Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](O)=[O:35])[CH2:9]1)=O)(C)(C)C.CN.C[C:40]#[N:41].O>CC#N>[CH3:40][NH:41][C:34]([C@H:10]1[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12][NH:8][CH2:9]1)=[O:35]
Reactant: CC#N
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)C(C)C)ccc1OC
Agent: CN
Solvent: O
Product: CNC(=O)[C@@H]1CNC[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C

Procedure:
The title compound is prepared analogously as described for the title compound Example 1, starting from (3S*,4R*)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester and methylamine. MS (LC-MS): 422.1 [MH]+; tR (HPLC, nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, flow: 1.5 ml/min): 3.83 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)(=[O:25])[CH3:24]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:18][C:19]([F:20])([F:21])[F:22])[CH2:4][CH2:3][CH2:2][O:1][C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:28][CH:29]=2)=[CH:7][C:8]=1[C:14]([F:16])([F:15])[F:17])#[N:11]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(OCCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(3-hydroxypropyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (APCI) m/z 460 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:4][CH2:3]1.[O:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:26][C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)[CH2:16][CH2:15]2)[CH2:6][CH2:7]1
Reactant: O=Cc1ccoc1
Reactant: CC1(C)CCC(c2ccccc2N2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(c2ccccc2N2CCN(Cc3ccoc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a mixture of 1-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine (30 mg, 0.11 mmol) produced in Example (3c), furan-3-carbaldehyde (21 mg, 0.22 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (119 mg, 0.559 mmol), followed by stirring for 1 hour and 50 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was filtered through Celite. The solvent was distilled off by nitrogen stream to the filtrate. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[2-(4,4-dimethylcyclohexyl)phenyl]-4-furan-3-ylmethylpiperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled off by nitrogen stream. Hexane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant hexane solution was removed and the resulting solid was dried to give 31 mg of the title compound as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][OH:40])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:41](Br)[CH:42]=[CH2:43]>CN(C)C=O.O>[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][O:40][CH2:43][CH:42]=[CH2:41])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Sodium hydride (1.78 g. of 50 wt. % dispersion in mineral oil, 37 mmoles) was added at 60° C. to a solution of 1,2-di-O-(n-hexadecyl)-glycerol (10 g., 18.5 mmoles) in N,N-dimethylformamide (100 ml.), and the resulting solution stirred for 20 minutes at 60° C. Allyl bromide (4.47 g., 37 mmoles) was then added dropwise and the resulting mixture stirred for 3 hours at 90° C., cooled, cautiosly diluted with water (200 ml.) to quench the reaction, and extracted with ether (3×150 ml.). The combined ether extract was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene) [10 g., 93% yield, oil, n.m.r. (CDCl3) δ5.66-6.16 (m, 1, --OCH2CH=CH2), 5.25 (d of doublets, 2, --OCH2CH=CH2) and 4.03 (d, 2, --OCH2CH=CH2)].
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1ccccc1

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with benzoyl chloride (0.041 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) to obtain 0.0084 (24% yield) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])=O.[NH3:33].CO>>[C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])(=[O:2])[NH2:33]
Reactant: N
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)c(C)o1
Solvent: CO
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(N)=O)c(C)o1
Temperature: 90 °C
Reaction time: 34 h

Procedure:
A mixture of 2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-oxazole-4-carboxylic acid methyl ester (40 mg, 0.091 mmol) in a 7 M solution of ammonia in methanol (525 μL, 3.66 mmol) was stirred at 90° C. in a sealed tube. After 34 hours, the reaction was cooled to room temperature, vented, opened and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in methylene chloride to afford the title compound as white solid. MS m/z 423.89 (MH+).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=C(C)C=C[C:20]=1S([O-])(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O)CC.[N-:42]=[N+:43]=[N-:44].[Na+].CN(C)C=O>O>[N:42]([CH2:20][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCOCc1c(S(=O)(=O)[O-])ccc(C)c1OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCCO
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(CN=[N+]=[N-])COCc1ccccc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 72.5 %

Procedure:
A mixture of 16.3 g of 2-[(hexadecyloxy)methyl]-3-(phenylmethoxy)-4-methylbenzenesulfonate-1-propanol, 9.22 g of sodium azide and 130 ml of N,N-dimethylformamide is stirred at 80° C. for 3.5 hours and then at room temperature overnight. The mixture is poured into water and extracted with ether. The ether layer is dried and the solvent removed. The residue is purified by chromatography, to give 8.9 g of the desired compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[I:13][C:14]1[CH:15]=[C:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:13][C:14]1[CH:15]=[C:16]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[N:17]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH:18]=1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: O=C(c1cc(I)c[nH]1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(I)cc2C(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 33.4 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.63 g), 4-iodo-2-(trifluoroacetyl)pyrrole (0.89 g) and potassium carbonate (0.57 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4-iodo-1-(3-methyl-4-nitrobenzyl)-2-trifluoroacetyl-1H-pyrrole (0.45 g).
Reaction SMILES: ClC1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[NH:10][CH:11]([CH2:15]C2C=CC=CC=2)[C:12](O)=O)=[CH:4][CH:3]=1.C1C=C[C:26]2N(O)N=[N:29][C:27]=2C=1.CC[N:35]=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH3:26][C:27]1[N:10]2[C:9](=[O:22])[N:8]([CH:5]3[CH2:4][CH2:3][NH:35][CH2:7][CH2:6]3)[CH2:12][C:11]2=[CH:15][N:29]=1
Reactant: O=C(Nc1ccc(Cl)cc1)NC(Cc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Yield: 99.5 %

