Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:6].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CC(=O)CC>C(=O)(O)[O-].[K+].C(Cl)Cl>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:19][CH3:20])[CH:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:7]([C:5]([NH:4][CH2:3][CH2:2][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:6])[CH2:16][CH2:15]2
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCCl)CC2
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCN1CCCCC1)CC2
Temperature: 65 °C

Procedure:
A mixture of 3.0 parts of the N-(2-chloroethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide prepared in Example 8 and 4.3 parts of piperidine in approximately 40 parts of 2-butanone is heated at 65°C. for 20 hours. The reaction mixture is then stripped in vacuo and the residue taken up in dilute aqueous potassium bicarbonate solution and methylene chloride. The organic layer is dried and stripped in vacuo and the residue is crystallized from ether to afford 6,7-dimethoxy-1-phenyl-N-(2-piperidinoethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxamide, melting at about 101°-102°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:11]([N:14]1[C:18]([NH2:19])=[N:17][N:16]=[N:15]1)[CH2:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:19][C:18]1[N:14]([CH2:11][CH2:12][CH3:13])[N:15]=[N:16][N:17]=1)=[O:7]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CCCn1nnnc1N
Product: CCCn1nnnc1NC(=O)c1cccc(Br)c1
Yield: 34 %

Procedure:
Employing 0.25 g (1.2 mmol) of 3-bromo-benzoic acid and 0.16 g (1.2 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et3N (9.8:0.1:0.1) gave the product in 34% yield.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:16].[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH:28][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[C:8]([CH3:16])[CH:9]=3)[CH3:27])=[N:25][C:21]=2[CH:20]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCS1(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCS1(=O)=O

Procedure:
Prepared analogously to Example 1f from 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF with subsequent extraction with ethyl acetate, drying over magnesium sulphate, activated charcoal and silica gel followed by purification on silica gel (eluant: dichloromethane/isopropanol 95:5).
Reaction SMILES: [F:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:13][C:12](=[O:14])[C:11](=[O:15])[CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[C:3]=1[O:18][CH3:19])([CH3:17])[CH3:16])[CH3:26]
Reactant: COc1c(C(C)(C)CC(=O)C(=O)O)ccc(C)c1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(C)c(F)c1OC
Yield: 83.7 %

Procedure:
6.04 g (22.52 mmol) of 4-(3-fluoro-2-methoxy-4-methylphenyl)-4-methyl-2-oxo-pentanoic acid is dissolved in 140 ml of ethanol, mixed with 2.5 ml of sulfuric acid, and refluxed for six hours. The ethanol is drawn off in a rotary evaporator, and the residue is carefully mixed with 300 ml of saturated sodium bicarbonate solution. It is extracted three times with ethyl acetate. The combined organic extracts are washed once with saturated sodium bicarbonate solution and once with brine. After drying, and after the desiccant is filtered off and the solvent is spun in, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 5.58 g (83.7%) of the desired compound is isolated.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([OH:24])=O)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:35]>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:25])[C:22]([NH2:35])=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CCN(C(=O)C(=O)O)CC2)cc1CC1CCCC1
Reactant: CC#N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C(=O)C(N)=O)CC2)cc1CC1CCCC1

Procedure:
Following the procedure of Example 9, 2-[4-(3-cyclopentylmethyl-4-methoxyphenyl)piperidin-1-yl]-2-oxo-acetic acid (2.2 mmol, 0.750 g), oxalyl chloride (2.42 mmol, 1.21 mL; 2M solution in CH2Cl2), DMF (4 drops), and saturated NH3 /CH3CN (22 mL) in dry toluene (22 mL) afforded a solid which was purified by flash chromatography (SiO2 : 40% EtOAc/hexane) to give the title compound as a white solid, mp=117°-118° C. (1.1 mmol, 0.388 g, 51%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH:16]=[CH:17]\[CH2:18][CH3:19])C.Cl>C1(C)C=CC=CC=1>[CH:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH:16]=[CH:17]\[CH2:18][CH3:19]
Reactant: CC/C=C/C=C\CC/C=C\CCCCCC(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CC/C=C/C=C\CC/C=C\CCCCCC=O
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
(Z,Z,E)-1,1-Diethoxy-7,11,13-hexadecatriene (49.36 g, 0.16 mol) and toluene (30 g) were placed in a reaction vessel and stirred at 20 to 25° C. for 30 minutes. After stirring, 10% by weight hydrochloric acid (19.3 g) was added dropwise to the reaction mixture at 20 to 25° C., and stirred for one hour. The reaction mixture was separated into phases. Then, the organic phase was washed with an aqueous sodium bicarbonate solution, and concentrated by removal of the solvent under reduced pressure to obtain (Z,Z,E)-7,11,13-hexadecatrienal (30.47 g, 0.13 mol) with a yield of 82.7%.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[C:4]([CH:17]([CH3:19])[CH3:18])[CH:3]=1.FC(S(O)(=O)=O)(F)F.[I:28]N1C(=O)CCC1=O>C1COCC1>[F:1][C:2]1[C:16]([I:28])=[CH:15][C:5]([O:6][C:7]2[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[C:4]([CH:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)c1cc(F)ccc1Oc1cnc(N)nc1N
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)c1cc(F)c(I)cc1Oc1cnc(N)nc1N
Reaction time: 0.17 h

