, 2.48 mmol) in tetrahydrofuran (4 mL) at 0° C. was charged with triethyl amine (1.04 mL, 7.42 mmol), and then a solution of methanesulfonic anhydride (0.56 g, 3.22 mmol) in tetrahydrofuran (6 mL) added over 30 minutes. The reaction mixture was stirred at 0° C. for 2 hrs and then pyrrolidine (0.21 mL, 2.48 mmol) was added and the mixture was warmed to room temperature. After sixteen days the reaction mixture was poured into aqueous hydrogen chloride (1 M, 10 mL) and dichloromethane (10 mL) The layers were separated and the organic layer was extracted with aqueous hydrogen chloride (1 M, 10 mL). The combined aqueous layers were neutralized with aqueous sodium hydroxide (2 M) until pH=10 and then extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:4]([F:14])[CH:3]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].O>C1COCC1.C(=O)=O.CC(C)=O>[Cl:1][C:2]1[C:3]([CH:22]=[O:23])=[C:4]([F:14])[C:5]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:7]=1
Reactant: Fc1cc(Cl)ccc1OCC(F)(F)F
Reactant: CN(C)C=O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1F
Reaction time: 0.5 h

Procedure:
To 4-Chloro-2-fluoro-1-(2,2,2-trifluoro-ethoxy)-benzene (522, 0.80 g, 3.5 mmol) in THF (20 mL), cooled in dry ice/acetone bath and under an atmosphere of nitrogen, was slowly added n-butyllithium (1.60 M in Hexane, 2.30 mL). After an hour, N,N-dimethylformamide (0.298 mL, 3.85 mmol) was added to the reaction. After 30 minutes, the reaction was allowed to reach room temperature and was stirred for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound (523, 450 mg, 50%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])C1C=CC=CC=1.CCN(C(C)C)C(C)C>CO.[Pd]>[F:19][C:16]([F:17])([F:18])[CH2:15][O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: FC(F)(F)COC[C@@H]1CCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: FC(F)(F)COC[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of (S)-1-benzyl-2-(2,2,2-trifluoroethoxymethyl)-pyrrolidine (0.5 g, 1.83 mmol) in MeOH (20 mL) was added Hunig's base (1.18 g, 9.15 mmol). The flask was purged three times with Ar and 10% Pd/C (0.487 g, 0.457 mmol) was added to the mixture. The flask was purged three times with hydrogen and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a pad of Celite, washed with MeOH (20 mL) and the resulting solution was concentrated in vacuo to give the title compound (0.250 g, 75%) as a colorless semi-solid. MS: 184.1 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]1([CH:7]([CH3:11])[CH2:8][CH:9]2[NH:17][C:15](=[O:16])[CH2:14][NH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC(N)=O
Reactant: CC(CC=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(CC1NCC(=O)N1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 3-phenylbutanal (Trifernal®, 0.67 g, 4.5 mmol), glycinamide hydrochloride (0.50 g, 4.5 mmol), triethylamine (0.46 g, 4.5 mmol) and K2CO3 in ethanol (4 ml) was heated to 60° C. for 24 h. Then the solvent was removed under vacuum at 40° C. The residue was taken up in ether and the solvent evaporated to yield 0.52 g (57%) of a highly viscous oil as a mixture of diastereoisomers.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17](=[NH:19])[NH2:18])=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:22](CC)CC)C.O.NN>C(O)C>[CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:17](=[NH:18])[NH:19][NH2:22])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(CC2CCCC2)c2ncc(F)cc12
Agent: NN
Solvent: CCO
Solvent: O
Product: N=C(NN)c1nn(CC2CCCC2)c2ncc(F)cc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.400 g (5.358 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide were initially charged in 26 ml of ethanol, and the mixture was cooled to 0° C. 2.169 g (21.431 mmol) of triethylamine and 335 mg (5.358 mmol) of 80% strength hydrazine hydrate were added, and the mixture was stirred at room temperature for 18 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, concentrated on a rotary evaporator and dried under high vacuum. This gave 1.070 g (purity 77%, 56% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:5]2[CH:10]([CH3:11])[CH2:9][CH2:8][O:7][C:6]=12.C([B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([B:22]3[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]3)=[C:6]3[O:7][CH2:8][CH2:9][CH:10]([CH3:11])[N:5]3[N:4]=2)=[CH:13][CH:14]=1
Reactant: CC(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC1CCOc2c(Br)c(-c3ccc(F)cc3)nn21
Solvent: C1CCOC1
Product: CC1CCOc2c(B3OC(C)(C)C(C)(C)O3)c(-c3ccc(F)cc3)nn21
Reaction time: 0.33 h
Yield: 44 %

