Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[O:23][CH3:22])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccccc1CCl
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccccc1CN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and 2-methoxybenzylchloride as described for compound 78. Purified by chromatography (dichloromethane). Crystallized from diethyl ether at -20° C. M.p. 96°-99° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.C(O)(=O)C.[N:18]1([C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([O:28]CC)=[O:27])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCOCC1>[C:26]([C:25]1[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH2:20][CH2:19]1)([OH:28])=[O:27]
Reactant: CCOC(=O)c1ccccc1N1CCNCC1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(CN2CCN(c3ccccc3C(=O)O)CC2)cc1
Yield: 57.3 %

Procedure:
Using 2.4 g of methyl 4-bromomethylphenylacetate, 2.9 g of ethyl 2-piperazinylbenzoate acetate, 3 ml of triethylamine, and 80 ml of dioxane, the reaction procedure of Example 2 was otherwise repeated and the reaction product was recrystallized from ethanol-water to provide 2.0 g of the title compound melting at 179° C.-181° C.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:9][NH:8][CH2:7][C@H:6]1[NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH:2]=[CH2:3].[N:27]1([C:33]([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:44]2[CH2:43][CH2:42][N:41]([C:38]3[CH:37]=[CH:36][C:35]([C:33]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:34])=[CH:40][CH:39]=3)[CH2:46][CH2:45]2)[CH2:7][C@H:6]1[NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1CNC[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCN(c2ccc(C(=O)N3CCOCC3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: C=CCO[C@@H]1CN(C2CCN(c3ccc(C(=O)N4CCOCC4)cc3)CC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To the solution of rel-N-(2-{[(3R,4R)-4-(allyloxy)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (60 mg, 0.16 mmol) in methanol (5 mL) was added 1-[4-(morpholin-4-ylcarbonyl)phenyl]piperidin-4-one (70 mg, 0.24 mmol) and sodium triacetoxyborohydride (68.5 mg, 0.32 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water (5 mL), and mixture then was extracted with EtOAc (15 mL×3). The organic phases were combined, dried over MgSO4, filtered, concentrated under reduced pressure and subjected to column chromatography (ethyl acetate, methanol and ammonium hydroxide (85:15:1) to afford the title compound (57 mg, 55%) as a white solid. 1H-NMR (CDCl3) δ: 1.44-1.62 (m, 2H), 1.79-1.88 (m, 2H), 2.00-2.18 (m, 2H), 2.24-2.37 (m, 2H), 2.61-2.68 (m, 4H), 3.25-3.33 (r, 1H), 3.59-3.68 (m, 8H), 3.78-3.79 (m, 1H), 3.92-3.99 (m, 1H), 4.05 (d, J=4.8 Hz, 2H), 4.08-4.16 (m, 1H), 4.27 (b, 1H), 5.09-5.25 (m, 2H), 5.76-5.89 (m, 1H), 6.81 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.47-7.52 (m, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 8.03 (s, 1H). MS m/z: 644 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12.S(Cl)([Cl:20])=O>CN(C)C=O>[ClH:20].[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1ccc2nc3cscc3c(=O)n2c1
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1ccc2nc3cscc3c(=O)n2c1
Temperature: 70 °C

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxamide (0.3 g., 0.0012 mol) and thionyl chloride (0.18 ml, 0.0025 mol) in dimethylformamide (5 ml) is heated at 70° C. under nitrogen for 4 hours. The reaction mixture is cooled in an ice bath. The product, which precipitates, is filtered off and washed with water. Recrystallization from dimethylformamide gives a crystalline product (0.15 g.), mp 294° C. (dec).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]([O:20][CH:21](OCC)[CH2:22][C:23](Cl)=[O:24])[CH3:19]>ClCCl>[CH2:18]([O:20]/[CH:21]=[CH:22]/[C:23]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:24])[CH3:19]
Reactant: CCOC(CC(=O)Cl)OCC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCO/C=C/C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 97 %