Procedure:
5-(4-Fluoro-2-isopropyl-phenoxy)-pyrimidine-2,4-diamine (400 mg, 1.53 mmol, prepared using the procedure of example 1) was dissolved in dry THF at ice bath temperature, and trifluoromethylsulfonic acid (0.67 mL, 7.63 mmol) was added. After stirring for 10 minutes, N-iodosuccinimide (378 g, 1.68 mmol) was added in portions. The ice bath was removed and the reaction mixture was stirred for three hours. The reaction mixture was then poured over ice and extracted with dichloromethane. The combined organic layers were washed with 10% aqueous sodium bisulfite solution and water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (95%:5%:1% CH2Cl2:MeOH:NH4OH) to give 338 mg of 5-(4-fluoro-5-iodo-2-isopropyl-phenoxy)-pyrimidine -2,4-diamine, MS (M+H)=389.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][C:57]([C@@H:60]2[CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61]2)([CH3:59])[CH3:58])[N:53]=[C:52]([S:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=2[F:76])[N:51]=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]>[F:76][C:70]1[C:71]([F:75])=[CH:72][CH:73]=[CH:74][C:69]=1[CH2:68][S:67][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][C:57]([C@@H:60]2[CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61]2)([CH3:59])[CH3:58])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC1(C)OC[C@@H](C(C)(C)Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)OC[C@@H](C(C)(C)Oc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.17 g), tris(dibenzylideneacetone)dipalladium (0) (78 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (40 mg), cesium carbonate (0.42 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methylethoxy]-pyrimidine (0.37 g) in dioxane (8 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8 to 3:7 gradient) as eluent to give the subtitle compound as a pale yellow oil. Yield: 0.37 g
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O.O.C(OCC)(=O)C>[N:41]1([C:14]([C:13]2[C:12]([C:18]([F:21])([F:19])[F:20])=[CH:11][C:10]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:17]=2)=[O:15])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)O)cc1OCc1ccccc1
Reactant: C1COCCN1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-4-{[(phenylmethyl)oxy]carbonyl}-2-(trifluoromethyl)benzoic acid (may be prepared as described in Description 55; 71 mg, 0.16 mmol) in N,N-dimethylformamide (4 ml) was added diisopropylethylamine (0.07 ml, 0.39 mmol), morpholine (0.03 ml, 0.29 mmol), 1-hydroxy-7-azabenzotriazole (34.2 mg, 0.25 mmol) and EDC (66.6 mg, 0.35 mmol). The mixture was stirred at room temperature for 18 hours. Ethyl acetate (10 ml) and water (10 ml) were added and the organic layer was separated, washed with water (2×10 ml), dried (MgSO4) and solvent removed in vacuo. Purification by column chromatography (SiO2, 1:1 ethyl acetate/cyclohexane) gave the title compound as a solid. 66 mg.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.Cl.[CH:14]1([NH:20][NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[CH:14]1([N:20]2[C:2]3=[C:3]4[CH:12]=[CH:11][NH:10][C:4]4=[N:5][CH:6]=[C:7]3[CH:8]=[N:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc2c(ncc3cnn(C4CCCCC4)c32)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
A solution containing 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.100 g, 0.554 mmol, Adesis), cyclohexylhydrazine hydrochloride (0.125 g, 0.831 mmol) and DIEA (0.19 mL, 1.1 mmol) in t-BuOH (5 mL) was stirred at ambient temperature for about 1 h, then heated at about 70° C. for about 1 h, followed by heating in a Biotage microwave at about 200° C. for about 1 h. The insoluble residue was removed by filtration and the filtrate was subjected to purification by preparative RP-HPLC (Table 2, Method p) to yield 1-cyclohexyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.045 g, 0.187 mmol, 34%) as an off-white solid: LC/MS (Table 2, Method d,) Rt 2.13 min; m/z: 241 (M+H)+, 239 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:58])[CH2:5][N:6]([C:8](=[O:57])[C@@H:9]([NH:25][C:26](=[O:56])[C@@H:27]([NH:52][C:53](=[O:55])[CH3:54])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:46])([CH3:45])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:36])=[O:35])[CH2:10][N:11]([CH3:24])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH3:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].SCC(CO)O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:58])[CH2:5][N:6]([C:8](=[O:57])[C@@H:9]([NH:25][C:26](=[O:56])[C@@H:27]([NH:52][C:53](=[O:55])[CH3:54])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:46])([CH3:45])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:36])=[O:35])[CH2:10][NH:11][CH3:24])[CH3:7])[CH3:2]
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@H](CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(C)=O
Agent: O=C([O-])[O-]
Agent: OCC(O)CS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C(=O)[C@H](CNC)NC(=O)[C@H](CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a solution of compound G (5.5 g, 6.5 mmol) in DMF (21 mL) at ambient temperature was added K2CO3 (8.9 g, 64.5 mmol) followed by thioglycerol (5.6 mL, 64.5 mmol). The reaction mixture was stirred at ambient temperature for 1 h, filtered off and DMF was removed in vacuo. The residue was diluted with water (500 mL) and extracted with EtOAc (2×300 mL) and CHCl3 (2×300 mL). Combined organic layers were dried and removal of the solvents in vacuo afforded the crude product. The crude product was purified by flash chromatography eluting with EtOAc followed by 10% MeOH in CHCl3 to afford compound H (1.3 g, 30%). LC-MS [M+H] 668.3 (C30H49N7O8S+H, calc: 667.8). Purity >95% (UV/254 nm).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:16][CH2:17][CH2:18]Br)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[C:13]([O:16][CH2:17][CH2:18][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)(=[O:15])[CH3:14]
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCCOc1cccc2ccc(C)nc12
Temperature: 70 °C
Yield: 62.2 %

