Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:18]=[C:19]2[CH:25]=[C:24]([C:26](O)=[O:27])[N:23]([CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[C:20]2=[N:21][CH:22]=1>>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:6]=[CH:7][C:2]=1[NH:1][C:26]([C:24]1[N:23]([CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[C:20]2=[N:21][CH:22]=[C:17]([C:16]([F:15])([F:36])[F:37])[CH:18]=[C:19]2[CH:25]=1)=[O:27]
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1ccncc1
Reactant: COc1cc(N2CCCC2)ncc1N
Product: COc1cc(N2CCCC2)ncc1NC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1ccncc1

Procedure:
The method described in Example 12.3 is followed, starting from 5-amino-4-methoxy-2-(pyrrolidin-1-yl)pyridine, prepared in the preceding stage, and 5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid prepared in Stage 9.2.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18][O:19][CH3:20])=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][C:11]1[NH:10][C:9]2[C:8](=[O:14])[N:7]3[C:15]([CH2:18][O:19][CH3:20])=[N:16][N:17]=[C:6]3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=2[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCn1c2nc[nH]c2c(=O)n2c(COC)nnc12
Solvent: C1CCOC1
Product: CCCCn1c2nc(Br)[nH]c2c(=O)n2c(COC)nnc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The mixture of 9-butyl-3-(methoxymethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (6 mg, 21.7 mmol), N-bromosuccinimide (4.64 mg, 26.0 mmol) in tetrahydrofuran (10 ml) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by prep LCMS to yield the desired product. LCMS calculated for C13H18BrN6O2 (M+H): 369.1. Found 371.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20]>C(=O)(O)[O-].[Na+].ClCCl>[NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1nc(C2CCNCC2)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)N1CCC(c2cnc(N)c(C(=O)OC)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a rapidly stirring biphasic solution of methyl 3-amino-6-(4-piperidyl)pyrazine-2-carboxylate (135 mg, 0.57 mmol) in 50% saturated sodium bicarbonate and dichloromethane (20 mL) at 25° C. was added propanoyl chloride (79 mg, 75 μL, 0.86 mmol) dropwise. The reaction was stirred at room temperature for 30 minutes. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to provide methyl 3-amino-6-(1-propionylpiperidin-4-yl)pyrazine-2-carboxylate (111 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.19 (s, 2H), 4.51 (d, J=12.9 Hz, 1H), 3.95 (d, J=13.6 Hz, 1H), 3.84 (s, 3H), 3.08 (t, J=12.2 Hz, 1H), 2.88 (ddd, J=15.5, 7.9, 3.7 Hz, 1H), 2.61 (t, J=11.7 Hz, 1H), 2.34 (q, J=7.5 Hz, 2H), 1.80 (t, J=13.7 Hz, 2H), 1.69-1.39 (m, 2H), 1.00 (t, J=7.4 Hz, 3H). LC/MS m/z 293.5 [M+H]
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O.CC(C)=O>O>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: O=C1CNC2(CCCCC2)N1
Reactant: CC(C)COC(=O)CC1CO1
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)CN1CC(O)CC1=O
Reaction time: 11 h

Procedure:
1 g of 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (8.70 mmoles) is dissolved in 1 ml water. 1.5 g 2-methylpropyl 3,4-epoxybutanoate ((4); X=isobutyl) (9.48 mmoles) are added and the mixture is heated at 50° for 11 h with stirring by a magnetic stirrer. Heating is then continued at the boiling point for a further 11 h. The mixture is cooled, 10 ml acetone is added, stirring is performed for 30 min and the mixture is filtered. The product obtained is crystallised from methanol to give oxiractam of m.p. 167°-70° C. as a white crystalline powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[CH:13]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.[CH3:29][CH2:30][OH:31]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:30]([O:31][C:5]1[C:6]([OH:8])=[CH:7][C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[CH:13]=2)[CH:4]=1)[C:29]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CCO
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: Oc1ccc2oc(-c3cc(OCc4ccccc4)c(O)cc3-c3ccccc3)cc2c1

