Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([N:18]2[CH2:23][C@@H:22]([CH3:24])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=3)[CH2:20][C@@H:19]2[CH3:37])=[O:17])[CH:12]=[CH:11][N:10]=1>N1C=CC=CC=1>[C:5]([NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([N:18]2[CH2:23][C@@H:22]([CH3:24])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=3)[CH2:20][C@@H:19]2[CH3:37])=[O:17])[CH:12]=[CH:11][N:10]=1)(=[O:7])[CH3:6]
Reactant: C[C@@H]1CN(C(=O)Nc2ccnc(N)n2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nccc(NC(=O)N2C[C@@H](C)N(c3ccc(C#N)c(C(F)(F)F)c3)C[C@@H]2C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 1.2 ml portion of acetic anhydride was added to 10 ml of pyridine solution containing 0.51 g of (+/−)-trans-N-(2-amino-pyrimidin-4-yl)-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethylpiperazine-1-carboxamide synthesized in the same manner as described in Example 21, and the mixture was stirred at room temperature for about 12 hours and then heated at 70° C. for about 1 hour. The reaction solution was evaporated under reduced pressure, and the thus obtained residue was mixed with 0.5 N aqueous sodium hydroxide and extracted with chloroform. The thus obtained organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the crude product obtained by evaporating the solvent was separated by a silica gel column chromatography to obtain 0.46 g of the title compound from chloroform-methanol-28% aqueous ammonia (500:9:1, v/v/v) eluate. Thereafter, this was crystallized from ethyl acetate-hexane solution to obtain 0.31 g of white crystals.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][C@@H:3]([CH2:11][OH:12])[C@@H:2]1[CH2:13][OH:14].[H-].[Na+].[CH3:17]N(C=O)C>>[CH3:17][O:12][CH2:11][C@@H:3]1[O:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1][C@H:2]1[CH2:13][OH:14]
Reactant: CN(C)C=O
Reactant: OC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Agent: [H-]
Agent: [Na+]
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.03 %

Procedure:
(2S,3S)-1,4-dioxaspiro[4.5]decane-2,3diyldimethanol (65 g, 321.4 mmol) was dissolved in DMF (500 mL) and cooled in an ice bath. 60% Sodium hydride (15.43 g, 385.7 mmol) was added slowly and the reaction was stirred for 30 minutes in an ice bath then warmed to ambient temperature for 2 hours. Idomethane (20.05 ml, 321.4 mmol) was added and the reaction was stirred at ambient temperature overnight. The majority of the DMF was removed on a rotary evaporator, and the residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified over 1 Kg of SiO2 (20 to 40% EtOAc in hexanes) to afford ((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-yl)methanol (3.13 g, 144.7 mmol, 45.03% yield) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9](=[CH:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:8][C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:1][C:2]1[C:11]2[O:10][C:9](=[CH:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:8][C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC(=CN2CCOCC2)Oc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC(=CN2CCOCC2)Oc2c(OCc3ccccc3)cccc21
Temperature: 70 °C
Yield: 70 %

