Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[OH-].[Na+]>O.C(O)C.ClCCl>[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[N:2][OH:3]
Reactant: NO
Reactant: O=Cc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: ON=Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.7 %

Procedure:
A solution of hydroxylamine hydrochloride (3.68 g, 53 mmol) in water (5 ml) was added to a solution of 3-chlorobenzaldehyde (5.00 ml, 44 mmol) in ethanol (20 ml). A solution of sodium hydroxide (2.64 g, 66 mmol) in water (5 ml) was added. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was given onto water/ice (150 ml). The formed precipitation was isolated by filtration and dissolved in dichloromethane (200 ml). This solution was dried over magnesium sulphate. The solvent was removed to give 3.88 g of 3-chlorobenzaldehyde oxime, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].S(O)(O)(=O)=O.NO.C(C1C=C(N)[O:23][N:22]=1)(C)C>>[NH2:8][C:7]1[O:23][N:22]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: CC(C)(C#N)C(=O)CC#N
Reactant: CC(C)c1cc(N)on1
Agent: NO
Agent: O=S(=O)(O)O
Product: CC(C)(C#N)c1cc(N)on1
Yield: 23 %

Procedure:
Prepared from 2,2-dimethyl-3-oxopentanedinitrile (500 mg, 3.68 mmol) and hydroxylamine sulfate (332 mg, 2.02 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2. Purification via silica gel chromatography eluting with 5% to 60% ethyl acetate in hexanes, afforded 2-(5-aminoisoxazol-3-yl)-2-methylpropanenitrile as a colorless solid (130 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 5.22 (s, 1H), 4.58 (brs, 2H), 1.72 (s, 6H); LC-MS (ESI) m/z 152 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:12]([C:14](=[C:19](SC)SC)[C:15]([O:17][CH3:18])=[O:16])#[N:13].[NH2:24][C@H:25]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:32][C:33]([N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[C:26]1=[O:40]>C(#N)C>[CH3:18][O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:19]([NH:24][C@H:25]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:32][C:33](=[O:34])[N:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)[C:26]1=[O:40])[NH:11][C:9]1[CH:8]=[CH:7][C:5]2[CH:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Reactant: Cc1cc2ccc(N)cc2o1
Solvent: CC#N
Product: COC(=O)C(C#N)=C(Nc1ccc2cc(C)oc2c1)N[C@H]1CCCCN(CC(=O)N2CCCC2)C1=O
Yield: 7 %