Procedure:
To a solution of 2-(N′-(4-chlorophenyl)ureido)-3-phenylpropanoic acid (0.16 g) obtained in Example 1b) and HOBt (0.12 g) in DMF (10 ml) was added WSC (0.14 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one (0.11 g) obtained in Reference Example 1 and N-methylmorpholine (0.08 ml) were added thereto. The reaction mixture was mixed at room temperature for 15 hours, and then the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=10/1). The product was washed with diethyl ether to obtain the title compound as colorless powder (0.13 g, 50%).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[N:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[ClH:1].[N:13]1([CH:19]2[CH2:24][CH2:23][N:22]([C:2]([Cl:1])=[O:4])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)N1CCC(N2CCCCC2)CC1
Temperature: 25 °C

Procedure:
Triphosgene (100 g) was dissolved in 1280 ml of methylene chloride. Solution of 129.5 g of 4-piperidinopiperidine was dissolved in 1280 ml of methylene chloride and this solution was added at 20-25° C. into the triphosgene solution while cooling the mixture (exothermic reaction). Part of the methylene chloride (1500 ml) was distilled off. Acetonitrile (580 ml) was added gradually. Methylene chloride was distilled off until the temperature rose to 63° C. Toluene (2000 ml) was added gradually. The mixture was cooled to room temperature. The crystalline compound was filtered and washed with toluene (about 1000 ml). The compound was dried under reduced pressure at about 40° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 82.9 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and diethylamine (0.40 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N,N-diethyl-2 (trifluoromethyl)benzenesulfonamide (0.46 g, 83%) was provided after purification. MS (ESI) m/z 360. HPLC purity 100.0% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [O:1]1[C:6]2=[N:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]2[CH2:4]CC1.[I:14]C.[CH3:16][C:17](=O)[CH3:18]>>[I:14][CH2:16][CH2:17][CH2:18][N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH3:4])[C:6]1=[O:1]
Reactant: c1ccc2c(c1)nc1n2CCCO1
Reactant: CI
Reactant: CC(C)=O
Product: Cn1c(=O)n(CCCI)c2ccccc21

Procedure:
To a solution of 5.7 parts of 3,4-dihydro-2H-[1,3]oxazino-[3,2-a]benzimidazole in 80 parts of 2-propanone is added 5.7 parts of iodomethane and the whole is stirred and refluxed for 2 h, 50. Then there is added a second portion of 5.7 parts of iodomethane and the whole is further stirred and refluxed for 2 h, 50. The solvent is evaporated, yielding 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([NH:48][C:7]([C:3]1[O:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccoc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccoc1C(=O)NCc1ccccc1
Reaction time: 16 h
Yield: 42.2 %

