Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:19]=3[C:20]([NH2:22])=[O:21])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:30]1CCOC[CH2:31]1>>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:18]4[C:19](=[C:23]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:25][CH:26]=4)[C:20](=[O:21])[NH:22][C:31]3=[O:30])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1c(NCCCCN2CC=C(c3ccccc3)CC2)cccc1[N+](=O)[O-]
Reactant: C1COCCO1
Product: O=c1[nH]c(=O)n(CCCCN2CC=C(c3ccccc3)CC2)c2cccc([N+](=O)[O-])c12
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamino]-6-nitrobenzamide (300 mg) and N,N'-carbonyldiimidazole (554 mg) in dioxane (3 ml) was stirred for 2 hours at 150° C. The solvent was removed during the reaction. The residue was crystallized from a mixture of ethanol and ether. The crude crystalline materials were collected, washed with methylene chloride, and recrystallized from ethanol to afford 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4(1H,3H)-quinazolinedione (265 mg).
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[O:8]=[CH:9][C:10]([Cl:13])([Cl:12])[Cl:11].O>C(OCC)C>[Cl:11][C:10]([Cl:13])([Cl:12])[CH:9]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[OH:8]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Brc1cccs1
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: OC(c1cccs1)C(Cl)(Cl)Cl
Temperature: 5 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
Under a dry argon atmosphere a Grignard reagent was prepared by combining 13.1 g (0.54 mole) of magnesium turnings with 86.4 g (0.53 mole) of 2-bromothiophene in dry diethyl ether. The Grignard reagent was stirred and cooled to 5° C., and 77.8 g (0.53 mole) of chloral was added slowly. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was poured into 500 ml of cold water and extracted with three 250 ml portions of ethyl acetate. The combined organic extracts were dried with magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to yield a liquid. The liquid was distilled under reduced pressure to give 67.2 g of 2,2,2-trichloro-1-(2-thienyl)ethanol; bp 113°-115° C./19.95 pa. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])/[C:5](/O)=[CH:6]/[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].O.[NH2:23][NH2:24]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[NH:24][N:23]=1)=[O:21])[CH3:2]
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(OC(F)(F)F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)[nH]n1

Procedure:
In analogy to the procedure described for example 4 b], (Z)-2-hydroxy-4-oxo-4-(4-trifluoromethoxy-phenyl)-but-2-enoic acid ethyl ester was reacted with hydrazine monohydrate in ethanol under reflux conditions to give 5-(4-trifluoromethoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester as yellow crystals.
Reaction SMILES: [Cl-].[NH4+].C(O)C.[N+:6]([C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([O-])=O>[Fe].O>[NH2:6][C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cccc(Oc2ccccc2)c1N

Procedure:
To a mixture of iron powder (9 g.), ammonium chloride (0.9 g.), ethanol (80 ml.) and water (40 ml.) was added ethyl 2-(2-nitro-3-phenoxyphenyl)acetate (10.9 g.) over 5 minutes under mild reflux and stirring and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was filtered under heating and ethanol was distilled off from the filtrate under reduced pressure. To the residue was added water and the mixture was extracted with diethyl ether. The extract was washed with water and dried over magnesium sulfate, and diethyl ether was distilled off under reduced pressure to give the viscous captioned compound (9.5 g.).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([NH:17]C(OC(C)(C)C)=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:7][CH2:8][C@H:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(=O)C(C)(C)C)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A cooled solution of compound 94 (1.006 g, 3 mmol) in CH2Cl2 (10 ml) at 0° C. was treated with trifluoroacetic acid (2.5 ml) and stirred for 1 hr at room temperature. The mixture was concentrated in vacuo to give compound 96 as a yellow oil which was used for the next step without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21]([CH3:23])=[O:22])[CH3:17].[NH4+].[Cl-]>CCOCC>[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)([OH:22])[CH3:23])[CH3:17]
Reactant: CCOC(=O)CC(C)=O
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)CC(C)(O)c1ccc(Oc2ccccc2)cc1

Procedure:
A solution of p-phenoxyphenylmagnesium bromide (obtained from 2.49 g. of 4-bromodiphenyl ether and 0.24 g. of magnesium in 100 ml. of ether) is added dropwise at 20°, with stirring, to a solution of 1.3 g. of acetoacetic acid ethyl ester in 40 ml. of ether, and the mixture is stirred for a further two hours, the resulting alcoholate is decomposed by means of ice and saturated NH4Cl solution, and the ethereal phase is dried and evaporated to give 3-p-phenoxyphenyl-3-hydroxybutyric acid ethyl ester.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[CH2:8][CH3:9])=[CH:3][CH:2]=1>C(OCC)C.[O-2].[Mn+4].[O-2]>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][CH:6]=1
Reactant: CCC(O)c1ccc(-c2ccccc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CCC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 45 h
Yield: 73.2 %

