Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8](F)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([NH:26][C:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]2)=[O:28])=[C:18]([F:35])[CH:17]=1.O>C(#N)C.C(OCC)(=O)C>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([N:26]2[C:27](=[O:28])[CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[CH:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:18]([F:35])[CH:17]=1
Reactant: CC(C)Oc1cc(NC(=O)C2CCCCN2)c(F)cc1Cl
Reactant: CCOC(=O)C(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C1N(c2cc(OC(C)C)c(Cl)cc2F)C(=O)C2CCCCN21
Yield: 21.1 %

Procedure:
A mixture of potassium carbonate (724 mg, 5.24 mmol), ethyl bromofluoroacetate (882 mg, 4.76 mmol) and the product of Step A (1.5 g, 4.76 mmol) in acetonitrile (50 mL) was heated at reflux overnight. 100 mL of H2O and 200 mL of ethyl acetate were added to the mixture. The organic layer was separated, dried (MgSO4), filtered, and evaporated under vacuum to dryness. Flash chromatography yielded the title compound of Step B as a white solid (400 mg) m.p. 83°-85° C. 1H NMR δ7.21 (d,1H), 7.18 (d,1H), 4.92 (s,1H), 4.50 (m,1H), 4.16-4.09 (m,2H), 3.29 (m,1H), 2.95 (m,1H), 2.50 (m,1H), 2.10 (m,1H), 1.96 (m,1H), 1.80-1.58 (m,2H), 1.37 (d,6H), 1.35 (t,3H).
Reaction SMILES: [CH3:1][CH:2]([N:28]([CH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=1)[C:29]([CH:31]([OH:40])[CH:32]([C:37]([O-:39])=[O:38])[CH2:33][C:34]([O-:36])=[O:35])=[O:30])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1.[Na+].[Na+].O[C:55]([C:65](=O)N(C(C)C(C1C=CC2OCOC=2C=1)CC1OC(C(=O)NC2C=CC=CC=2)=CC=1)CC1C=CC2C(=CC=CC=2)C=1)=[C:56](C(OC)=O)CC(O)=O.C(Br)C=C.O>CN(C)C=O>[CH2:65]([O:38][C:37]([C:32](=[C:31]([OH:40])[C:29](=[O:30])[N:28]([CH:2]([CH3:1])[CH:3]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:4][C:5]1[O:6][C:7]([C:10](=[O:18])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=1)[CH2:33][C:34]([OH:36])=[O:35])=[O:39])[CH:55]=[CH2:56]
Reactant: CC(C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)C(O)C(CC(=O)[O-])C(=O)[O-]
Reactant: COC(=O)C(CC(=O)O)=C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C=CCBr
Product: C=CCOC(=O)C(CC(=O)O)=C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 2.4 %