Procedure:
To a solution of 4-(trifluoromethyl)aniline (2.56 g, 15.9 mmol) in dichloromethane (40 ml) was added pyridine (3.77 g, 47.7 mmol). The solution was cooled to 0° C. before a solution of 3,3-diethoxypropanoyl chloride (4 g, crude) in dichloromethane (10 ml) was added dropwise with stirring. The resulting solution was stirred for 4 hours at 20° C. and then washed with water (200 ml). The resulting mixture was extracted with dichloromethane (3×80 ml) and the organic layers were combined and concentrated under vacuum. The crude residue was purified by Pre-TLC with 1-20% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford (2E)-3-ethoxy-N-(4-trifluoromethylphenyl)prop-2-enamide as a yellow solid (4.0 g). (ES, m/z): [M+H]+ 260; 1H NMR (300 MHz, DMSO): δ 10.10 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.72 (s, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.50-7.56 (m, 1H), 5.52 (d, J=12.4 Hz, 1H), 3.90-4.01 (m, 2H), 1.15-1.30 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][CH2:20][NH2:21])[CH3:14].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:21][CH2:20][CH2:19][C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CCOc1cccc(CCN)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1cccc(CCNCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.245 ml of 3-ethoxyphenethyl-amine (1.5 mmol) were dissolved in 5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) of sodium borohydride were added and after 10 min stirring at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 0.15 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue, 461 mg of a light yellow oil, was not further purified and used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][N:26]([CH3:39])[S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:32]=[CH:31][C:30]([S:27]([N:26]([CH3:39])[CH3:25])(=[O:28])=[O:29])=[CH:35][CH:34]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(S(=O)(=O)N(C)C)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 9.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(N,N-dimethyl-sulfamoyl)phenylboronic acid (23.8 mg, 0.104 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzenesulfonamide (2.4 mg, 9%). 1H-NMR (CDCl3): 2.31 (t, 1H), 2.57 (t, 1H), 2.78 (s, 6H), 3.33 (d, 3H), 3.56 (s, 2H), 5.88 (d, 1H), 7.20 (d, 1H), 7.26 (s, 1H), 7.48 (m, 5H), 7.57 (m, 1H), 7.62 (d, 2H), 7.80 (d, 2H).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:11][S:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cccc(S)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSc1cccc(C(C)=O)c1
Yield: 77 %

Procedure:
A suspension of 3′-mercaptoacetophenone (Reference compound No. 4-1, 1.5 g, 9.9 mmol), potassium carbonate (1.6 g, 12 mmol) and iodomethane (740 μL, 12 mmol) in N,N-dimethylformamide was stirred at 50° C. for 75 minutes. Water (50 mL) was added to the reaction mixture, extracted with a mixed solvent (50 mL) which consists of hexane and ethyl acetate (3:1). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title reference compound (1.3 g) as a brown oil (Yield 77%).
Reaction SMILES: BrCC(C1(C2C=CC(Cl)=CC=2)CCC1)=O.[Cl:16][CH2:17][C:18]([C:20]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:23][CH2:22][CH2:21]1)=[O:19].B.CSC.O1CCBN1>>[Cl:16][CH2:17][CH:18]([C:20]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:21][CH2:22][CH2:23]1)[OH:19]
Reactant: COc1ccccc1C1(C(=O)CCl)CCC1
Agent: B
Agent: B1CCON1
Agent: O=C(CBr)C1(c2ccc(Cl)cc2)CCC1
Solvent: CSC
Product: COc1ccccc1C1(C(O)CCl)CCC1
Yield: 70 %

