Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:23]2[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([F:33])[CH:32]=1>>[CH:23]1([C:9]2[N:8]([CH2:7][C:5]3[O:6][C:2]([C:29]4[CH:28]=[C:27]([F:26])[CH:32]=[C:31]([F:33])[CH:30]=4)=[CH:3][CH:4]=3)[C:16]3[C:11]([CH:10]=2)=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:25][CH2:24]1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(Br)o2)c1C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(-c3cc(F)cc(F)c3)o2)c1C(F)(F)F

Procedure:
Synthesizes as described in Example 310D using (1-[(5-bromo-2-furanyl)methyl]-2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 310C) and (3,5-difluorophenyl)boronic acid: MS (ES) m/z 443 (M+1).
Reaction SMILES: [NH2:1][C:2]([NH2:26])=[N:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([O:15]CC2C=CC=CC=2)=[CH:7][C:6]=1[CH2:23][CH3:24].[H][H]>C1(C)C=CC=CC=1.[Pd].[C]>[NH2:26][C:2]([NH2:1])=[N:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([OH:15])=[CH:7][C:6]=1[CH2:23][CH3:24]
Reactant: [H][H]
Reactant: CCc1cc(OCc2ccccc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCc1cc(O)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
1.1 g of N-diaminomethylene-2-ethyl-4-benzyloxy-5-methylsulfonylbenzamide (obtainable according to Ex. 6) are dissolved in 30 ml of toluene and treated at room temperature for one hour with hydrogen gas (p=1 atm) under the catalytic action of 150 mg of Pd-carbon (Pd content 1%). The reaction mixture is then filtered, and customary working up gives N-diaminomethylene-2-ethyl-4-hyrdoxy-5-methylsulfonylbenzamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[N:9]=[CH:10][CH:11]=[C:5]2[CH:4]=1)[CH3:2].C1C(=O)N([Br:19])C(=O)C1.O>ClCCl>[Br:19][C:11]1[CH:10]=[N:9][N:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccn2nccc2c1
Solvent: ClCCl
Solvent: O
Product: CCc1ccn2ncc(Br)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 116622.5 %

Procedure:
To a stirred solution of 5-ethylpyrazolo[1,5-a]pyridine (1.1 g, 0.008 mmol) in dichloromethane (10 mL) at 0° C. was added NBS (1.75 g, 0.009 mmol) and reaction mixture was stirred at room temperature for 5 min. Subsequently, water was added and the reaction mixture was extracted with dichloromethane (2×10 mL). The organic layer was washed with water (1×30 mL), sat. NaHCO3 solution (1×10 mL), brine (1×10 mL), dried over Na2SO4 and concentrated to afford 2.1 g (84%) of 3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17) as a brownish highly viscous liquid. The crude was progressed to next step without any further purification. ESI-LC/MS (m/z): [M+H]+ 225.0, [(M+2)+H]+227.0, RT 2.50 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(-c2cc(CNS(=O)(=O)C3CC3)ccc2Cl)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example-100 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), cyclopropanesulfonyl chloride (0.2 mL), DIPEA (3 mL), and dry THF (5 mL) to afford 0.029 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 0.86-0.92 (m, 4H), 1.14-1.24 (m, 1H), 4.26-4.28 (d, J=6.4 Hz, 2H), 7.57-7.60 (d, J=8.4 Hz, 1H), 7.63-7.68 (d, J=8.4 Hz, 1H), 7.58-7.81 (m, 1H), 7.86-7.88 (d, J=8.8 Hz, 2H), 8.19-8.21 (d, J=8.4 Hz, 2H), 12.89 (br s, 1H); MS (m/z): 471.30 (M−H−).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][C:19]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][C:33]=4[C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[CH2:27][CH2:26]3)[CH:22]=[CH:21][C:20]=2[C:47](=[O:70])[NH:48][S:49]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][CH2:59][C:60]3([F:66])[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[C:54]([N+:67]([O-:69])=[O:68])[CH:53]=2)(=[O:51])=[O:50])[N:11](C(OC(C)(C)C)=O)[N:10]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][C:19]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][C:33]=4[C:40]4[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=4)[CH2:27][CH2:26]3)[CH:22]=[CH:21][C:20]=2[C:47]([NH:48][S:49]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][CH2:59][C:60]3([F:66])[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[C:54]([N+:67]([O-:69])=[O:68])[CH:53]=2)(=[O:51])=[O:50])=[O:70])[NH:11][N:10]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5(F)CCOCC5)c([N+](=O)[O-])c4)c(Oc4cccc5c4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nn5C(=O)OC(C)(C)C)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5(F)CCOCC5)c([N+](=O)[O-])c4)c(Oc4cccc5[nH]nc(N)c45)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 2 h