Procedure:
Compound 102 (0.23 g, 7.9 mmol) in a solution consisting of Tol/EtOH/2M Na2CO3 aq (15 mL/2 mL/15 mL) was treated with 4-benzloxy phenylboronic acid (0.12 g, 1.0 mmol) and cat Pd(PPh3)4 and heated to reflux until TLC analysis indicated complete reaction. The reaction mixture was treated with 2 N HCl aq and extracted with EtOAc. The EtOAc layer was washed with saturated NaHCO3 aq, brine and dried over MgSO4. After filtration, the residue was chromatographed on silica gel (1:4 EtOAc/hexanes) to yield the desired product as an orange solid. The orange solid thus obtained was triturated with CH2Cl2 to yield the pdt (2.4 g) as a white solid: Mp=186–187° C.; 1H NMR (DMSO-d6) δ 9.90 (br s, 1 H), 9.05 (br s, 1 H), 7.65 (d, 1 H, J=8.5 Hz), 7.51–7.31 (m, 5 H), 7.19 (d, 1 H, J=8.5 Hz), 7.17 (d, 2 H, J=8.6 Hz), 7.02 (d, 2 H, J=8.7 Hz), 6.86 (dd; 1 H, J=8.5 Hz, 2.4 Hz), 6.70 (d, 2 H, J=1.8 Hz), 6.63 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 5.86 (s, 1 H), 5.14 (s, 2 H); MS 407 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[F:15][C:16]1[CH:17]=[C:18]([NH2:31])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].O>CN(C)C(=O)C>[F:15][C:16]1[CH:17]=[C:18]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)c(F)c1)C(F)(F)F
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.71 g, 4.5 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.54 g, 4.5 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 3-Fluoro-4-(phenyl sulfonyl)benzeneamine (0.75 g, 3.0 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered through Celite. The Celite was washed with methylene chloride (75 mL), the organic extract dried (MgSO4) and concentrated in vacuo to a tan solid. Purification by flash column chromatography (5% v/v ethyl acetate/methylene chloride) yielded the title propanamide as a white solid (0.79 g, 68%); mp 147°-149° C. 1H-NMR (250 MHz, d6-DMSO): 1.58 (s, 3H, CH3) 7.65-7.69 (m, 4H, aromatic+OH) 7.74 (d, 1H, J=7.2 Hz, aromatic) 7.83-7.94 (m, 3H, aromatic) 8.02 (t, 1H, J=8.3 Hz, aromatic) 10.61 (s, 1H, NH). MS (CI, CH4): 392 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-[4-nitro-3-(trifluoromethyl)phenyl]-1-ethanone (1.41 g, 6.05 mmol), Fe powder (1.69 g, 30.2 mmol), and NH4Cl (324 mg, 6.05 mmol) in EtOH (24 ml) and water (9 ml) was heated to reflux for 2.5 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite and the filtrate was concentrated. And the residue was dissolved with ethyl acetate (100 ml), washed with water (100 ml), dried over MgSO4, and concentrated in vacuo to give 1.22 g (quant.) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:56]1[CH2:61][CH2:60][CH:59]([C:62]2[C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][C:65]=3[O:64][N:63]=2)[CH2:58][CH2:57]1>CN(C=O)C>[O:64]1[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=2[C:62]([CH:59]2[CH2:60][CH2:61][N:56]([C:21](=[O:22])[CH2:20][N:10]3[C:11]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)=[N:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9]3)[CH2:57][CH2:58]2)=[N:63]1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCC(c2noc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.4 %

Procedure:
32 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 32 mg TBTU and 26 μL DIPEA were added to this solution and the mixture was stirred for 5 minutes at RT. Then, 24 mg 3-piperidin-4-yl-benzo[d]isoxazolehydrochloride was added. The mixture was stirred for 2 h at RT. The reaction solution was purified by HPLC to yield 19.8 mg of the desired compound. Rt: 2.24 (method D), (M+H)+: 500
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[NH:13][C:12](=[O:21])[C:11]1=[O:22])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].F[B-](F)(F)F.[O:28]=[N+:29]=[O:30].O>C(Cl)Cl>[CH2:6]([O:5][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:29]([O-:30])=[O:28])=[C:17]([F:20])[CH:18]=2)[NH:13][C:12](=[O:21])[C:11]1=[O:22])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2ccc(F)cc21)OCC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
615 mg of (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is mixed in 60 ml of methylene chloride with 743 mg of nitronium tetrafluoroborate. The batch is stirred for 2 hours at room temperature. It is mixed with 50 ml of water and, after separation of the organic phase, it is extracted three times with methylene chloride. The collected organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 350 mg of (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6](=[O:17])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=1.[CH3:19]O.[H][H]>[Pd]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:19]=2)[C:6]1=[O:17]
Reactant: COC(=O)CC1=CCN(Cc2ccccc2)C1=O
Reactant: [H][H]
Reactant: CO
Agent: [Pd]
Product: COC(=O)CC1CCN(CCc2ccccc2)C1=O
Yield: 95 %

