Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:5][CH2:4]1.[C:13]([NH:20][CH2:21][C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:13]([NH:20][CH2:21][C:22]([N:5]1[CH2:4][CH:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:23])([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: COC1CNCc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC1CN(C(=O)CNC(=O)OC(C)(C)C)Cc2ccccc21
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of 4-methoxy-1,2,3,4-tetrahydroisoquinoline (5.88 g, 36 mmol) in 100 mL of CH2Cl2 were added Boc-glycine (12.6 g, 72 mmol), 4-dimethylaminopyridine (8.80 g, 72 mmol), and dicyclohexyl carbodiimide (14.9 g, 72 mmol). After stirring overnight, the resulting precipitate was filtered and the filtrate was evaporated. A SiO2 chromatography (EtOAc:hexane=1:1) of the residue gave 4.9 g (43%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[N:19][CH:20]=1.S(Cl)(Cl)=O.O[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O.C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cncc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(OCc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A mixture of [5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methanol (1.20 g), thionyl chloride (0.6 mL), tetrahydrofuran (20 mL) and toluene (20 mL) was stirred at room temperature for 2 hrs. The precipitated crystals were collected by filtration and washed with diisopropyl ether to give crude crystals. A mixture of the obtained crystals, methyl 2-(4-hydroxyphenyl)acetate (0.70 g), anhydrous potassium carbonate (0.92 g) and N,N-dimethylformamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[4-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetate as a pale-yellow oil (1.52 g, 0.84%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:15][CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>Cl.CO>[C:1]12([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)NCCc1ccc(OCC23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: CO
Product: NCCc1ccc(OCC23CC4CC(CC(C4)C2)C3)cc1
Yield: 87.3 %

Procedure:
Obtained from Intermediate 35 (1.3 g, 3.37 mmol) in hydrogen chloride 1.25M in methanol by the same procedure described in Intermediate 17. The precipitate obtained was separated by filtration giving the title compound as a yellow solid (0.84 g, 87%). MS (M+): 286.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:15]([NH:14][C:3]2[C:2]([Cl:1])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=2)[CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
A mixture of ethyl 5,6-dichloronicotinate (5.0 g), tert-butyl (3R)-3-amino-1-pyrrolidinecarboxylate (5.08 g) and K2CO3 (4.71 g) in DMF (40 ml) was stirred at 100° C. for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with n-Hexane-AcOEt (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5-chloronicotinate (6.6 g).
Reaction SMILES: OC1C(C)=CC(N)=CC=1C.[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[O:23].[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>>[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[O:23].[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[N:32][NH:31][C:30]1[CH:29]=[CH:28][C:27]([S:33]([NH2:36])(=[O:34])=[O:35])=[CH:26][CH:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cc1cc(N)cc(C)c1O
Agent: Cc1cc2c(c(C)c1O)C(=O)C(=O)N2
Agent: Cl
Product: Cc1cc2c(c(C)c1O)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione was prepared from 4-hydroxy-3,5-dimethylaniline according to Procedure A. The title compound was prepared from 5-hydroxy-4,6-dimethyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 2.18 (s, 3H), 2.47 (s, 3H), 6.50 (s, 1H), 7.22 (s, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.99 (s, 1H), 10.78 (s, 1H), 12.98 (s, 1H); APCI-MS: m/z 359 (M−H)−. Anal. Calcd for C16H16N4O4S.0.25H2O: C, 52.67; H, 4.56; N, 15.35; S, 8.79. Found: C, 52.69; H, 4.47; N, 15.33; S, 8.87.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:7]([C:5]5[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:25]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)c(C(F)(F)F)n1
Yield: 71.4 %

