Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](O)=[O:14])=[CH:11][N:10]=[C:9]2[S:16]([CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=2[F:27])=[O:17])=[CH:4][CH:3]=1.FC1C=CC(N2C(C=O)=CN=C2SCC2C(F)=CC=C(F)C=2F)=CC=1.OOS([O-])=O.[K+].C(=O)(O)[O-].[Na+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:9]2[S:16]([CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=2[F:27])=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=Cc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: O=S([O-])OO
Solvent: CC(C)=O
Product: O=Cc1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazole-5-carbaldehyde (33) was prepared in a similar manner as that described for the synthesis of compound 20 using 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carbaldehyde (32) (150 mg, 0.41 mmol), Oxone (629 mg, 1.02 mmol), acetone (4 mL) and 0.2M sodium bicarbonate (4 mL).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[C:10]([OH:12])=[O:11].[OH-].[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O.O1CCOCC1>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C@@H:2]2[C:10]([OH:12])=[O:11])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)[C@H]1Cc2ccccc2N1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of (R)-2,3-dihydro-1H-indole-2-carboxylic acid (2.89 g, 14.5 mmol) and 1N sodium hydroxide (37.7 mL, 37.7 mmol) in water (79 mL) stirring at room temperature is added dropwise a solution of 4-benzyloxybenzenesulfonyl chloride (4.1 g, 14.5 mmol) in dioxane (104 mL). Upon completion of the addition, the pH of the reaction mixture is monitored and maintained between 7–8 by slow addition of 1N aqueous sodium hydroxide over the next 2 hours. The reaction mixture is stirred overnight at room temperature. The solution is poured into crushed ice and the resulting mixture is acidified to pH 2–3 with 1N aqueous hydrochloric acid (15 mL). The product is extracted into dichloromethane (2×150 mL). The extract is washed with water (150 mL), brine (150 mL), dried over anhydrous magnesium sulfate (MgSO4), filtered and concentrated to give 5.5 g of (R)-1-(4-benzyloxy-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid as an oil: [M+1]+=410.32, [M−1]−=408.24.
Reaction SMILES: [OH-].[Na+].C(O)C.[I:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]([C:17]([O:19]CC)=[O:18])[C:10]2=[O:22].Cl>O>[I:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]([C:17]([OH:19])=[O:18])[C:10]2=[O:22]
Reactant: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c[nH]c2ccc(I)cc2c1=O

Procedure:
Sodium hydroxide (9.8 g) was dissolved in water (61 ml) and ethanol (30 ml) was added. The resultant solution was added to Intermediate 11, and the mixture was heated under reflux for 60 min with stirring under nitrogen. Concentrated hydrochloric acid was added, giving a white precipitate. After stirring for 16 h, the precipitate was filtered off, washed with water and dried in vacuo to give the title compound as a white solid (8.15 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10].Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24][CH2:23][C:22]1=[O:31].CO>C(#N)C>[CH2:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH2:23][C:22]2=[O:31])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC1CCNCC1
Reactant: O=C1CSc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CCCCC1CCN(CCCN2C(=O)CSc3ccccc32)CC1
Reaction time: 13 h

Procedure:
NAI (1.24 g, 8.27 mmol), K2CO3 (1.14 g, 8.27 mmol), and 4-butylpiperidine (0.62 g, 4.34 mmol) in acetonitrile (10 mL) were stirred at rt. 4-(3-chloropropyl)-4H-benzo[1,4]thiazin-3-one (1.0 g, 4.14 mmol) in acetonitrile (15 mL) was added via a syringe. The reaction was stirred at 60 C. for 13 hours and then 80 C. for another 25 hours under nitrogen atmosphere and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1.63 g of crude. The crude product was subjected to CC[eluent:EtOAC:MeOH(100:1-5%)] to give the pure title compound. Yield 1.06 g 74.2% HPLC-MS [M+H]+347 (UV/MS(%)=100/99. 1H NMR (CDCl3): δ 0.88 (t, 3H), 1.23 (m, 9H), 1.64 (d, 2H), 1.85 (m, 4H), 2.34 (t, 2H), 2.83 (d, 2H), 3.36 (s, 1H), 4.03 (t, 2H), 6.99 (m, 1H), 7.22 (d, 2H), 7.34 (d, 1H), 13C NMR (CDCl3): δ 14.21, 23.03, 25.23, 29.15, 31.80, 32.63, 35.90, 36.44, 43.28, 54.26, 55.91, 118.18, 123.45, 124.17, 127.27, 128.56, 139.63, 165.19.
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH:7]1([NH:10][NH2:11])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[CH:7]1([N:10]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:11]2)[CH2:9][CH2:8]1
Reactant: C/C(N)=C/C#N
Reactant: NNC1CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)n(C2CC2)n1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
(2Z)-3-amino-2-butenenitrile (903 mg, 11.00 mmol), cyclopropylhydrazine (1194 mg, 11 mmol) and triethylamine (3.07 mL, 22.00 mmol) were suspended in ethanol (100 mL) and heated to 70° C. for 16 hours. The solvent was removed in vacuo. The residue was suspended in 50 mL of saturated NaHCO3 and stirred for 10 minutes. The contents were extracted with DCM, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0% to 100% gradient EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.13 (m, 4 H), 2.13 (s, 3 H), 3.06 (m, J=6.95, 6.95, 3.79, 3.54 Hz, 1 H), 3.76-3.88 (m, 2 H), 5.24 (s, 1 H). LCMS(ES) [M+H]+ 138.1
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=1)[CH2:16][CH:13]1[CH2:15][CH2:14]1)=[O:6]
Reactant: COc1cccc(C(=O)O)c1C
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Product: COc1cccc(C(=O)NCC(CC2CC2)c2cnc(C(F)(F)F)nc2)c1C