Procedure:
80 mg of disodium (3RS,4RS)-4-[N-[(1RS,2RS)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-(2-naphthylmethyl)carbamoyl]-3-carboxylato-4-hydroxybutanoate as the starting material of Example 28, was dissolved in 2 ml of dimethylformamide, and 37 μl of allyl bromide was added thereto, followed by stirring at room temperature for 3 days. The reaction solution was poured into water and extracted with ethyl ether and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2), and the obtained diallyl ester was treated in the same manner as in Example 25(2) and (3) to obtain 4.4 mg (yield: 2.4%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]=3[O:22][CH3:23])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:57][C@H:56]([CH2:55][O:54][C:51]1[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=1)[CH2:58][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[S:18][C:19]4[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=4[C:21]=3[O:22][CH3:23])=[O:16])[CH2:13][CH2:14]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)sc2ccccc12
Product: COc1c(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)sc2ccccc12
Yield: 30.6 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(3-methoxy-1-benzothiophen-2-yl)methanone (0.189 g, 0.461 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.187 g, 0.461 mmol) according to Procedure G to give the title compound (0.119 g, 0.141 mmol).
Reaction SMILES: [C:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:15])[C:10]=2[Br:14])[CH:5]1[CH2:16][C:17]([O:19]C)=O)(=[O:3])[CH3:2].BrC1C(F)=CC=C2C=1C=C[N:26]=C2.C([Si](OC(OC)=C)(C)C)(C)(C)C.Cl>C(Cl)Cl>[Br:14][C:10]1[C:9]([F:15])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:26][C:17](=[O:19])[CH:16]=[C:5]12
Reactant: Fc1ccc2cnccc2c1Br
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2C=CN1C(C)=O
Agent: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate. To a stirred solution of 5-bromo-6-fluoroisoquinoline (43.9 g, 194 mmol) in DCM (880 mL) acetyl chloride (14.49 mL, 204 mmol) was dropped at RT and the solution was stirred for 60 min. The solution was cooled to −78° C. (yellow suspension) and then a solution of tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (38.4 g, 204 mmol) in DCM (220 mL) was added in one portion. The resulting yellow solution was stirred at −78° C. for 1 h and then allowed to warm to rt overnight. 2N aqueous HCl was added and the reaction mixture was stirred for 10 min. The organic layer was separated and washed with brine (2×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether, charcoal was added and the mixture was filtrated through a pad of celite. The solvent was evaporated and the crude product was dried under high vacuo overnight to yield the title compound (70.6 g) which was used without further purification. UPLC-MS: MS 342.2/344.2 (M+H+); UPLC rt 1.05 min.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[C:15]2[C:19]=1[C:18](=[O:20])[CH2:17][CH2:16]2.C([C:33]([O:35][CH3:36])=[O:34])#N>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[C:15]2[C:19]=1[C:18](=[O:20])[CH:17]([C:33]([O:35][CH3:36])=[O:34])[CH2:16]2
Reactant: COC(=O)C#N
Reactant: COc1ccc(-c2cccc(C(F)(F)F)c2)c2c1C(=O)CC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1Cc2c(-c3cccc(C(F)(F)F)c3)ccc(OC)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A solution of lithium diisopropylamide (2.0 M in THF, 0.18 mL, 0.36 mmol) was added to a solution of 7-methoxy-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-one (103 mg, 0.34 mmol) in THF (1.1 mL) at −78° C. After 1 h at −78° C., methyl cyanoformate (40 μL, 0.50 mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (3×40 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (12 g column, hexanes→EtOAc, gradient) to afford 26 mg (21%) of methyl 7-methoxy-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][C:4]=1/[CH:17]=[CH:18]/[C:19](=O)[CH2:20][C:21](=O)/[CH:22]=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1.C1COCC1.O.[NH2:37][NH2:38].C([O-])(O)=O.[Na+]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1/[CH:17]=[CH:18]/[C:19]1[CH:20]=[C:21](/[CH:22]=[CH:23]/[C:24]2[NH:25][CH:26]=[CH:27][CH:28]=2)[NH:38][N:37]=1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(OCc2ccccn2)ccc1/C=C/C(=O)CC(=O)/C=C/c1ccc[nH]1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OCc2ccccn2)ccc1/C=C/c1cc(/C=C/c2ccc[nH]2)[nH]n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To 30 mg of (1E,6E)-1-[2-methoxy-4-(2-pyridylmethoxy)phenyl]-7-(1H-pyrrol-2-yl)hepta-1,6-diene-3,5-dione were added 1 mL of THF, 3 μL of AcOH and 4 μL of hydrazine monohydrate, and the mixture was stirred at 60° C. for 4 hours. To this, 500 μL of AcOH was added and the mixture was stirred at 80° C. for 1 hour. To this, 4 μL of hydrazine monohydrate was added and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was allowed to cool back to room temperature, and a saturated aqueous NaHCO3 solution was added. After extraction with AcOEt, the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over MgSO4, and concentrated. The residue was purified by PTLC (CHCl3/methanol or AcOEt system) to give 8 mg of the title compound (27% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:13]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cscn2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cscn2)c(F)c1
Yield: 81.1 %