Procedure:
Following the same procedures used for the asymmetric reduction of 2-Bromo-1-[1-(4-chloro-phenyl)-cyclobutyl]-ethanone (See Example 127), 500 mg samples of 2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanone were reduced to the enantiomerically enriched alcohols with borane-methyl sulfide in the presence of S-2-methyl CBS-oxazaborolidine or R-2-methyl CBS-oxazaborolidine. Each isomer of 2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanol was obtained in approximately 70% yield and ca. 90% e.e. based on chiral HPLC analysis. 240 mg of each chloroalcohol was converted to the corresponding epoxide using 1.1 equivalents of cesium carbonate in 5 mL of THF at 50° C. for 3 hours. Dilution with 20 mL of water, addition of 30 mL ether, and extractive workup gave in each instance, after concentration of the organic layers in vacuo and chromatography on silica gel, each of the desired epoxides (176 mg and 184 mg; 86% and 90% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[CH:7]=1)[CH3:2].[Cl:18]N1C(=O)CCC1=O.Cl.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[CH:12]=2)[C:7]=1[Cl:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Nc1ccc2cc(F)ccc2c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Nc1ccc2cc(F)ccc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of N-(6-fluoro-2-naphthyl)carbamic acid ethyl ester (548 mg, 2.35 mmol), N-chlorosuccinimide (313 mg, 2.35 mmol) and 1 M HCl in acetic acid (2.35 mL, 2.35 mmol) in acetic acid (20 mL) is heated at 50° C. under N2 atmosphere for 1 hour. After cooling to room temperature, water (10 mL) is added. The resulting precipitate is removed by filtration to give N-(1-chloro-6-fluoro-2-naphthyl)carbamic acid ethyl ester as a yellow solid.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17])[C:10](Cl)=[O:11]>C(#N)C>[CH3:19][O:18][C:14]1[CH:13]=[C:9]([CH:8]=[C:7]([O:6][CH3:5])[C:15]=1[O:16][CH3:17])[C:10]([N:3]=[C:2]=[S:1])=[O:11]
Reactant: N#C[S-]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)N=C=S)cc(OC)c1OC
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
Potassium thiocyanate is added to a solution of 3,4,5-trimethoxybenzoylchloride (2.3 g) in acetonitrile (40 ml). After stirring for 15 minutes at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure in order to produce the expected compound in the form of a beige powder (2.4 g, 96% yield). Melting point=101° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH3:26][Si:27](Cl)([CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:27]([CH3:34])([CH3:26])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Reactant: C[Si](C)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1(CO[Si](C)(C)c2ccccc2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (4.2 mmol) was dissolved in 20 ml of dichloromethane. The solution was cooled in ice-water bath, and 1 ml of triethyl amine (7 mmol) was added thereto. After stirring for 5 minutes, 1 ml of dimethylphenylsilyl chloride (6.2 mmol) was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the remainder was purified through column chromatography to give 1.44 g of concentrate (yield 92.4%).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]=[CH:7][C:8]=1[CH3:9])#N.[OH-:20].[K+].[OH2:22]>>[C:1]([C:3]1[C:4](=[O:19])[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]=[CH:7][C:8]=1[CH3:9])([OH:22])=[O:20]
Reactant: COc1ccc(Cn2ncc(C)c(C#N)c2=O)cc1
Reactant: [OH-]
Reactant: O
Agent: [K+]
Product: COc1ccc(Cn2ncc(C)c(C(=O)O)c2=O)cc1