Procedure:
In the same manner as in Example 55 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (78.6 mg, 0.405 mmol), tetrahydrofuran (5 mL), thionyl chloride (70.0 μL, 0.807 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.367 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (132 mg, 72%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])[C:11](=[O:24])[N:10]([CH2:25][C:26]([NH:28][C:29]([CH3:41])([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])[C:11](=[O:24])[N:10]([CH2:25][C:26]([NH:28][C:29]([CH3:41])([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)[CH3:30])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NC(C)(C)c3cccc(C(F)(F)F)c3)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)O)c2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
180 mg (0.31 mmol) of methyl 3-(3-(4-chlorophenyl)-1-[2-(1-methyl-1-[3-(trifluoromethyl)phenyl]-ethylamino)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-ylmethyl)-benzoate (Example 411) are dissolved in 3 ml of methanol and 3 ml of THF, treated with 0.3 ml of 2 N aqueous sodium hydroxide and stirred for 1 hr at 70° C. The reaction mixture is then introduced into ca. of 10 ml water, brought to pH 4 with 1 N hydrochloric acid, and stirred for 2 hrs at RT. The resulting precipitate is filtered off at the pump, washed with water and freed of solvent residues under high vacuum. 154 mg (88% of theory) of the target compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[N:6])[CH3:2].[CH2:8]([OH:10])[CH3:9]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])[C:5]([O:10][CH2:8][CH3:9])=[NH:6])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C#N
Solvent: CCOCC
Product: CCOC(=N)C(=O)OCC
Temperature: -40 °C

Procedure:
Nitriloacetic acid ethyl ester (83 mmol) was dissolved in diethyl ether (water free, 25 ml) and ethanol (water free, 85 mmol) was added and the stirred mixture cooled to −40° C. At this temperature, HCl (gaz, dried through concentrated sulfuric acid; 18 g total consumption) was bubbled into the solution over 1 hour. The cooling bath was removed and at 0° C. the reaction mixture warmed up quickly (additional cooling required) and the product precipitated. The solid material was filtered off, washed with diethyl ether and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C([SiH](CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:44]1([S:50]([C:53]2[CH:60]=[CH:59][CH:58]=[CH:57][C:54]=2[CH:55]=O)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[C:10]([CH3:13])=[C:11]([CH2:55][C:54]3[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=3[S:50]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:52])=[O:51])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Reactant: Cc1ccc(-c2ccnc(Cl)c2)n1CC(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)cc(-c2ccnc(Cl)c2)n1CC(=O)OCc1ccccc1
Yield: 17 %

Procedure:
was followed using benzyl 2-(2-(2-chloropyridin-4-yl)-5-methyl-1H-pyrrol-1-yl)acetate (0.900 g, 2.64 mmol), triethylsilane (1.27 ml, 7.92 mmol), trimethylsilyl trifluoromethanesulfonate (0.954 ml, 5.28 mmol) and 2-(phenylsulfonyl)benzaldehyde (0.650 g, 2.64 mmol) to afford benzyl 2-(5-(2-chloropyridin-4-yl)-2-methyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (514 mg, 0.450 mmol, 17% yield). 1D-NOESY experiment was performed to confirm the drawn regioisomer (irradiation of methyl group and 1-2% interaction with both methylene groups).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[C:4]([Br:12])[C:3]=1[Cl:13].[C:14](=[O:21])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:15].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:12][C:4]1[C:3]([Cl:13])=[C:2]([NH:15][C:14](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: FC(F)Oc1cc(Br)c(Cl)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(OC(F)F)cc(Br)c1Cl
Temperature: 105 °C
Yield: 71.9 %

Procedure:
1,3-Dibromo-2-chloro-5-(difluoromethoxy)benzene (4.38 g, 13.02 mmol), tert-butyl carbamate (1.220 g, 10.42 mmol), palladium(ii) acetate (0.146 g, 0.651 mmol), XANTPHOS (0.942 g, 1.628 mmol) and cesium carbonate (16.97 g, 52.1 mmol) were suspended in dioxane (87 ml) at room temperature. The reaction mixture was degassed through evacuating under vacuum and backfilling with N2 (Repeated 3×) and heated to 105° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through celite and concentrated. Column chromatography (120 g SiO2, 0 to 20% EtOAc-hexane gradient elution) afforded tert-butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)carbamate (2.79 g).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][S:9][N:8]=2)=[CH:3][CH:2]=1.B(F)(F)F.[CH3:20][CH2:21]OCC>C(O)C>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([C:7]2[C:11]([C:12]([O:14][CH2:20][CH3:21])=[O:13])=[CH:10][S:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2nscc2C(=O)O)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1csnc1-c1ccc(C)cc1
Yield: 89.7 %