Procedure:
A solution of tert-butyl 3-fluoro-4-(thiazol-4-yl)phenylcarbamate (270 mg, 0.92 mmol) in CH2Cl2 (2 mL) and TFA (4 mL) was stirred at room temperature for 60 min. It was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (20 mL), which was washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 3-fluoro-4-(thiazol-4-yl)benzenamine (145 mg) as free base. MS 195.2 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C@H:19]([CH3:22])[CH2:20][OH:21])[N:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)Cl.ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29].CO.C(=O)([O-])[O-].[K+].[K+].O>>[C:28](=[O:29])([O:21][CH2:20][C@H:19]([C:14]1[N:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=2)[N:15]=1)[CH3:22])[NH2:30]
Reactant: CCCCCCCOc1ccc2nc([C@H](C)CO)ncc2c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCCCCCCOc1ccc2nc([C@H](C)COC(N)=O)ncc2c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
(S)-2-(6-Heptyloxy-quinazolin-2-yl)-propan-1-ol (13, 950 mg, 0.0031 mol) was dissolved in methylene chloride (100 mL, 2 mol), followed by trichloroacetyl isocyanate (449 μL, 0.00377 mol) dropwise at 0° C. The reaction mixture was then gradually warmed up to 23° C., and stirred for additional for 1 hour. Solvent was removed under vacuum, and the residue was redissolved in methanol (100 mL, 3 mol), followed by potassium carbonate (5000 mg, 0.03 mol) and water (20 mL, 1 mol) at 0° C. The reaction mixture was then warmed up to at 23° C. and stirred for 3 hours. MeOH was removed under vacuum, and the aqueous layer was treated with DCM (10×5 mL). The combined organic layers were then washed with water and brine, and then dried over Na2SO4. The crude mixture was purified via chromatography (SiO2, 4 g, 0-100% ethyl acetate/hexanes) to give 1.05 g, (97%). 1H NMR (400 MHz, CHLOROFORM-d) δ: 9.24 (s, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.53 (dd, J=9.0, 2.8 Hz, 1H), 7.11 (d, J=2.8 Hz, 1H), 4.60 (dd, J=10.5, 8.0 Hz, 1H), 4.51 (br. s., 2H), 4.45 (dd, J=10.5, 6.0 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.47-3.62 (m, 1H), 1.81-1.92 (m, 2H), 1.40-1.65 (m, 11H), 0.82-0.96 (m, 3H). MS (ES, M+1): 346.30.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[CH:15](O)=O>>[CH2:1]([N:5]1[C:10]2[N:11]=[CH:15][NH:12][C:9]=2[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=CO
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
A solution of 36.6 g of 1-butyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (X) in 100 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 42.9 g (not dried). (XI). The amide (XI) was refluxed in 100 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and washed with ethanol. Yield 28.4 g (74%) (XII), NMR. ##STR9##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([S:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.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>[CH3:30][O:29][C:25](=[O:28])[CH:26]=[CH:27][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17]
Reactant: C=CC(=O)OC
Reactant: O=S(=O)(c1cc(F)ccc1OS(=O)(=O)C(F)(F)F)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Temperature: 120 °C
Yield: 43 %

Procedure:
To a solution of the product of example 85 (100 mg 0.254 mmol) in dry DMF (3 ml) was added methyl acrylate (0.09 ml, 1.02 mmol), Pd(PPh3)2Cl2(17.83 mg, 0.0254 mmol), DPPP (10.5 mg, 0.0254 mmol) and DIPEA (0.2 ml, 1.02 mmol) successively at room temperature in sealed tube. The mixture was heated at 120° C. for about 24 h. After cooling to room temperature, the mixture was poured into ice water and extracted with EA three times. The combined extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=5/1) to give the desire product (36 mg, yield 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]=[C:4]2[CH:3]=1.[CH2:27]([Sn:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([O-:16])=[O:15])[N:8]=[C:4]2[CH:3]=1.[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([O-:16])=[O:15])[N:8]=[C:4]2[CH:3]=1.[CH2:27]([Sn+2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Cl)cc3n2)c1O
Product: CC(C)(C)c1cc(CCC(=O)[O-])cc(-n2nc3ccc(Cl)cc3n2)c1O
Product: CCCC[Sn+2]CCCC

Procedure:
Following the synthetic procedure of Example 25, the title compound is prepared by reaction of the corresponding equivalent amounts of 3-(5-chloro-2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamic acid and dibutyltin oxide to give the title compound as a yellow resin (47.24 g, 97.6% yield) whose structure is consistent with 1Hnmr.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH2:19][CH:20]=[CH:21][CH3:22]>C(Cl)Cl>[O:9]1[CH:21]([CH3:22])[CH:20]1[CH2:19][CH2:18][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:27][CH2:28]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1OC1CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.49 g of 90% m-chloroperbenzoic acid in 100 ml of methylene chloride was treated with 11.3 g of powdered potassium carbonate. The mixture was treated dropwise at 0° C. within 5 minutes with a solution of 5.93 g of p-[trans-4-(3-pentenyl)cyclohexyl]benzonitrile in 20 ml of methylene chloride and stirred at room temperature for 2 hours. The mixture was subsequently treated with a further 4.49 g of 90% m-chloroperbenzoic acid and the resulting mixture was stirred further. After a total of 70 hours, the mixture was partitioned three times in methylene chloride/10% sodium thiosulphate solution. The organic extracts were washed with sodium thiosulphate solution and water, dried over magnesium sulphate, filtered and concentrated. Chromatographic separation of the resulting, light yellowish oil (6.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 6.27 g (99.5%) of p-[trans-4-(3,4-epoxypentyl)cyclohexyl]benzonitrile as a colourless oil.
Reaction SMILES: C[C:2](P(OC)(O)=O)([C:4]([O-:6])=[O:5])C.[Na].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=O)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[CH:16][CH:15]=1.[CH3:37]N(C=O)C>C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][C:25](/[C:29](/[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:2]/[C:4]([O:6][CH3:37])=[O:5])=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[CH:16][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CN(C)C=O
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)/C=C(\c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 85 °C
Yield: 91 %