Procedure:
8-Hydroxy-2-(4-morpholinylmethylene)-4H-1-benzopyran-4-one (261 mg, 1 mmole) is suspended in 7 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension is treated successively with potassium carbonate (829 mg, 6 mmole) and benzyl bromide (150ul, 1.3 mmole) and the reaction mixture is warmed to 70° C. for 1 h. The mixture is cooled to room temperature and the acetonitrile is removed in vacuo. The residue is washed with 1×25 ml dichloromethane and the insoluble material is removed by filtration. The filtrate is concentrated in vacuo to a yellow oil. The oil is chromatographed over 15 g silica gel (230-400 mesh)eluting with 3% methanol/dichloromethane and collecting 6 ml fractions. Fractions 12-27 are combined and concentrated to afford a colorless oil which is crystallized from diethyl ether to provide 246 mg (70%) of the title compound as a white solid, mp. 107°-107.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(Cl)cc(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3,5-dichlorophenylboronic acid according to the coupling protocol of example 1. 1H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.16 (dd, J=8.7, 2.3 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.84 (m, 1H), 6.82 (m, 2H), 3.28 (s, 3H), 2.00 (m, 2H), 1.92 (m, 2H), 0.82 (t, J=7.4 Hz, 6H); MS (ESI) m/z 379/381/383 ([M+H]+); MS (ESI) m/z 377/379/381 ([M−H]−); Anal. calcd for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 60.10; H, 5.26; N, 7.26.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][C:20](C2C=CC=CC=2)(C2C=CC=CC=2)[C:21]2[CH:26]=CC=CC=2)=[CH:17][CH:18]=1)[C:5]([OH:15])([C:10]#[C:11][CH:12]1[CH2:14][CH2:13]1)[C:6]([F:9])([F:8])[F:7].N1C=CC=CC=1.BrCCC(Br)=[O:49]>CCOCC>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[NH:19][C:20](=[O:49])[C@H:21]([CH3:26])[O:15][C@:5](/[CH:10]=[CH:11]/[CH:12]3[CH2:14][CH2:13]3)([C:6]([F:9])([F:8])[F:7])[C:4]=2[CH:3]=1
Reactant: O=C(Br)CCBr
Reactant: OC(C#CC1CC1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred ice-cooled solition of 291 mg of trans-6-Amino-3-chloro-α-cyclopropylethenyl-α-(trifluoromethyl)benzyl alcohol (from Example 5, Part C.) in 13 mL of dry ether was added 0.180 mL of dry pyridine and 0.120 mL of bromopropionyl bromide. After 1 h, the reaction mixture was diluted with ether, washed with water and aqueous sodium bicarbonate, dried and evaporated. The residue was dissolved in 10 mL of dry DMF and was treated at 0° with 40 mg of 100% sodium hydride. After 15 min the cooliing bath was removed and stirring was continued at ambient temperature for 20 h. The reaction was poured onto aqueous ammonium chloride and extracted with ether. The ether layer was washed with brine, dried and evaporated. The residie was dissolved in a small amount of ethyl acetate, and addition of hexane resulted in the crystallization of 40 mg of the title compound as colorless crystals: mp 171-172°; HRMS: Calcd. for C16H16NO2ClF3 (M+H)+ : 346.082166. Found: 346.080681. A second crop of slightly less pure product weighed 41 mg.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:20]([O:22]CC)=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>OS(O)(=O)=O.O.CC(O)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cn(C2CCOCC2)c2cc(F)c(F)c(N)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CCOCC1
Temperature: 0 °C
Yield: 80.3 %

Procedure:
A suspension of ethyl 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylate (70.0 mg, 0.199 mmol) in a mixture of H2SO4/H2O/AcOH (1:5:6, 3 mL) was heated under reflux for 1 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were washed with water, and dried in vacuo to give 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylic acid (51.8 mg, 80%) as a yellow powder.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[CH:6]=1.[H][H]>C(O)C.[Pt]=O>[C:15]([NH:14][C:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][NH:11][C:10]2=[CH:9][N:8]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1cc(C=CN(C)C)c([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)Nc1cc2cc[nH]c2cn1
Yield: 33.3 %

Procedure:
N,N-Dimethyl-2-(2-acetylamino-5-nitropyridin-4-yl)ethenamine (6 g, 24 mmol) was hydrogenated over platinum oxide (0.5 g) in ethanol (120 mL) at 35 psi of hydrogen for 15 min. The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed on silica eluting with a gradient of 5 to 10% MeOH in DCM to afford a purple solid. This was triturated with ether and the precipitate collected by filtration to give the title compound (1.4 g, 33%) as a beige solid. mp 220° C. (dec.). 1H NMR (360 MHz, d6 -DMSO) δ 2.07 (3H, s), 6.45 (1H, s), 7.55-7.57 (1H, m), 8.21 (1H, s), 8.46 (1H, s), 10.16 (1H, br s) and 11.42 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)CC(=O)N2
Yield: 68.8 %

Procedure:
5-Nitro-1,3-dihydro-indol-2-one 30b (3.56 g, 20 mmol) was dissolved in 200 ml of acetic acid under stirring, and added with palladium on activated carbon (1.0 g, 5%) to the solution at room temperature. The reaction mixture was stirred under a hydrogen atmosphere. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered, and concentrated under reduced pressure to obtain the title compound 5-amino-1,3-dihydro-indol-2-one 30c (2.04 g, yield 68.9%) as a white solid.
Reaction SMILES: BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:22][C:23]1[C:24]([C:39]([NH:41][NH2:42])=[O:40])=[N:25][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:31][CH2:30]2)=[CH:27][N:28]=1.[Br:43][CH2:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=O)=[CH:47][CH:46]=1.CCN(C(C)C)C(C)C>CC#N.C(OCC)(=O)C>[NH2:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]2)=[N:25][C:24]=1[C:39]1[O:40][C:49]([C:48]2[CH:52]=[CH:53][C:45]([CH2:44][Br:43])=[CH:46][CH:47]=2)=[N:42][N:41]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CCC(=O)N1CCC(c2cnc(N)c(C(=O)NN)n2)CC1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(=O)N1CCC(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Reaction time: 1 h