Procedure:
3-(p-Tolyl)-4-isothiazolecarboxylic acid (1.5 g, 0.0068 mol), 20 ml of absolute ethanol, and boron trifluoride etherate (4.3 ml, 0.034 mol) were heated at reflux for 24 hours. Volatile materials were removed under reduced pressure. Water (25 ml) was added and the material extracted four times with ether. The ether was back-extracted with 5% NaHCO3, dried (CaSO4) and concentrated under reduced pressure to yield 1.51 g (0.0061 mol, 89.9%) of oil, nD25 =1.5671.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33]/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:47][C:48]1[S:49][CH:50]=[CH:51][N:52]=1>C(Cl)Cl>[S:49]1[CH:50]=[CH:51][N:52]=[C:48]1[NH:47][C:36](=[O:38])/[C:35](/[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=1)=[CH:34]/[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: O=C(O)/C(=C/CC1CCCC1)c1ccc(F)c(F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)/C(=C/CC1CCCC1)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A solution of triphenylphosphine (1.05 g, 4 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (712 mg, 4 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-4-cyclopentyl-2-(3,4-difluoro-phenyl)-but-2-enoic acid (0.63 g, 2.36 mmol) in methylene chloride (4 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (0.59 g, 5.9 mmol), and the resulting suspension was stirred at 25° C. over the weekend. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded (E)-4-cyclopentyl-2-(3,4-difluoro-phenyl)-but-2-enoic acid thiazol-2-ylamide (435 mg, 53%) as an amorphous solid: EI-HRMS m/e calcd for C18H18F2N2OS (M+) 348.1108, found 348.1103.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3C(OCC3C=CC=CC=3)=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCCC1c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(C3CCCN3)cc1)C2c1ccc(F)cc1
Yield: 11 %

Procedure:
Benzyl 2-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)phenyl)pyrrolidine-1-carboxylate (60 mg, 0.107 mmol) was dissolved in distilled methanol (15 mL), and the reaction mixture was stirred at room temperature under an atmosphere of hydrogen in the presence of a catalytic amount of palladium on carbon (11 mg, 0.01 mmol) for 2 hrs. After the reaction was completed, the catalyst was removed by filtration through a pad of Celite, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (MeOH:DCM=1:10) to give the title compound (5 mg, yield 11%) as a white foam. LC-MS (ESI) m/z: 426 (M+1)+ 1H-NMR (400 MHz, CD3O) δ (ppm): 1.78-1.88 (m, 1H), 1.95-2.08 (m, 2H), 2.24-2.32 (m, 1H), 3.05-3.12 (m, 1H), 3.21-3.27 (m, 1H), 4.17-4.21 (m, 1H), 4.34-4.36 (d, J=8.0 Hz, 1H), 4.75-4.77 (d, J=8.0 Hz, 1H), 6.91-6.95 (m, 2H), 7.09-7.15 (m, 2H), 7.17-7.25 (m, 1H), 7.22-7.25 (m, 1H), 7.29-7.34 (m, 4H), 7.55-7.57 (m, 1H), 7.63-7.67 (m, 1H).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)([OH:3])=O>O>[O:3]=[C:1]1[CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]2[CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:15]=[CH:16][C:17]1=2
Reactant: CC(C(=O)O)c1cccc(OCC2CCCCC2C(=O)O)c1
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)OCC1CCCCC1C2=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 8 %