Procedure:
To a stirred suspension of 4-cyano-2-(4-methoxybenzyl)-5-methyl-3-pyridazinone (0.51 g, 2.0 mmol) in water was added 5N aqueous KOH (2.61 mL). The mixture was heated under reflux for 24 hours. The mixture was cooled, filtered, and acidified with 10% HCl. The solid 4-carboxy-2-(4-methoxybenzyl)-5-methyl-3-pyridazinone was collected by filtration (0.54 g, 2.0 mmol, 100%).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:34][C:35]1[C:39]2[CH:40]=[C:41]([OH:44])[CH:42]=[CH:43][C:38]=2[O:37][C:36]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46].[C:50]([N:57]1[CH2:62][CH2:61][O:60][CH2:59][CH:58]1C(O)=O)([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>ClCCl>[CH3:34][C:35]1[C:39]2[CH:40]=[C:41]([O:44][CH2:1][CH:59]3[O:60][CH2:61][CH2:62][N:57]([C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:58]3)[CH:42]=[CH:43][C:38]=2[O:37][C:36]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: CCOC(=O)c1oc2ccc(O)cc2c1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1oc2ccc(OCC3CN(C(=O)OC(C)(C)C)CCO3)cc2c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triphenyl phosphine polymer bound (1.37 mmol) was suspended in anhydrous dichloromethane (10 ml) then diisopropyl azodicarboxylate (1.18 mmol) was added and the mixture was stirred for 15 minutes at room temperature. Then ethyl 3-methyl-5-hydroxybenzofuran carboxylate (0.91 mmol) was added over 5 minutes followed by the addition of 4-N-boc-3-morpholinecarboxylic acid (0.91 mmol) over 5 minutes too. The mixture was stirred at room temperature over night. The solvent was evaporated under vacuo and the residue purified by flash chromatography to obtain ethyl 3-methyl-5-(4-Boc-morpholin-2-ylmethoxy)-benzofuran-2-carboxylate: m/z=419 in MS ES+, as clear oil.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>N1C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:3])=[O:2]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Triflic anhydride (170 ml; 1.01 mol) was added to a solution of methyl 2-hydroxy-4-methylbenzoate (153 g; 0.92 mol) in pyridine (1.5 l), at 0° C., The mixture was stirred at ambient temperature overnight. After evaporation of the pyridine, the residue was acidified to pH 3.5 with 6N HCl and extracted with ether. The organic phase was evaporated and the residue purified by flash column chromatography eluting with a gradient of 0-5% ethyl acetate/petroleum ether to give methyl 2-trifluoromethylsulfonyloxy-4-methylbenzoate (245 g; 90%).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](OC([O-])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>ClCCl>[CH2:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: C1CCC2(C1)CCNCC2
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 8-azaspiro[4.5]decane (which has been described in WO 9800404 A1 6.2 g, 44.5 mmol) in dichloromethane (130 ml), which was cooled to 0° C., triethylamine (7.5 ml, 53.4 mmol) was added then a solution of tert-butyl dicarbonate (10.68 g, 48.9 mmol) in dichloromethane (50 ml) was added in 20 minutes. The clear solution was maintained under stirring at room temperature for 18 hours, then dichloromethane (50 ml) was added and the organic solution was washed with water (2×20 ml), HCl 0.1N (20 ml) then water (2×20 ml). The organic solvent was anhydrified (Na2SO4) and evaporated to give a crude that was purified on silica gel column (Hexane/AcOEt 95/5) to give 6 g of the title compound (light yellow solid).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:23]([F:37])([F:38])[C:24]1[CH:25]=[C:26]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=2)[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (2, 1.10 g, 3.32 mmol) and (3,5-bis(trifluoromethyl)phenyl)boronic acid (1.42 g, 3.32 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol) and 2 M Na2CO3 (20 mL) in DME (50 mL) was heated at 80° C. for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4×50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4-(3,5-bis(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (18) as a yellow oil (0.891 g, 68%): 1H NMR (300 MHz, DMSO-d6) δ 8.09-8.04 (m, 2H), 8.00-7.96 (m, 1H), 6.53-6.42 (m, 1H), 4.09-4.00 (m, 2H), 3.55 (t, J=5.7 Hz, 2H), 2.60-2.52 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@H:13](/[CH:16]=[CH:17]/[CH:18]([OH:25])[CH:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:11]2)([OH:3])=[O:2]>C(O)(C)C>[C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@H:13](/[CH:16]=[CH:17]/[C:18](=[O:25])[CH:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:11]2)([OH:3])=[O:2]
Reactant: CCCCC(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Solvent: CC(C)O
Product: CCCCC(F)C(=O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.5 h

Procedure:
(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (13') (0.140 g) was subjected to Jones oxidation between -15° C. and -20° C. The mixture was stirred for 30 minutes, isopropyl alcohol was added, and the resultant was treated by a usual work-up. The obtained crude product was purified on column chromatography (hexane/ethyl acetate=6/1-5/1) to give (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (14') as a colorless oily product. Yield: 0.106 g (76%)
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Methyl (7R)-7-[(tert-butoxycarbonyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.14 M) in DCM was treated with TFA (10 eq) and stirred at RT for 1 h. The reaction was diluted with DCM and cautiously basified with aq. NaHCO3, before separating the phases and extracting the aqueous with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the product as an off-white foam (100%) that was used without further purification. (ES+) m/z 405 (M+H)+; [α]D+42.3, c=1, MeOH