Procedure:
From 2-methyl-3-methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=394.0, tR (minutes, Method F)=2.59
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:23]([O:25]C)=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:28]>CO>[C:1]1([CH:7]=[CH:8][C:9]([NH:11][C@H:12]([C:23]([O-:25])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:28]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 98 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 8 (3.7 g), 1 mol/L of an aqueous sodium hydroxide solution (32 mL), and methanol (150 mL), to give the captioned compound (3.7 g, 98%) as crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.O>[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(CBr)n1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-(bromomethyl)-6-methoxypyridine (1.33 g, 6.58 mmol), 2-(bromomethyl)-6-methoxypyridine (1.33 g, 6.58 mmol), ethyl N-(diphenylmethylene)glycinate (1.76 g, 6.58 mmol, Acros, N.J.) and 5N sodium hydroxide (6.58 mL, 32.9 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give ethyl N-(diphenylmethylidene)-3-(6-methoxy-2-pyridinyl)alaninate (1.86 g) as a colorless oil.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[C:17]=1[CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[Cl:32]N1C(=O)CCC1=O>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:32])[C:19]([NH2:22])=[C:18]([CH3:23])[C:17]=1[CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)[C@@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Yield: 57 %

Procedure:
(R)-3-(2-(acetoxymethyl)-4-amino-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate (15.00 g, 38.9 mmol) in acetonitrile (200. ml, 3829 mmol) was added N-chlorosuccinimide (5.72 g, 42.8 mmol). The reaction mixture was then heated to reflux for 2 min. The solvent was removed and the crude product was washed with aqueous NaHCO3. The crude product was purified by flash chromatography using 30% EtOAc in hexane to give (R)-3-(2-(acetoxymethyl)-4-amino-5-chloro-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate in 57% yield. MS (ESI) 442 (M+H); Rf=2.42.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:15]
Reactant: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1nccs1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Referring to Scheme 3, a mixture of 2-(1,3-dioxoisoindolin-2-yl)-4-methylpentanoic acid (78 mg, 0.3 mmol), 2-aminothiazole (30 mg, 0.3 mmol), HBTU (114 mg, 0.3 mmol) and 0.1 mL of Et3N in DMF (2 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, MeOH-d4) δ: 7.83-7.86 (m, 2H), 7.89-7.92 (m, 2H), 7.41 (d, J=3.2 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 5.15 (dd, J=4.8, 11.6 Hz, 2H), 2.35-2.45 (m, 1H), 1.96-2.05 (m, 1H), 1.51 (m, 1H), 0.99 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H). [M+H] calc'd for C17H17N3O3S, 344. found, 344.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21](O)=[O:22])[C:15](=[O:24])[C@@H:14]2[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:22])[C:15](=[O:24])[C@@H:14]2[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Reactant: O[C@@H]1CNCCC12CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)N(CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Yield: 55.3 %

Procedure:
To a solution of 3-{(S)-4-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-3-methyl-2-oxo-piperazin-1-yl}-propionic acid (50 mg, 0.14 mmol), (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 24 mg, 0.15 mmol) and 4-methylmorpholine (41 mg, 0.41 mmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (77 mg, 0.20 mmol) at room temperature, then after 16 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (37 mg, 54%). White solid, MS: 478.2 (M+H, Cl)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[C:24]([CH3:30])[CH:25]=[C:26]([Cl:29])[CH:27]=2)[N:22]=[C:21]([CH3:31])[C:20]=1[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:29][C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([CH3:30])[CH:25]=1)[N:22]=[C:21]([CH3:31])[C:20]([CH3:32])=[C:19]2[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:6]=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1nc2c(C)cc(Cl)cc2c(Cl)c1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2c(C)cc(Cl)cc2c(N2CC(C)(C)c3ccc(N4CCOCC4)cc32)c1C