Procedure:
Dibromo(triphenyl)phosphorane (682 mg, 1.6 mmol) was added to a suspension of 3-amino-6-(1-propanoyl-4-piperidyl)pyrazine-2-carbohydrazide (105 mg, 0.36 mmol) and 4-(bromomethyl)benzoic acid (77 mg, 0.36 mmol) in MeCN (2 mL) at room temperature and the resulting solution was stirred for 1 h under an atmosphere of nitrogen. DIPEA (278.5 mg, 375.3 μL, 2.155 mmol) was added dropwise and the solution was stirred for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4, filtered, concentrated in vacuo to obtain 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-1-piperidyl]propan-1-one, which was taken to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:19](F)=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:22])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][S-:30].[Na+].Cl>O1CCCC1>[F:1][C:2]1[C:19]([S:30][CH3:29])=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6]([C:5](=[O:22])[C:4]=2[CH:3]=1)=[CH:7][C:8]1[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:14]=3
Reactant: O=C1c2cc(F)c(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: C[S-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1cc2c(cc1F)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
1 g (3.4 mmol) of 2,3-difluoronaphthacene-5,12-dione, 0.94 g (6.8 mmol) of potassium carbonate, 0.47 g (6.8 mmol) of sodium methanethiolate and 20 ml of tetrahydrofuran are stirred at 25° C. for 2.5 hours. The mixture is poured into dilute hydrochloric acid and extracted with THF/toluene. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with toluene. Yield 0.55 g (50%); melting point 230°-235° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]C.[C:7]([O:12]CC)(=O)[CH:8]([CH3:10])O>>[OH:12][CH:7]=[CH:8][C:10]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CCCCCC
Reactant: CCOC(=O)C(C)O
Product: OC=Cc1ccccc1

Procedure:
A solution prepared by dissolving 10.0 g of a poly(hydroxystyrene) resin having a weight-average molecular weight of 20000 with a dispersion of the molecular weight distribution Mw /Mn of 1.1 (VP-20000, a product by Nippon Soda Co.), which contained a few % by weight or less of unpolymerized monomer and oligomers having a molecular weight smaller than 1000, in 40 g of ethyl lactate was taken in a separatory funnel and admixed with 150 g of n-hexane and the mixture was thoroughly shaken followed by standing to effect phase separation into an upper layer of the n-hexane solution and lower layer of the ethyl lactate solution. The n-hexane solution as the upper layer was discarded and the ethyl lactate solution as the lower layer was again admixed with 150 g of n-hexane followed by vigorous shaking of the mixture. This fractionating extraction with n-hexane was repeatedly undertaken four times and the finally obtained ethyl lactate solution was subjected to replacement of solvent with methyl alcohol by repeating evaporation of ethyl lactate and addition of methyl alcohol. The thus obtained methyl alcohol solution was added dropwise into a large volume of water to effect precipitation of the polymer which was collected, washed with pure water and dried to give a poly(hydroxystyrene) resin substantially free from unpolymerized hydroxystyrene monomer and oligomers having a molecular weight smaller than 1000 as confirmed by the GPC method. Since the content of the low molecular weight fractions in the starting resin was relatively low, no significant changes were found in the weight-average molecular weight and in the dispersion of the molecular weight distribution.
Reaction SMILES: BrC1C=C2C(=CC=1)C[C@@H](NC(=O)C1C=CC(OC[C@@H]3CCCO3)=CC=1)CC2.C(=O)=O.C[Li].C([Li])CCC.[CH:38]([C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[CH2:46][C@H:45]([NH:50][C:51](=[O:65])[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][C@@H:60]3[CH2:64][CH2:63][CH2:62][O:61]3)=[CH:54][CH:53]=1)[CH2:44][CH2:43]2)=[O:39].BrC1C=C2C(=CC=1)C[C@H](NC(=O)C1C=CC(OC[C@@H]3CCCO3)=CC=1)CC2>O.C(O)(=O)C.CN(C=O)C.C1COCC1>[CH:38]([C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[CH2:46][C@@H:45]([NH:50][C:51](=[O:65])[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][C@@H:60]3[CH2:64][CH2:63][CH2:62][O:61]3)=[CH:54][CH:53]=1)[CH2:44][CH2:43]2)=[O:39]
Reactant: O=Cc1ccc2c(c1)CC[C@@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Agent: O=C(N[C@@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Agent: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C
Reaction time: 0.01 h