Procedure:
To a solution in diethyl ether (30.0 mL) of the compound (1.27 g) obtained in step (1) above, manganese(IV) oxide (9.57 g) was added and the mixture was stirred at room temperature for 45 hours. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in acetone (60.0 mL), a Jones' reagent {see Org. Synth., Coll. Vol. VI, 542 (1988)}(1.20 mL) was added until the color of the Jones' reagent was yet to disappear. The reaction mixture was concentrated under reduced pressure and ethyl acetate and water were added to the residue. Extraction with ethyl acetate was conducted three times and the combined organic layers were washed with saturated brine. After passage through a phase separator, the washed organic layers were concentrated under reduced pressure. The resulting residue was recrystallized with n-hexane to give the titled compound as a colorless solid (921 mg).
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].CCN(CC)CC.Cl.[NH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:26]2[B:27]([OH:34])[O:28][CH:29]([CH2:30][N+:31]([O-:33])=[O:32])[C:25]=2[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[OH:34][B:27]1[C:26]2[C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:16][C:2](=[O:3])[CH3:1])=[CH:22][CH:23]=[CH:24][C:25]=2[CH:29]([CH2:30][N+:31]([O-:33])=[O:32])[O:28]1
Reactant: NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ac2O (1.16 mL, 12.3 mmol) was added slowly to a solution of Et3N (2.33 mL, 16.5 mmol) and 7-(3-amino-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (1.69 g, 76.5 mmol) in CH2Cl2 (50 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 1 h and then quenched with H2O (50 mL). The mixture was extracted with CH2Cl2 and the organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound as a viscous liquid: yield 1.29 g (75%).
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.O[CH:9]([C:15]1[C:27]([CH3:28])=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:29])[CH:16]=1)[CH:10]([O:13][CH3:14])[O:11][CH3:12].C1(C)C=CC=CC=1>C(#N)C.N1C=CC=CC=1>[CH3:12][O:11][CH:10]([O:13][CH3:14])[CH2:9][C:15]1[C:27]([CH3:28])=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:29])[CH:16]=1
Reactant: CCOC(=O)COc1cc(C)c(C(O)C(OC)OC)cc1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)COc1cc(C)c(CC(OC)OC)cc1C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a stirred suspension of sodium iodide (72 g) and chlorotrimethylsilane (52 g) in acetonitrile (180 g) was added dropwise a solution of ethyl 2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (50 g) in acetonitrile (80 g) in an ice-salt bath. The mixture was stirred for 30 minutes, and then toluene (400 g) and pyridine (25 g) were added. The reaction mixture was washed with an aqueous solution of sodium thiosulfate, an aqueous solution of citric acid, an aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (43 g).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:28][CH3:29])=[O:27].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:27])[NH:28][CH3:29])[CH:10]=1
Reactant: CNC(=O)Nc1ccc(Cl)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)Nc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 26.3 %

Procedure:
(Step 3) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.3 g), 1-[2-(aminomethyl)-4-chlorophenyl]-3-methylurea hydrochloride obtained in Step 2 (2.45 g) and diisopropylethylamine (5 ml) were stirred in ethanol (15 ml) overnight at 70° C. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in ethanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from ethanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.52 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[N:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[CH3:28][O:29][C:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:10]2[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([NH:2][C:36]([C:35]4[CH:39]=[CH:40][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][CH:34]=4)=[O:37])[CH2:4]3)[N:9]=2)=[N:19][C:20]=1[O:26][CH3:27]
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)nc1OC
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)n4)c4ncsc4n3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a stirred solution of 5-(3-aminopyrrolidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (283 mg, 0.69 mmol), 4-(methoxycarbonyl)benzoic acid (161 mg, 0.89 mmol) in 10 mL of DMF were added HATU (340 mg, 0.89 mmol), DIEA (267 mg, 2.07 mmol), EDCI (145 mg, 0.759 mmol) and DMAP (93 mg, 0.76 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated at 80° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of dichloromethane and methanol (20:1)) to give methyl 4-(1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoate (350 mg, 94%) as a yellow solid. LC-MS: 536.1 [M+H]+, tR=1.68 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:15])[C:5]([CH:9]=[CH:10][C@H:11]([CH3:14])[CH2:12][CH3:13])=[C:6]([F:8])[CH:7]=1>CCCCCCC.[Pt]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][CH2:10][C@H:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([F:15])[CH:3]=1
Reactant: CC[C@@H](C)C=Cc1c(F)cc(Br)cc1F
Agent: [Pt]
Solvent: CCCCCCC
Product: CC[C@@H](C)CCc1c(F)cc(Br)cc1F
Reaction time: 20 h