Procedure:
The crude product of EXAMPLE 428F (0.10 g) was treated with 1:1 dichloromethane/trifluoroacetic acid (10 mL). The reaction was stirred for 2 hours. The solvents were removed, and the residue was purified by reverse phase Gilson Prep HPLC system with a Phenomenex prep column (Luna, 5μ, C18(2), 250×21.20 mm, 5 Å) eluting with 20-80% acetonitrile in water with 0.1% trifluoroacetic acid. Fractions containing product were concentrated, and the concentrate was diluted with dichloromethane, neutralized with aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.47 (s, 1H), 8.58 (t, 1H), 8.40 (d, 1H), 7.49-7.53 (m, 2H), 7.36 (d, 2H), 7.06 (d, 2H), 7.01 (d, 1H), 6.88 (t, 1H), 6.88 (d, 2H), 6.49 (d, 1H), 5.69 (s, 1H), 3.68-3.79 (m, 4H), 3.52-3.56 (m, 2H), 3.17 (br s, 4H), 2.81 (br s, 2H), 2.17-2.25 (m, 6H), 1.97 (s, 2H), 1.77-1.87 (m, 4H), 1.40 (t, 2H), 0.94 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][C:21]1[N:22]([CH2:29][CH2:30][NH2:31])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=1>>[CH3:20][C:21]1[N:22]([CH2:29][CH2:30][NH:31][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: Cc1ncc([N+](=O)[O-])n1CCN
Product: CCc1cc(-c2cncc(C(=O)NCCn3c([N+](=O)[O-])cnc3C)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl-amine to afford the title compound. MS: m/e=411 (M+H).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.O.[F:13][C:14]([F:19])([F:18])[C@H:15]([OH:17])[CH3:16]>CN(C)C=O>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][O:17][C@H:15]([CH3:16])[C:14]([F:19])([F:18])[F:13])[CH:6]=1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1cccc(F)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 69.3 %

Procedure:
Under argon atmosphere, a suspension of sodium hydride (76 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., a solution of N,N-dimethylformamide (2.0 ml) in (R)-1,1,1-trifluoropropan-2-ol (219 mg) was added thereto, and the mixture was stirred for 25 minutes. Then, a solution of 1-bromomethyl-3-fluorobenzene (297 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and then the mixture was stirred for 2 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/ethyl acetate=9/1) to give the titled compound (242 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1>CO.[Rh]>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:7]1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: [Rh]
Solvent: CO
Product: COC(=O)C[C@H]1CC[C@@H](O)CC1

Procedure:
A solution of methyl 4-hydroxyphenylacetate (10.01 g, 60.2 mmol, CAS 14199-15-6), rhodium (5% on Alumina) (0.073 g, 0.71 mmol) in MeOH (30 mL) was hydrogenated at 8 bar. The crude was filtered through Celite and concentrated at reduced pressure. The remaining colorless oil was dissolved in isohexane and EtOAc and purified by flash chromatography using EtOAc (20-50%) in isohexane to afford the title cis compound (4.31 g, 42%) as colorless oil. NMR analysis of both trans and cis isomers were compared to make sure that the right isomer was used in subsequent steps.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:25]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][C:17]([O:19][CH3:25])=[O:18])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
A mixture of 3-[5-(4-nitrophenyl)-4-isoxazolyl]propionic acid (5.28 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-nitrophenyl)-4-isoxazolyl]propionate (5.45 g, yield 98%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 118–119° C.
Reaction SMILES: [CH3:1][C:2](O)([CH3:14])[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:17].[C:21](#[N:23])[CH3:22]>O>[CH3:1][C:2]([NH:23][C:21](=[O:17])[CH3:22])([CH3:14])[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC#N
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)Cc1cccc2ccccc12
Solvent: O
Product: CC(=O)NC(C)(C)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
The crude alcohol (2.0 g, 10 mmol) was dissolved in acetonitrile (10 mL) and concentrated sulfuric acid (4.9 g, 50 mmol) was added dropwise at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic fractions were dried over sodium sulfate and evaporated. The residue was purified by silical gel column chromatography (petroleum ether/ethyl acetate) to give N—(2-methyl-1-(naphthalene-1-yl)propan-2-yl)acetamide (0.90 g, 37% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:18][C:12]3[NH:13][C:14](=[O:17])[N:15]=[CH:16][C:11]=3[C:10]=2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[CH:5][C:4]=1[O:31]COCCOC>C1COCC1.CO.Cl.CCOC(C)=O>[OH:31][C:4]1[CH:5]=[C:6]([C:9]2[O:18][C:12]3[NH:13][C:14](=[O:17])[N:15]=[CH:16][C:11]=3[C:10]=2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COCCOCOc1cc(-c2oc3[nH]c(=O)ncc3c2-c2cc(OC)c(OC)c(OC)c2)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(-c2oc3[nH]c(=O)ncc3c2-c2cc(OC)c(OC)c(OC)c2)cc1O