Procedure:
A mixture of 2-methylquinolin-8-ol (0.30 g, 1.9 mmol), 2-bromoethyl acetate (0.8.2 mL, 7.6 mmol) and potassium carbonate (1.6 g, 12 mmol) in acetone (7.5 mL, 1.9 mmol) was heated at 70° C. for 12 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to provide the title compound (0.29 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(OC(=O)C)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])/[CH:11]=[CH:12]/[C:13]1[O:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[N:15]=1
Reactant: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(/C=C/c2nc3ccccc3c(=O)o2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.5 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(3,4-dimethoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.41 g, 88%) as a yellow crystalline solid; mp 175-179° C.; δH (500 MHz, DMSO-d6) 3.82 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.94 (d, J=16.0 Hz, 1H, CH═CHCO), 7.02 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.35 (dd, J5′,6=8.0, J2′,6′=1.5 Hz, 1H, H6′), 7.47 (d, J2,6′=1.5 Hz, 1H, H2′), 7.58 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.61 (d, J3,4=8.0 Hz, 1H, H3), 7.73 (d, J=16.0 Hz, 1H, CH═CHCO), 7.92 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.12 (d, J5,6=8.0 Hz, 1H, H6); δC (125 MHz, DMSO-d6) 55.5, 55.6, 110.3, 111.6, 116.6, 122.9, 126.5, 127.4, 128.0, 128.0, 128.1, 136.8, 141.4, 146.8, 149.0, 150.9, 157.3, 158.8; HRMS (ESI) calculated for C18H15NO4 [M+H]+310.1074; found 310.1073; νmax 1020, 1254, 1515, 1634, 1755, 2835, 2940 cm−1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][C:19](=[O:20])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:22])([F:23])[F:1])=[N:4]3)=[CH:17][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: NC1CCCC1
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)NC1CCCC1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and cyclopentylamine using a similar procedure to that described for Example 2, except product was purified by mass directed auto-prep.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[C:8](/[CH:21]=[CH:22]/[C:23]#[N:24])[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8](/[CH:21]=[CH:22]/[C:23]#[N:24])[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:11]=1
Reactant: COc1ccccc1Oc1cc(Cl)cc(/C=C/C#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#C/C=C/c1cc(Cl)cc(Oc2ccccc2O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
A solution of BBr3 (9.0 mmol, 1M in CH2Cl2) was added dropwise to a solution of 10 (1.8 mmol) in dry CH2Cl2 (4.0 mL) under N2 at −78° C. The reaction mixture was stirred at this temperature for 1 h. After this period, the reaction was allowed to warm to room temperature and stirred for 12 h. After reaction completion, the solution was quenched with methanol, and concentrated in vacuo. The residue was extracted with CH2Cl2 and washed with a solution of NaHCO3. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to give (E)-3-(3-chloro-5-(2-hydroxyphenoxy)phenyl)acrylonitrile (11) (0.14 g, 51%) 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.21-7.10 (m, 2H), 7.11-7.01 (m, 2H), 6.92 (ddt, J=16.0, 14.5, 4.9 Hz, 3H), 5.85 (dd, J=16.6, 5.2 Hz, 1H), 5.51 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22].O>O1CCCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][Br:16]
Reactant: NCc1ccccn1
Reactant: O=C(Cl)CCCCBr
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCBr)NCc1ccccn1
Reaction time: 12 h
Yield: 92.6 %