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (10.0 g) and THF (130 ml) was cooled to −78° C. (dry ice bath) and a solution of methyl lithium (18.9 ml; 1.6 M in diethyl ether) was added dropwise. One minute after the addition had ended, a solution of butyllithium (13.9 ml; 2.5 M in toluene) was added dropwise. One minute after the addition had ended, DMF (5.1 g) was added, and, after a further 30 seconds, acetic acid (4.5 ml). After warming to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 379.46 (C23H25NO4); MS (ESI): 380 (M+H+). In an analogous manner, N-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide was prepared from N-((R)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].B(OB=O)=O.[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=O.C(OC)(OC)OC.C(N)CCC.Cl>C(OCC)(=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=BOB=O
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Solvent: CCCCN
Product: CC(=O)CC(=O)C=Cc1cc(O)ccc1Br
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
Ethyl acetate (3.1 mL), 2,4-pentanedione (4.25 mL, 41.4 mmol) and boron trioxide (2.6 g, 38 mmol) was placed in a 200 mL reaction vessel with a reflux condenser. To the stirring mixture at 85° C. was added dropwise a solution of 2-bromo-5-hydroxybenzaldehyde (1.26 g, 6.27 mmol) and trimethyl orthoformate (0.70 mL, 6.4 mmol) in 6 mL of ethyl acetate. After the reaction mixture was stirred for 30 min at 95° C., n-butylamine (3.1 mL, 31 mmol) was added dropwise with additional stirring for 2 h. The reaction mixture was cooled to 50° C. before addition of 3N HCl (15 mL). After being stirred at 50° C. for 30 min, the mixture was filtered to remove solids. The filtrate was diluted with ethyl acetate, washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) twice followed by recrystallization (hexane/ethyl acetate) to obtain the title compound as a yellow crystal (0.12 g, 7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][S:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCCCCC.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:19]=2[CH3:18])[CH2:10][C@@H:9]1[CH2:14][CH2:15][S:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1cccc(C(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CSCC[C@H]1CN(C(=O)c2cccc(C)c2C)CCN1C(=O)OC(C)(C)C
Yield: 88.9 %

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 1-tert-butoxycarbonyl-2(S)-(2-methylthioethyl)piperazine (1.87 g, 7.19 mmol), 2,3-dimethylbenzoic acid (1.08 g, 7.19 mmol), HOBT (0.970 g, 7.19 mmol), EDC.HCl (1.64 g, 8.62 mmol) in methylene chloride (50 mL). Triethylamine was added to adjust the pH to 7. Chromatography on silica gel with 30% ethyl acetate in hexane afforded the title compound as a clear oil (2.51 g). NMR (DMSO-d6, 300 MHz) δ 6.9-7.3 (3H, m), 4.22-4.50 (2H, mm), 3.62-4.06 (2H, mm), 2.66-3.24 (4H, mm), 2.4 (1H, m), 2.24 (3H, s), 1.92-2.18 (6H, ms),1.4-1.8 (2H, m), 1.39 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].[CH2:27]([N:29]1[C:34](=[O:35])[N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:32](=[O:43])[C:31]([C:44](O)=[O:45])=[N:30]1)[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:44]([C:31]2[C:32](=[O:43])[N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:34](=[O:35])[N:29]([CH2:27][CH3:28])[N:30]=2)=[O:45])=[CH:18][C:17]=1[C:23]([F:25])([F:26])[F:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C(F)(F)F)c2cc1OC
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C(F)(F)F)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-trifluoromethyl-phenylamine and 2-ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid using the procedure for example 1. mp=148-50° C.; LCMS m/z=626 (M+1); 1H NMR (DMSO): 10.95 (s, 1H), 8.52 (d, 1H), 8.32 (s, 1H), 8.04 (m, 1H), 7.35-7.49 (m, 8H), 6.60 (m, 1H), 4.08 (q, 2H, J=7Hz), 3.97 (s, 3H), 3.89 (s, 3H), 1.35 (t, 3H, J=7Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)=[CH:29][CH:30]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cn1ccc(-c2ccc(CCl)cc2)n1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.97 g), 3-[4-(chloromethyl)phenyl]-1-methyl-1H-pyrazole (0.65 g) and sodium carbonate (0.67 g) in a mixed solvent of 1,2-dimethoxyethane (12.0 mL)-water (4.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.18 g) under argon atmosphere, and the mixture was stirred overnight at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.65 g).