Procedure:
In a procedure similar to that in example 36, the title compound (8 mg, 11%) was synthesized from 2-methyl-6-benzofuranamine (34 mg, 0.23 mmol), methyl 2-cyano-3,3-bis(methylthio)-2-propenoate (47 mg, 0.23 mmol), and 1-[[(3S)-3-aminohexahydro-2-oxo-1H-azepin-1-yl]acetyl]pyrrolidine (102 mg, 0.43 mmol) using acetonitrile as the reaction solvent: MS (ESI, pos, ion) m/z 494 (M+H); HPLC (method C) tR 3.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[O:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH:19]=[CH:18][C:17]=3[CH3:28])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.I[CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:32][CH3:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[O:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH:19]=[CH:18][C:17]=3[CH3:28])=[CH:14][CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: CCI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(Cl)cc4)cc3)c2)o1
Product: CCN(Cc1ccc(Cl)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-(4-Chlorobenzyl)-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(4-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, s), 7.58-7.42,(8H, m), 7.27,(1H, b), 4.69-4.53,(2H, m), 3.37-3.23,(2H, m), 2.55,(3H, s), 2.32,(3H, s), 1.06,(3H, b). LCMS; retention time 3.74 min, MH+ 446/448.
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH3:17])[CH:16]=1>[OH-].[Na+]>[N+:18]([C:14]1[CH:13]=[CH:12][C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:16][C:15]=1[CH3:17])([O-:20])=[O:19]
Reactant: Oc1ccccc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Combine potassium hydroxide (3 g, 0.054 mol) and phenol (15 g, 0.16 mol), and heat to 110° C. until the potassium hydroxide is dissolved. Cool the mixture to room temperature and add 5-fluoro-2-nitrotoluene (7.75 g, 0.05 mol) in one aliquot. Heat the reaction mixture to 130° C. for 30 min, cool to room temperature, and then pour into 10% NaOH (200 mL). Extract the aqueous solution with ether (2×100 mL), combine the organic layers and wash with 10% NaOH (2×100 mL), water (2×100 mL), dry over Na2SO4 and concentrate in vacuo. Chromatograph on silica gel eluting with hexanes/ethyl acetate to give 2-nitro-5-phenoxytoluene as a solid: 1H NMR (300 MHz, CDCl3) 2.59 (s, 3H), 6.81-6.85 (m, 2H), 7.06-7.09 (m, 2H), 7.22-7.26 (m, 1H), 7.40-7.45 (m, 2H), 8.03-8.06 (m, 1H).
Reaction SMILES: CN(C)CC[C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[N:10]([CH2:16][O:17][CH3:18])[C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=3[C:7]=2[N:6]=1>C(O)C.ClCCl.[Pd]>[CH3:11][N:10]([CH3:16])[CH2:9][CH2:8][C:21]1[CH:20]=[CH:19][C:9]2[N:10]([CH2:16][O:17][CH3:18])[C:11](=[O:15])[C:12]3[CH2:13][CH2:14][CH2:5][NH:6][C:7]=3[C:8]=2[CH:22]=1
Reactant: COCn1c(=O)c2ccc(CCN(C)C)nc2c2ccccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COCn1c(=O)c2c(c3cc(CCN(C)C)ccc31)NCCC2
Reaction time: 24 h
Yield: 181.2 %

Procedure:
The compound (22 mg, 0.07 mmol) prepared in step 6 was dissolved in ethanol (4 ml)/dichloromethane (2 ml), added with 10%-palladium (Pd) (5 mg) at room temperature. The resulting mixture was stirred for one day under hydrogen gas and filtered using celite to remove 10%-palladium (Pd). The filtrate was then concentrated under reduced pressure to obtain the title compound (20 mg, yield: 90%, white solid).
Reaction SMILES: C(O)C.Cl.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-])=O)=[CH:13][N:12]=2)=[CH:8][C:7]=1[C:23]([F:26])([F:25])[F:24]>[Fe].O>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([NH2:18])=[C:15]([CH3:17])[CH:16]=2)=[CH:8][C:7]=1[C:23]([F:26])([F:24])[F:25]
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1N
Temperature: 50 °C
Yield: 87 %

Procedure:
A 100 ml two-necked round-bottomed flask equipped with a KPG-stirrer, a thermometer and a reflux condenser is charged with ethanol (50 ml), water (5 ml), iron (1.29 g) and hydrochloric acid 37% (0.2 ml). The reaction mixture is heated at 50° C. 2-(4-chloro-3-trifluoromethyl-phenoxy)-4-methyl-5-nitro-pyridine (2.4 g) is added portionwise. The mixture is heated at reflux for 1 hour. After cooling the mixture to 50° C. is filtered through celite. The filtrate is poured into water (100 ml) and extracted with ethylacetate (2×50 ml). The combined organic layers are washed with brine (100 ml), dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification by flash chromatography over silica gel with hexane/ethyl acetate 1:1 (v:v) gives 1.90 g of the compound as a brownish solid (MP: 105-107° C.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([NH2:23])[S:22][C:18]=2[CH:17]=1.[P:26]([O-:31])([O:29][CH3:30])[O:27][CH3:28].ClCCl.CCOC(C)=O>C1(C)C=CC=CC=1>[CH3:28][O:27][P:26]([CH:1]([NH:23][C:21]1[S:22][C:18]2[CH:17]=[C:16]([O:15][CH3:14])[CH:25]=[CH:24][C:19]=2[N:20]=1)[C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])([O:29][CH3:30])=[O:31]
Reactant: COC(=O)c1cc(C=O)ccc1O
Reactant: COc1ccc2nc(N)sc2c1
Reactant: COP([O-])OC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(Nc2nc3ccc(OC)cc3s2)P(=O)(OC)OC)ccc1O