Procedure:
30 mg of (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid methyl ester was dissolved in methanol solution (0.12 mmol) under nitrogen atmosphere. Then 2.6 mg of Pd—C (0.02 mmol) was added thereto, and hydrogenated under a hydrogen balloon for 1 to 2 hrs at room temperature. The reaction mixture was filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with BtOAc and hexane (1:1) as an eluant to give (2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetic acid methyl ester (25r) (yield: 95%).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=4[Cl:39])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)=[O:8])(=[NH:5])[NH2:4].C1COCC1.[ClH:45]>CCO>[ClH:39].[ClH:45].[C:3]([NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=4[Cl:39])[CH2:27][CH2:28]3)=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)=[O:8])(=[NH:4])[NH2:5]
Reactant: COC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CNC(=O)NC(=N)N)c4)cn3)CC2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N=C(N)NC(=O)NCc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4Cl)CC3)nc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1M aqueous NaOH solution was added to a mixture of methyl 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate (208 mg), THF (2 ml), and EtOH (2 ml), followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized with 1M hydrochloric acid, and the precipitated solid was collected by filtration. A 4M hydrogen chloride/dioxane solution (1 ml) was added to a mixture of the obtained solid and dioxane (3 ml), followed by stirring at room temperature overnight. The insoluble matter was collected by filtration to obtain 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoic acid dihydrochloride (112 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([OH:15])[C@H:13]([CH2:16][OH:17])[C@@H:12]([OH:18])[C@H:11]([OH:19])[C@H:10]2[OH:20])=[CH:5][C:4]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1.[CH3:30][C:31]#N.[CH3:33]O>CC(C)=O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@H:14]3[O:15][C:31]([CH3:30])([CH3:33])[O:17][CH2:16][C@@H:13]3[C@@H:12]([OH:18])[C@H:11]([OH:19])[C@H:10]2[OH:20])=[CH:5][C:4]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=1
Reactant: CO
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]3O)ccc2Cl)cc1
Reactant: CC#N
Agent: Cl
Solvent: CC(C)=O
Product: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@H]4COC(C)(C)O[C@@H]43)ccc2Cl)cc1
Reaction time: 8 h
Yield: 75.3 %

Procedure:
1N HCl (5 mL) was added dropwised into the solution of (1R,2R,3S,4R,5R,6S)-4-(4-chloro-3-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)cyclohexane-1,2,3,5-tetraol (5, R=Et, 1 g, 2.46 mmol) in MeOH (80 mL) and acetone (20 mL), and stirred overnight, then the mixture was evaporated to dryness. The residue was purified by preparative HPLC to give the target compound (864 mg, white solid, yield of 75.3%). 1H-NMR (400 MHz, CD3COCD3): δ 7.26-7.29 (2H, m), 7.10-7.16 (5H, m), 3.74-4.21 (6H, m), 3.46-3.51 (1H, m), 3.35-3.37 (1H, m), 2.56-2.66 (3H, m), 1.72-1.75 (1H, m), 1.28 (3H, s), 1.18 (3H, t, J=7.6 Hz), 1.13 (3H, s); MS (ESI+): 447 [M+H]+, 488 [M+H+CH3CN]+, 910 [2M+NH4]+, 491 [M+HCOO]−, 937 [2M+HCOO]−.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)cnc1Cl