Procedure:
Trimethylphosphonoacetate (2.4 g, 13.4 mmol) was dissolved in 15 mL anhydrous DMF and treated with sodium hexadimethylsilazane (13.4 mmol, 1 M in THF). (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanone (1.63 g, 5.16 mmol) was added and the reaction was heated to 85° C. for 16 hours. The following day, the cooled reaction was extracted from brine using ether×3 and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel using 25% EtOAc in hexanes to give 1.74 g (91%) of (E)-methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylacrylate as a clear oil. MS found: (M+H)+=373.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]2=[O:15].Cl.C([O:19][C:20](=[O:30])[CH2:21][CH:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C.CN1CCOCC1.F[P-](F)(F)(F)(F)F.[N:45]1(OC(N(C)C)=[N+](C)C)[C:49]2N=CC=C[C:48]=2[N:47]=N1>CN(C=O)C>[NH2:45][CH2:49][CH2:48][NH:47][C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([NH:29][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][C:20]([OH:19])=[O:30])=[O:14])[C:6]2=[O:15]
Reactant: O=C(O)c1ccc2cc(Cl)ccn2c1=O
Reactant: CCOC(=O)CC(N)c1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NCCNc1ccn2c(=O)c(C(=O)NC(CC(=O)O)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a stirring mixture of 8-Chloro-4-oxo-4H-quinolizine-3-carboxylic acid (22 mg, 0.098 mmol) in anhydrous DMF (1.5 ml) at room temperature was sequentially added (+/−)-3-amino-3-phenyl-propionic acid ethyl ester hydrochloride (28.4 mg, 0.123 mmol), N-methylmorpholine (32.4 μl, 0.295 mmol) and O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (48.6 mg, 0.128 mmol). The resulting mixture was allowed to stir at room temperature for 2 h. The solvent was removed under vacuum and the resulting residue was subjected to a silica gel chromatography (Rex:EtOAc=1:1 to pure EtOAc) to give desired product as yellowish solid (32 mg, 81%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:15]>CN(C)C=O>[Br:15][C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: Oc1ccnc2c(F)cc(F)cc12
Solvent: CN(C)C=O
Product: Fc1cc(F)c2nccc(Br)c2c1

Procedure:
This was prepared from 4-hydroxy-6,8-difluoro-quinoline by heating with phosphorus tribromide in dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([OH:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([O:18][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccccc2nc1-c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccc(F)cc3)c2cc1OC
Temperature: 145 °C
Reaction time: 5 h
Yield: 63.7 %

Procedure:
2-(4-Fluoro-phenyl)-quinolin-3-ol (52 mg), 4-chloro-6,7-dimethoxyquinoline (145 mg), and 4-dimethylaminopyridine (214 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 145° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (59 mg, yield 64%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:18]([O:20][C:21]([C@@H:23]([NH:32][C@H:33]([C:35](O)=[O:36])[CH3:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])[CH3:19].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:35](=[O:36])[C@H:33]([CH3:34])[NH:32][C@H:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 125.2 %

Procedure:
To an ice-cooled solution of L-proline benzylester hydrochloride (0.58 g) and crude N-(1-(s)-Ethoxycarbonyl-3-Phenylpropyl)-L-Alanine Hydrochloride (0.73 g) in DMF/CH2Cl2 (1:1, 20 ml) is added N-methylmorpholine (0.53 g), followed by 1-hydroxybenzotriazole (0.38 g). After 15 min of stirring, a cold solution of dicyclohexylcarbodiimide (0.65 g) in dry methylenedichloride (6 ml) is added and the mixture stirred at 0°-5° C. for 1 hour, then allowed to cool at room temperature overnight. The mixture is filtered and the filtrate after washing with aqueous NaHCO3 concentrated in vacuo to dryness to give 1.35 g of yellow viscous oil [TLC (Silica gel; CHCl3 /acetone=9:1); Rf=0.4]. The crude product is used for next reaction without further purification.