Procedure:
6-[4-Methoxy-3-(2-methoxy-ethoxymethoxy)-phenyl]-5-(3,4,5-trimethoxyphenyl)-1H-furo[2,3-d]pyrimidin-2-one (Example 6) (102 mg, 0.2 mmol) was dissolved in mixture of THF (2 ml) and MeOH (2 ml) and 0.2 ml of concentrated HCl was added slowly with stirring. The reaction mixture was stirred for overnight with slow evaporation of solvents. The residue was dissolved in EtOAc (50 ml) and washed with water (5 ml). The organic layer was concentrated and purified by silica gel column chromatography using increasing gradient of EtOAc in CH2Cl2 and finally with 5% MeOH in 1:1 mixture of EtOAc and CH2Cl2. Yield (42%); 1H NMR (300 MHz, DMSO-d6) δ: 3.69 (s, 9H, 3×OMe), 3.75 (s, 3H, OMe), 6.71 (s, 2H), 6.92-7.11 (m, 3H), 8.15 (s, 1H).
Reaction SMILES: O1CCOCC1.FC(F)(F)C1C=CC([N+]([O-])=O)=CC=1N.[N+](C1C=CC(C(F)(F)F)=CC=1N)([O-])=O.C[O:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1>O>[C:37]([OH:44])(=[O:36])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1
Reactant: COC(=O)c1cccnc1
Agent: Nc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: Nc1cc([N+](=O)[O-])ccc1C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccnc1
Yield: 46.4 %

Procedure:
Add 20 ml of dioxan and 10 g of 2-trifluoromethyl-5-nitroaniline or 2-nitro-5-trifluoromethyl-aniline to 12 g of nicotinic acid methyl ester. Reflux for 60 hours; then pour the reaction mass into water. Filter the resulting solid and recrystallize several times from ethanol. 5 g of (I) or (III) are thus obtained with the same melting-point values as the products of Examples 1 and 3.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([CH3:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([CH:3]1[CH:8]([CH3:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:4]1)=[O:1]
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1CCN(C(=O)OC(C)(C)C)CC1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (2.58 g, 11.2 mmol, Preparation #S.1) in DCM (50 mL) was added Dess-Martin periodinane (5.73 g, 13.5 mmol). The reaction was stirred at ambient temperature for about 16 h before it was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL). The organic layer was filtered through Celite® then washed with saturated aqueous Na2CO3 (2×150 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a constant weight to afford tert-butyl 3-formyl-4-methylpiperidine-1-carboxylate as a clear oil (1.49 g, 58%): LC/MS (Table 2, Method a) Rt=2.39 min; MS m/z: 228 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:15]=[C:14]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=1)[CH2:13][CH:12]([CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:34][CH2:35][CH3:36])=[O:33])[C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=C(C=Cc1cc(-c2ccccc2)cs1)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(C(F)(F)F)cc1)c1cc(-c2ccccc2)cs1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-phenylthiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one and diethyl malonate, diethyl 2-(3-oxo-1-(4-phenylthiophen-2-yl)-3-(4-(trifluoromethyl)-phenyl)propyl)malonate was obtained as yellow oil.
Reaction SMILES: O[C:2]1([C:20]([F:23])([F:22])[F:21])[CH2:7][C:6](O)([C:8]([F:11])([F:10])[F:9])[NH:5][C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:7]=[C:2]([C:20]([F:23])([F:21])[F:22])[N:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:5]=1
Reactant: CCOC(=O)CCC1=NC(O)(C(F)(F)F)CC(O)(C(F)(F)F)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1nc(C(F)(F)F)cc(C(F)(F)F)n1
Temperature: 110 °C
Yield: 27.7 %