Procedure:
To a mixture of 3-methylfuran-2-carboxylic acid (0.79 g, 6.28 mmol), 1-hydroxybenzotriazole (1.27 g, 9.42 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.81 g, 9.42 mmol) in N,N-dimethylformamide (6 mL) was added N,N-diisopropylethylamine (3.30 mL, 18.94 mmol) and benzylamine (0.69 mL, 6.28 mmol). The reaction mixture was stirred for 16 hours, and then diluted with ethyl acetate (75 mL). The organic layer was washed with 10% aqueous hydrochloric acid (2×25 mL), saturated aqueous sodium bicarbonate (2×25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford N-benzyl-3-methylfuran-2-carboxamide as a light brown solid (0.57 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 7.27 (d, J=1.5 Hz, 1H), 6.61 (br s, 1H), 6.34 (d, J=1.5 Hz, 1H), 4.59 (d, J=5.9 Hz, 2H), 2.42 (s, 3H); MS (ES+) m/z 216.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][CH2:9][C:10]2[C:14]([C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=[O:18])=[C:13]([CH3:23])[O:12][N:11]=2)=[CH:5][CH:4]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:17]([C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]2[C:10]([CH2:9][O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=3)=[N:11][O:12][C:13]=2[CH3:23])[OH:18])=[CH:29][CH:28]=1
Reactant: COc1ccc(COCc2noc(C)c2-c2ccccc2C=O)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(COCc2noc(C)c2-c2ccccc2C(O)c2ccc(Cl)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round bottomed flask was added 2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)benzaldehyde (94 mg, 0.279 mmol) and THF. The solution was cooled to −78° C. before addition of (4-chlorophenyl)magnesium bromide solution (418 μl, 1M in THF, 0.418 mmol) and the reaction stirred at −78° C. for 30 min. The solution was quenched via the addition of water and warmed to room temperature. The aqueous was extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-chlorophenyl)(2-(3-((4-methoxybenzyloxy)methyl)-5-methylisoxazol-4-yl)phenyl)methanol. LC/MS m/z 450 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cncc(Br)c1Cl
Reactant: NC1CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cncc(Br)c1NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 2 (8.01 g, ca. 30 mmol) in dichloromethane (100 ml) at 0° C. was added cyclopropylamine (4.16 ml, 60 mmol) drop-wise. The resulting mixture was stirred overnight at room temperature, then concentrated under vacuum to a residue and re-dissolved in ethyl acetate, basifying with sodium bicarbonate. The organic phase was washed with water three times, followed by twice with brine before concentrating under vacuum to a crude solid. This oil was purified by column chromatography eluting with a gradient of 50% DCM/hexane to DCM affording product as a yellow solid, 6.22 g (80%); MS (ES+) m/e 258/260 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:33][CH3:34])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH:26]5[CH2:30][NH:31][CH2:32][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CO.[CH2:37](Cl)Cl.C=O>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:33][CH3:34])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH:26]5[CH2:30][N:31]([CH3:37])[CH2:32][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClCCl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC2CNCC21
Agent: C=O
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC2CN(C)CC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(octahydro-1H-pyrrolo[3,4-b]pyridin-1-yl) propoxy)quinazolin-4-amine (0.45 g) in the mixture solvent of MeOH and CH2Cl2 (1:1) was added 37% HCHO (1.00 mL) and acetic acid (0.50 mL) dropwise. The reaction mixture was stirred for 30 min at room temperature, NaB(OCOCH3)3H (1.50 g) was added in portions. The reaction mixture was stirred for another 2 h at room temperature, poured into water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.60 g, 70.00%), HPLC: 98.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 500.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.82 (m, 1H), 2.33 (m, 4H), 1.94 (m, 1H), 2.19-2.20 (m, 2H), 2.50-2.52 (m, 1H), 2.67-2.70 (m, 2H), 3.58 (s, 3H), 4.01-4.02 (m, 2H), 4.03-4.04 (m, 5H), 4.05-4.07 (m, 1H), 4.40 (s, 2H), 7.44 (s, 1H), 7.50 (t, J=4.8 Hz, 1H), 7.83-7.88 (m, 1H), 8.07-8.08 (m, 1H), 8.89-8.91 (m, 1H), 9.05 (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH:9]([C:11]([O:13]C)=O)[NH2:10].[CH:15](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH:15]=[N:10][NH:9][C:11]2=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cccc(Br)c1
Reactant: COC(=O)NN
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]ncn1-c1cccc(Br)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 3-bromoaniline (1.0 mL, 9.18 mmol), methyl hydrazinocarboxylate (788 mg, 8.75 mmol), triethyl orthoformate (0.96 mL, 8.75 mmol), and TsOH (25 mg) in MeOH (20 mL) was stirred at 65° C. for 3 hr. After cooling to room temperature, NaOMe (1.47 g, 26.2 mmol) was added and the mixture stirred at room temperature for 16 hr. After concentration in vacuo the residue was taken up in EtOAc and H2O then acidified with 1N HCl. The aqueous phase was extracted with EtOAc and the combined organics washed with H2O then extracted twice with 1N NaOH. Combined NaOH extracts were acidified with conc. HCl and aged 5 min. Resulting solids were collected by filtration, washed with H2O and dried to give 4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.42-7.46 (m, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 8.43 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.II.[Mg].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>CO.C1(C)C=CC=CC=1.CCOCC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:21]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=2)=[NH:22])=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: N=C(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Yield: 68.2 %

Procedure:
One part of 4-bromobenzotrifluoride (12.4 g, 55 mmol) and a small quantity of iodine were added to an Et2O suspension (10 mL) of magnesium (1.34 g, 55 mmol) under an argon atmosphere. And, they were heated appropriately. After the reaction start was observed, the remaining Et2O solution (15 mL) of the remaining 4-bromobenzotrifluoride was added slowly. After heat refluxing for one hour, a toluene solution (10 mL) of 4-(trifluoromethyl)benzonitrile (11.8 g, 86 mmol) was added slowly at room temperature. After heat refluxing for 20 hours, anhydrous methanol (12 mL) was added slowly at room temperature. And, the stirring-up was conducted for thirty minutes. Insoluble compounds were removed with the celite filtering. The filtrate was concentrated under reduced pressure. Thereafter, the obtained crude product was distillated under reduced pressure. And, the target product (11.9 g, 75%) was obtained. After distillation, the product was solidified.