Procedure:
0.4 g of 5% Pt/C (dry) is added to a solution of 1.8 g (5.9 mmol) of 2 in 50 ml of heptane, and the mixture is hydrogenated at atmospheric pressure for 20 hours. The solvent is removed under reduced pressure, and the entire amount is converted into 4.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[N:8][CH2:7]1)C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:4]([OH:40])=[O:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COCCOC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of ethyl{2-[5-({6-[(2-methoxyethoxy)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (190 mg) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the concentrate was washed with ethyl acetate. To the aqueous layer was added 1N hydrochloric acid (3 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (157 mg, yield 87%) as a brown oil.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([OH:24])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].S(OC)(O[CH3:31])(=O)=O>C1COCC1.CN(C=O)C>[C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([O:24][CH3:31])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(Adamantan-1-yloxymethyl)-2-cyclohexyl-2H-pyrazol-3-ol (0.29 g, 0.88 mmol) and sodium hydride (50 mg, 1.25 mmol of a 40% suspension in mineral oil) were stirred in THF-DMF (1:1) (10 mL) at 0° C. for 0.5 h, then allowed to warm to room temperature. Dimethyl sulphate (0.1 mL, 1 mmol) was added and the mixture stirred overnight. After concentration in vacuo, the mixture was poured into water (10 mL) and extracted with EtOAc (20 mL). The organic layer was separated washed with water (2×10 mL) and dried (MgSO4). Filtration and evaporation of the solvent afforded a yellow oil, which was purified by chromatography with EtOAc-hexane (1:1) as eluant. (0.24 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:27]3[C:22]([CH3:21])=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1ncccc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-methyl-3-pyridinecarboxylic acid as starting materials, MS (LC/MS): 421.8 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:13]1([CH3:22])[C:14]([C:19](Cl)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>ClCCl>[CH3:22][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([NH:9][CH2:8][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])=[O:20]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C[C@@H](CN)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccccc1C(=O)NC[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (R)-2-phenylpropyl amine (1.24 g; 9.17 mmol), 1N NaOH (20 mL), and dichloromethane (20 mL) is treated with o-toluoyl chloride (1.42 g; 9.17 mmol) added dropwise; the mixture is then stirred at room temperature for 1 hour. The phases are separated and the aqueous layer extracted with dichloromethane (2×70 ml). The combined extracts are washed with water (1×30 mL) and brine (1×30 mL), dried over magnesium sulfate, and evaporated to give the product as a white solid.
Reaction SMILES: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)C1C=CC=CC=1Br.[Br:20][C:21]1[CH:41]=[CH:40][CH:39]=[CH:38][C:22]=1[C:23]([N:25]1[CH2:32][C@@H:31]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24]>>[Br:20][C:21]1[CH:41]=[CH:40][CH:39]=[CH:38][C:22]=1[C:23]([N:25]1[CH2:32][CH:31]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24]
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)O)N(C(=O)c2ccccc2Br)C1
Agent: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1Br
Product: CS(=O)(=O)OC1C[C@@H](C(=O)O)N(C(=O)c2ccccc2Br)C1

Procedure:
Following the procedure outlined in Example 1C, (cis)-1-o-bromobenzoyl-4-hydroxy-L-proline methyl ester was converted to (cis)-1-o-bromo- benzoyl-4-mesyloxy-L-proline (foam). MS(CI): m/e 392 (M+H), 390 (M-H).
Reaction SMILES: O.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1)=[O:10]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of (S)-1-methylpyrrolidine-2-carboxylic acid monohydrate (14 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (49 μL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-((S)-1-methylpyrrolidine-2-carboxamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH:2]1([CH2:1][OH:5])[CH2:3][CH2:4][CH:2]([CH2:1][OH:5])[CH2:3][CH2:4]1
Reactant: CCCCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: OCC1CCC(CO)CC1

Procedure:
20.09 g of titanium tetraisopropoxide in n-butanol (2.54 weight percent Ti)
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:3]=[C:2]2[C:36]1[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a 500 ml round bottom flask equipped with a magnetic stir bar was added 3-bromo-5-nitro-1-trityl-1H-indazole (13.13 g, 27.1 mmol), followed by the additions of 4-pyridine boronic acid (5.00 g, 40.7 mmol), PdCl2(dppf) (2.21 g, 2.7 mmol) and K3PO4 (14.39 g, 67.8 mmol). The mixture was dissolved in a mixture of 160 ml of dioxane and 40 ml of H2O and stirred overnight at 80° C. Upon completion, the reaction mixture was filtered through a pad of celite and washed with water (3×100 ml). The organic phase was then dried over anhydrous MgSO4, filtered and concentrated to give a crude product. The crude product was column purified (30% EtAOc/Hexane) to give 5-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazole (10.7 g) as a yellow solid.