Procedure:
Part A. A solution of 2-(aminomethyl)pyridine (4.07 g, 37.6 mmol) and triethylamine (7.50 mL, 53.8 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C., then treated with a solution of 5-bromovaleryl chloride (5.00 mL, 37.6 mmol) in tetrahydrofuran (20 mL) dropwise. After stirring for 12 hours, the mixture was poured into water (150 mL) and extracted with methylene chloride (2×150 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the oily product, N-(2-pyridylmethyl)-5-bromopentanamide (9.44 g, 34.8 mmol, 93%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[C:11]([OH:12])=[C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:9]([OH:18])=[C:8]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C:7]=1[OH:24])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:35](Cl)=O>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[F:31][C:32]1[CH:33]=[C:34]([C:35]2[O:24][C:7]3[C:8]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[C:9]([OH:18])[C:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[C:11]([OH:12])[C:6]=3[C:4](=[O:5])[C:3]=2[O:2][CH3:1])[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: COCC(=O)c1c(O)c(CC=C(C)C)c(O)c(CC=C(C)C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2oc3c(CC=C(C)C)c(O)c(CC=C(C)C)c(O)c3c(=O)c2OC)cc1F
Temperature: 25 °C
Yield: 32.8 %

Procedure:
Under nitrogen atmosphere, 2-methoxy-1-[2,4,6-trihydroxy-3,5-di(3-methyl-2-buten-1-yl)phenyl]ethanone (300 mg, 0.897 mmol), anhydrous potassium carbonate powder (744 mg, 5.38 mmol), TBAB (tetrabutyl ammonium bromide, 434 mg, 1.346 mmol), and 3-fluoro-4-methoxybenzoyl chloride (388 mg, 2.057 mmol) were dissolved in toluene (84 mL), and refluxed for 6 hours. After cooling, toluene was removed, and then water (20 mL) was added. The aqueous solution was extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. A brown residue was obtained after removal of solvent. The residue was dissolved in a 20 mL methanol-H2O (4:1) mixture, to which was added potassium hydroxide (1 g). The mixture was heated to reflux for 2 hours, then cooled to ambient temperature, acidified to pH 4 with 1N HCl solution, and extracted with dichloromethane three times. The combined organic phase was dried over anhydrous sodium sulfate, with removal of solvent. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether, 1:50) to give the desired compound (137.8 mg, yield 32.6%). 1H NMR (400 MHz, CDCl3): δ=12.89 (s, 1H), 7.94 (dt, 1H, J1=8.8 Hz, J2=2.0 Hz), 7.90 (dd, 1H, J1=8.8 Hz, J2=2.0 Hz), 7.08 (t, 1H, J=8.8 Hz), 6.36 (s, 1H), 5.27-5.23 (m, 2H), 3.99 (s, 3H,), 3.88 (s, 3H), 3.54 (d, 2H, J=6.8 Hz), 3.47 (d, 2H, J=6.8 Hz), 1.85 (s, 3H), 1.84 (s, 3H), 1.77 (s, 3H), 1.75 (s, 3H); LC-MS (ESI) m/z 469.5 [M+14]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=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+]>O1CCCC1.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[C:4]([O:9][CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ncccc1CBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccnc1OC)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a 100-mL round-bottomed flask were added 3-(bromomethyl)-2-methoxypyridine (1.10 g, 5.44 mmol), ethyl N-(diphenylmethylene)glycinate (1.46 g, 5.44 mmol, Acros, N.J.) and 5N sodium hydroxide (5.44 mL, 27.2 mmol) in tetrahydrofuran (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 (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give ethyl N-(diphenylmethylidene)-3-(2-methoxy-3-pyridinyl)alaninate (1.52 g) as viscous oil.