Procedure:
To a suspension of 2-chloro-5-(trifluoromethyl)nicotinic acid (1.147 g, 4.83 mmol) in DCM (20 mL) was added oxalyl chloride (630 L, 7.35 mmol) dropwise with stirring. A single drop of DMF was added and the reaction mixture was stirred 40° C. for 1 hour. Concentration of the reaction mixture in vacuo resulted in the title compound as a brown oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:23])([CH3:24])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (15 g, 38.7 mmol) in methanol (50.0 mL) and tetrahydrofuran (50.0 mL) was added 50% sodium hydroxide in water (8.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (12.5 g, 90%) as a light yellow solid: LC/MS m/e calcd for C18H18BrNO2 (M+H)+: 361.25, observed: 360.0 & 362.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>[Br:13][CH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Methyl 4-methylsalicylate (98.1 g, 590 mmoles) was dissolved in carbon tetrachloride (600 mL), and N-bromosuccinimide (105.0 g, 590 mmoles) and benzoyl peroxide (0.7 g, 3 mmoles) were added. The mixture was refluxed under nitrogen. After 2 hours, an additional portion (0.7 g) of N-bromosuccinimide was added. Reflux was continued for 16 hours. The reaction mixture was cooled to room temperature and the solid removed by filtration. The yellow filtrate was evaporated to dryness to afford a thick yellow syrup that solidified on standing. Hexanes (500 mL) was added to the solid, and the mixture was boiled until almost all solids dissolved. The hot hexanes solution was filtered and concentrated until a solid just began to precipitate. The mixture was heated to dissolve the solid, and the solution was allowed to cool slowly to room temperature. Pale yellow crystals formed slowly. The mixture was then chilled in ice for 2 hours to complete crystallization. Finally, the solid was filtered, washed with cold hexanes (100 mL), and dried in vacuo to afford 83.5 g (58% yield) of methyl 4-bromomethylsalicylate (m.p. 73°-75° C., open capillary, uncorrected).
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:29])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16])[C:11]([OH:13])=[O:12]>C(Cl)Cl>[C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C@H:10]2[C:11](=[O:13])[O:12][C@H:9]2[CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
In a two necked round bottom flask, Et3N (0.34 ml, 2.42 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-({[(5-phenylpentyl)oxy]carbonyl}amino)-butanoic acid (0.25 g, 0.81 mmol) in dry CH2Cl2 (10 mL) under argon. After cooling at 0° C., HTBU (0.46 g, 1.21 mmol) was added and the mixture stirred 3 h at 0° C., then 16 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography eluting with Cy/AcOEt (from 98:2 to 80:20). The title compound (0.107 g, 45%), was obtained as white solid, which was further triturated with cyclohexane. MS (ESI) m/z: 290.21 [M−H]−. FTIR (cm−1): 3330, 3064, 3027, 2936, 2858, 1849, 1695, 1540, 1387, 1333, 1262, 1129, 1076, 1023, 985, 921, 845, 822, 741, 697. 1H NMR (CDCl3): δ 1.38 (m, 2H); 1.44 (d, 3H); 1.62-1.67 (m, 4H); 2.62 (t, 2H); 4.05-4.13 (m, 2H); 4.86 (m, 1H); 5.44 (t, 1H); 5.33 (d, 1H); 7.16-7.19 (m, 3H); 7.25-7.29 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:31]=4)=[O:28])=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:40]#[N:41])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O.C(OCC)(=O)C>[C:40]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:41]
Reactant: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCc5ccccc5)c(C#N)cc34)cc2)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(O)c(C#N)cc34)cc2)c1
Temperature: 65 °C
Reaction time: 19 h
Yield: 72 %

Procedure:
After dissolving N-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea (1.43 g, 2.5 mmol) in trifluoroacetic acid (10 ml) and thioanisole (1.17 ml, 10 mmol) under a nitrogen atmosphere, the solution was stirred at 65° C. for 19 hours. The reaction solution was concentrated under reduced pressure, and after adding 5% aqueous sodium bicarbonate (30 ml) and ethyl acetate (50 ml) to the obtained residue and stirring, the precipitated crystals were filtered out, washed with water and ethyl acetate and dried under reduced pressure. The organic layer of the filtrate was separated, washed with saturated brine and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a yellow crystalline residue. This was combined with the previous crystals, suspended in ethyl acetate (40 ml) and subjected to sonication, and then the crystals were filtered out, washed with diethyl ether and dried at 60° C. to obtain the title compound (862 mg, 1.8 mmol, 72.7%) as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH3:18])[N:17]=[C:13]3[NH:12][C:11]([CH3:19])=[C:10]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5][CH:4]=1)#[N:2].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH3:18])[N:17]=[C:13]3[N:12]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=3)[C:11]([CH3:19])=[C:10]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc(C)nn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(C)nn2C1c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
(rac)-Ethyl 7-(4-cyanophenyl)-2,5-dimethyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (50 mg, 0.15 mmol), 3-(trifluoromethyl)phenylboronic acid (88 mg, 0.46 mmol, 3 eq.), anhydrous copper(II) acetate (140 mg, 0.77 mmol, 5 eq.) and molecular sieve (80 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (4 ml), pyridine (125 μl, 1.55 mmol, 10 eq.) and triethylamine (108 μl, 0.77 mmol, 5 eq.) were added. After 24 h of stirring, the mixture was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.05% TFA). After lyophilization, the product was obtained as a solid (4.5 mg, 6% of theory).