Procedure:
To a solution of 3-bromo-2-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.5 g, 4.82 mmol, 1 eq) in THF (40 ml) is added a solution of n-Buli (3.314 ml, 1.6 M, 5.30 mmol, 1.1 eq) dropwise at −78° C. After 20 min of stirring, a solution of 1.23 g of 2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.23 mmol, 1.1 eq) in THF is added dropwise and the reaction mixture is stirred for 2 hours at −78° C. Then the reaction mixture is quenched by the addition of an aqueous solution of NH4Cl and is extracted with EtOAc. The combined organic phases are washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude is purified by silica gel chromatography (eluent cyclohexane/ethyl acetate). 760 mg (42%) of 2-(4-fluorophenyl)-7-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20]([C:22]2[C:23](=[O:35])[N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]([CH3:28])[C:26]=2[CH3:27])=[O:21])=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](C(N)=O)[CH:9]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:53]>CCOC(C)=O.O>[NH2:53][C:10]1[CH:9]=[C:8]([O:7][C:6]2[C:5]([F:18])=[CH:4][C:3]([NH:19][C:20]([C:22]3[C:23](=[O:35])[N:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:25]([CH3:28])[C:26]=3[CH3:27])=[O:21])=[C:2]([Cl:1])[CH:17]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a suspension of 4-(5-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)picolinamide (297.6 mg, 0.6 mmol) in EtOAc (4 mL), CH3CN (4 mL) and H2O (2 mL) was added PhI(OAc)2 (97 mg, 0.3 mmol) at 0° C., the mixture was stirred at 0° C. for 30 minutes, then warmed up to rt and stirred for 12 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=20/1) to give the title compound as a light beige solid (220 mg, 78.3%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1>>[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30][CH2:2][CH2:3][OH:4])[CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1
Reactant: Cc1cncc2cccc(N[C@H]3CC[C@H](N)CC3)c12
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: Cc1cncc2cccc(N[C@H]3CC[C@H](NCCO)CC3)c12

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 121 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:18]([CH3:20])[CH3:19])=[N:4][C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH2:21]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6][C:5]([O:11][CH2:12][C:13]([N:34]([CH:31]2[CH2:30][CH2:29][N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33][CH2:32]2)[CH3:35])=[O:15])=[N:4][C:3]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)COc1nc(C(C)C)c(N)c(C(C)C)n1
Product: CC(C)c1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C(C)C)c1N

Procedure:
As in Example 11, a carboxylic acid derivative was synthesized from Compound 13. Then, the title compound was synthesized from the obtained carboxylic acid derivative and 1-benzyl-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]2)=[C:18]([C:32]([F:35])([F:34])[F:33])[CH:17]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][CH2:27]3)=[C:18]([C:32]([F:33])([F:35])[F:34])[CH:17]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: COC(=O)C1CCN(c2ccc(Nc3c([N+](=O)[O-])cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1CCN(c2ccc(Nc3c(N)cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 73.2 %

Procedure:
To a solution of compound 8.2 methyl 1-(4-(6-bromo-3-nitroquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.26 g, 0.47 mmol, 1 equiv.) in dioxane (3 mL) at room temperature was added Tin(II) chloride dihydrate (0.53 g, 2.35 mmol, 5 equiv.). The resulting mixture was heated to 80° C. under argon for 5 hours. Upon cooling to room temperature, the mixture was neutralized with aqueous NaHCO3 and filtered. The filtrate was extracted with EtOAc (30 mL×2) and the combined organic layer was washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (hexanes:EtOAc 1:1) to afford desired product 8.3 methyl 1-(4-(3-amino-6-bromoquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.18 g; 73%). LC-MS (M+H): 523.10