Procedure:
2-[3-(2-Carboxycyclohexylmethyloxy)phenyl]propionic acid (14 g) was added to polyphophoric acid (80 g) and the mixture was heated with stirring for 2.5 hours in an oil bath maintained at 100° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel, using methanol-chloroform (2:98, v/v) as an eluent, to give 2-(6,6a,7,8,9,10,10a,11-octahydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid (1.05 g) as an oil. IR νmaxfilm cm-1 : 1700, 1680 (C=O). HRMS m/e: 288.1390 (M+) (Molecular weight calculated for C17H20O4 : 288.1362).
Reaction SMILES: [NH3:1].CCO.F[C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([F:17])[C:7]=1[C:8]#[N:9]>C1COCC1>[NH2:1][C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([F:17])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: N
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1c(F)ccc([N+](=O)[O-])c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of NH3 in EtOH (19 mL, 8.6 M, 160 mmol) was added dropwise to a solution of 2,6-difluoro-3-nitrobenzonitrile (10 g, 54 mmol) in THF (50 mL) at 0° C. under Ar and the resulting mixture was stirred at 0° C. for 1 h. The mixture was concentrated and the residue washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:49][CH:48]=1>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:54]([O:53][C:50]1[CH:49]=[CH:48][C:47]([C:5]2[S:1][C:2]([C:6]3[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=3)=[N:3][CH:4]=2)=[CH:52][CH:51]=1)[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCCOc1ccc(Br)cc1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=O)cc3)s2)cc1
Temperature: 100 °C
Yield: 38.7 %

Procedure:
To a stirring suspension of 4-(thiazol-2-yl)benzaldehyde (349 mg, 1.84 mmol), tricyclohexylphosphine (27 mg, 0.07 mmol), pivalic acid (64.2 μl, 0.55 mmol), potassium carbonate (382 mg, 2.77 mmol) and palladium (II) acetate (8 mg, 0.04 mmol) in DMA (5.15 mL) under nitrogen was added a solution of 1-bromo-4-(heptyloxy)benzene (500 mg, 1.84 mmol) in DMA (1 mL). The reaction mixture was evacuated and purged with nitrogen 3 times then heated at 100° C. for 6 h. Once cooled, the reaction mixture was diluted with EA (40 mL), washed with water (3×40 mL) and brine (40 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford a brown-green solid. The crude product was purified by chromatography (0-50% EA in hexanes) to afford 270 mg (37%) of 4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde as an iridescent yellow solid. LCMS-ESI (m/z) calculated for C23H25NO2S: 379.5. found 380.0 [M+H]+, tR=2.99 min. (Method 8).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:2].C(N(CC)CC)C.[CH3:18][O:19][P:20]([O-:23])[O:21][CH3:22]>C(OCC)(=O)C>[CH3:18][O:19][P:20]([CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([C:6]#[N:7])[CH:4]=1)[OH:2])(=[O:23])[O:21][CH3:22]
Reactant: COP([O-])OC
Reactant: N#Cc1cccc(C=O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COP(=O)(OC)C(O)c1cccc(C#N)c1
Yield: 74 %

Procedure:
A mixture of 3-formyl-benzonitrile (10 g, 76.26 mmol), triethylamine (9.26 g, 91.05 mmol) and dimethyl-phosphite (10.91 g, 99.14 mmol) was stirred in ethyl acetate at room temperature for 2 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (50 ml), washed with a saturated ammonium chloride solution (1×50 ml), dried (Na2SO4) and the filtrate was evaporated affording the crude [(3-cyanophenyl-hydroxymethyl]-phosphonic acid dimethyl ester as a yellow solid (13.60 g, 56.43 mmol, 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:13]([OH:16])[CH:14]=[CH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(C)[CH:26]=CC(S(O)(=O)=O)=C[CH:22]=1.C(OCC)(=O)C>COC(OC)(C)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:13]([CH:14]=[CH2:15])[O:16][C:21]1([CH3:26])[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 1369.8 %

Procedure:
124 mg of (3RS,4S)-4-(benzyloxycarbonyl)amino-6-methylhepten-3-ol was dissolved in 0.33 ml of 2,2-dimethoxypropane, and 4 mg of dry p-toluenesulfonic acid was added thereto. The mixture was stirred at room temperature overnight. Then, 20 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 101 mg of (4S,5RS)-3-benzyloxycarbonyl-2,2-dimethyl-5-ethenyl-4-isobutyloxazolidine as colorless oily substance.