Procedure:
A mixture of ethyl 3-(4,6-dihydroxy-4,6-bis(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)propanoate (400 mg, 1.14 mmol), p-toluenesulfonic acid (210 mg, 1.14 mmol), and toluene was heated to 110° C. for 2 h. The reaction was then cooled to room temperature, the mixture was neutralized with saturated sodium carbonate solution to pH 7 and then extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; and the residue was purified by prep-TLC to give the title compound (100 mg). MS (ESI): m/z 317 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].C(#N)C.[Cl:22]N1C(=O)CCC1=O.O>ClCCl>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[Cl:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
5.34 g (0.02 mol) of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) is dissolved in 60 mL of dichloromethane and 60 mL of acetonitrile is added to the solution. 5.34 g (0.04 mol, 2 eq) of N-chlorosuccinimide in solid form is added dropwise at −8±2° C. in 20 min. The reaction mixture is stirred for 2 hours at this temperature and then heated up to 20° C. The reaction mixture is poured into 200 mL of water. The product is extracted with 2×80 mL of dichloromethane. The organic layer is evaporated and the residue is purified by column chromatography (spheric silica; eluent: toluene:methanol=7:3) to give 4.59 g (76%) of the title compound (IIIa) as a yellowish-brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([CH3:23])[C:15]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:7]1[C:2]([O:24][C:15]2[C:14]([CH3:13])=[CH:19][C:18]([N+:20]([O-:22])=[O:21])=[CH:17][C:16]=2[CH3:23])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ncc(C(F)(F)F)cc1Cl
Yield: 121.1 %

Procedure:
2,3-Dichloro-5-trifluoromethylpyridine (1.04 g), 0.8 g of 2,6-dimethyl-4-nitrophenol, and 0.5 g of potassium carbonate were added to 3 mL of dimethylacetamide, and the mixture was allowed to react at 155 to 165° C. for one hr. The reaction mixture was cooled, ethyl acetate and distilled water were then added thereto, followed by separation and washing with brine. The ethyl acetate layer was concentrated to give 2.01 g of 3-chloro-2-(2,6-dimethyl-4-nitrophenoxy)-5-trifluoromethylpyridine (yield 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:35][C@@H:36]([OH:40])[C:37]([OH:39])=[O:38])[NH:26][C:27]([C:29]2[N:30]=[N:31][N:32]([OH:34])[CH:33]=2)=[O:28])=[CH:20][CH:19]=1.CC(C)=O.CCN(CC)CC>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:35][C@@H:36]([OH:40])[C:37]([OH:39])=[O:38])[NH:26][C:27]([C:29]2[N:30]=[N:31][N:32]([O:34][CH2:2][C:3]3[O:4][C:5](=[O:9])[O:6][C:7]=3[CH3:8])[CH:33]=2)=[O:28])=[CH:22][CH:23]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1oc(=O)oc1COn1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3Cl)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
4-Chloromethyl-5-methyl-1,3-dioxol-2-one (14.9 mg, 100 μmol) was added to a solution of (R)-3-[N-(2′,5′-dichlorobiphenyl-4-ylmethyl)-N′-(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)hydrazino]-2-hydroxypropionic acid (31.2 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol) followed by Et3N (18.6 μL, 134 μmol). The resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound (10.0 mg, purity 99%) as a white solid. MS m/z [M+H]+ calc'd for C24H21Cl2N5O8, 578.08. found 578.1.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[N:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[Br:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[CH:6][N:7]=2)[CH:16]=[N:17][CH:18]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: CN(C)Cc1ccc(I)nc1
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: COCCOC
Solvent: CCO
Product: CN(C)Cc1ccc(-c2cncc(Br)c2)nc1

Procedure:
To a solution of (6-iodo-pyridin-3-ylmethyl)-dimethyl-amine (Intermediate 219) (1 eq, 3.89 mmol, 1.02 g) in DME/EtOH (1:1, 10 ml) are added 5-bromo-pyridine-3-boronic acid (Intermediate 100) (1.1 eq, 4.28 mmol, 0.864 g), Pd(PPh3)4 (0.05 eq, 0.195 mmol, 0.225 g), and aqueous Na2CO3 solution (4M, 3 eq, 11.7 mmol, 2.92 ml). The resulting mixture is heated using microwave radiation at 130° C. for 20 min. The mixture is filtered through a pad of Celite and concentrated under reduced pressure. 2M aqueous HCl is added, and the mixture is washed with DCM. The aqueous layer is adjusted to pH 11 using aqueous NaOH, and extracted with DCM. The organic layer is dried over MgSO4, and the solvents are removed in vacuo. The crude mixture is purified using reversed phase HPLC to give the title compound; [M+H]+=292/294.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCCCCCCOCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCCCCCCOCCCCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a stirred solution of 3-hydroxy-4-methoxybenzaldehyde (4.8 grams) in dimethylformamide (100 ml) at room temperature is added potassium carbonate (4.9 grams) and 1-bromo-6-(4-phenylbut-1-yloxy)hexane (10.0 grams). After stirring at 80° C. over 4 hours the reaction mixture is poured into water and extracted with ethyl acetate. The combined organics are washed with 1N sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting amber oil is filtered through a 5×10 cm pad of silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, to give 12.0 grams of a colorless oil. MS (m/z) 384.