Procedure:
Prepared according to procedure T using 4-(3,3-dimethylindolin-6-yl)morpholine (0.2 g, 0.86 mmol), 4,6-dichloro-2,3,8-trimethylquinoline (0.413 g, 1.72 mmol), cesium carbonate (0.561 g, 1.72 mmol), Pd2(dba)3 (0.079 g, 0.086 mmol) and (±) BINAP (0.084 g, 0.129 mmol) in 1,4-dioxane (2 mL). After purification by HPLC 6-chloro-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-2,3,8-trimethylquinoline was obtained. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.56-7.60 (2H, m), 7.05 (1H, d, J=8.3 Hz), 6.25 (1H, dd, J=8.1, 2.2 Hz), 5.44 (1H, d, J=2.2 Hz), 3.68 (1H, m), 3.58 (4H, m), 2.85 (5H, d, J=4.9 Hz), 2.71 (6H, d, J=13.2 Hz), 2.20 (3H, s), 1.42 (6H, d, J=17.9 Hz). Mass Spectrum (ESI) m/e=436 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15](O)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH3:20][N:21]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:24][CH:23]=[N:22]1.[Li+].[Cl-]>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:25]3[N:21]([CH3:20])[N:22]=[CH:23][CH:24]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3ccnn3C)ccc21
Reaction time: 4 h

Procedure:
To a solution of N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, O-trifluoromethanesulfonate (100 mg, 0.25 mmol) in dimethylformamide (2 mL) was treated with (2-methyl-2H-pyrazol-3-yl)-tri-n-butyltin (138 mg, 0.37 mmol), LiCl (21 mg, 0.50 mmol), Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) and stirred at 100 C for 4 hours. The product mixture was diluted with EtOAc (20 mL), washed twice with water (10 mL), once with brine (10 mL), dried with Na2SO4 and concentrated. Flash chromatography (30% EtOAc in hexane, silica) resulted in 80 mg of a clear oil. MS calculated for C17H18F3N3O+H: 338, observed: 338.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc(CC2CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-Benzylpiperidine was treated with 1-bromo-2-phenoxyethane and excess potassium carbonate as a solution in methylethylketone and heated at reflux for 12 hours. Standard workup and chromatography gave the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[I-].C[N+]1C=CN([C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C=1.C(N(CC)CC)C>C(#N)C>[N+:8]([C:7]1[C:2]([O:1][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1O
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ncccc1[N+](=O)[O-])c1ccccc1
Yield: 50 %

Procedure:
A solution of 2-hydroxy-3-nitropyridine (0.42 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.41 g, 50% yield) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:30]([C:27]1[CH:28]=[CH:29][C:24]([C:6]2[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=4)[N:15]=3)=[CH:8][CH:7]=2)=[CH:25][CH:26]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCc1ccccc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 62.1 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with benzylamine (available from Aldrich Chemical Company, Inc.; 66 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4′-benzylcarbamoyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (73 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (br s, 1H), 9.15 (t, J=6.0 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.34 (d, J=4.3 Hz, 4H), 7.21-7.29 (m, 1H), 4.52 (d, J=6.0 Hz, 2H).
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][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[CH:44][C:45]([C:48]#[N:49])=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(C#N)cc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C#N)cc4)c3)c2cc1OC
Yield: 35.5 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-ylcarbamate (108 mg, 0.3 mmol), described in the previous step, to afford 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (60 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (s, 9H), 3.99 (s, 6H), 6.40 (s, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.34-7.40 (m, 2H), 7.52-7.55 (m, 2H), 7.79 (d, J=7.8 Hz, 2H), 7.99 (d, J=7.8 Hz, 2H), 8.55 (s, 1H), 8.62 (s, 1H), 9.24 (s, 1H); LC-MS (ESI) m/z 564 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][CH3:22])[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(Br)C(=O)C1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([CH:8]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][CH3:22])[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2ccc(OC)cc21
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)C=Cc2ccc(OC)cc21
Yield: 125.1 %

Procedure:
A three-necked flask, equipped with reflux condenser, was charged with 3-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (4.0 g, 12.52 mmol), NBS (2.452 g, 13.76 mmol), N,O-bis(trimethylsilyl)acetamide (1.712 mL, 6.88 mmol), BPO (ca. 20 mg) and carbon tetrachloride (160 mL). The suspension was heated to reflux when another portion (ca. 20 mg) of BPO was added. After being refluxed for 3 hrs, the reaction mixture was diluted with DCM (100 mL), washed with water and dried over Na2SO4. The reaction was repeated for another 5 times and the combined organic layers were filtered and evaporated. The residue was repeatedly purified by flash chromatograghy on silica column eluted by ethyl acetate/DCM (2.5%) or ethyl acetate/hexane (20%). The crystal residue was further washed with ethyl acetate/hexane (20%) and dried in vacuum, giving the title compound (4.970 g, 21%) as white crystal.