Procedure:
The mixture of methyl 5-formyl-2-hydroxybenzoate (2) (0.1 g, 5 mmol) and Mg(ClO4)2 (0.12 g, 5 mol %) was stirred for 10-15 minutes in anhydrous toluene (5 mL), after which time 6-methoxybenzo[d]thiazol-2-amine (1) (0.1 g, 5 mmol) and dimethyl phosphite (0.061 g, 5 mmol) were added, and the reaction mixture was refluxed for 6 hours. The progress of the reaction was monitored by TLC (Dichloromethane:EtOAc 1:9). After completion of the reaction, the solvent was removed under reduced pressure. The combined EtOAc extracts were dried (Na2SO4) and concentrated under reduced pressure to afford a white solid, which was purified by passing through silica gel column using EtOAc:dichloromethane (4:1) as eluent to afford compound (4). The same experimental procedure was adopted for the preparation of the remaining title compounds 5-7, 9-14 and 16-17.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[CH3:13][O-:14].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:14][CH3:13])[CH3:2]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cccnc1OC
Yield: 91 %

Procedure:
Ethyl-2-chloronicotinate (11.14g, 60 mmol) was dissolved in anhydrous methanol (60 mL). Sodium methoxide (18 mL, 25 wt-% in methanol) was added slowly at room temperature under nitrogen. The reaction mixture was stirred under reflux for 15 hours. Methanol was removed under vacuum. The residue was dissolved in ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous NH4Cl solution (1×100 mL) and brine (50 mL). Dried over anhydrous Na2SO4. Removal of solvent gave ethyl-2-methoxynicotinate as yellow oil (9.88 g, 91%). To a solution of 3,5-dimethyl-4-hydroxyacetophenone (2.46 g, 15 mmol) in anhydrous DMF (75 mL) was added imidazole (3.27 g, 48 mmol) and tert-butyldimethylsilylchloride (2.71 g, 18 mmol). The reaction mixture was stirred at room temperature under nitrogen for 15 hours. Water (200 mL) was added. The mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 3,5-demthyl-4-tert-butyldimethylsilyloxy acetophenone as a colorless oil in quantitative yield (4.4 g). To a stirred solution of 3,5-demthyl-4-tert-butyldimethylsilyloxy acetophenone (1.58 g, 5.6 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl) amide (6.8 mL, 1.0M solution in THF) at −40° C. over a period of 15 min. under nitrogen. Stirring was continued at −40° C. for 15 min. A solution of ethyl-2-ethoxynicotinate in anhydrous THF (15 mL) was added slowly. Stirring was continued at 40° C. for 10 min. The mixture was allowed to warm to room temperature. Stirring was continued for another 15 h at room temperature. The reaction mixture was diluted with ethyl acetate (200 mL). A saturated aqueous NH4Cl solution (50 mL) was added. The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave the desired crude compound (2.4 g) which was used in next step without purification. The above compound (2.31 g, 5.6 mmol) and pyridinium hydrochloride (6.47 g, 56 mmol) was mixed together and stirred at 190° C. for 3 hours. The mixture was cooled to room temperature. Water (100 mL) was added. The solid was filtered off, washed with water and dried under vacuum. The crude product was purified by column chromatography (SilicaGel 230-400 mesh; 2% methanol in CH2Cl2 as eluent) to give 2-(4-hydroxy-3,5-dimethylphenyl)-4H-pyrano[2,3-b]pyridin-4-one (0.598 g, 40% yield over two steps); MS (ES) m/z: 268.91 (M+1), 267.88 (M); MP 295-297 C
Reaction SMILES: [C:1]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23]>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([OH:23])[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Brc1cccc2ccccc12
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1cccc2ccccc12

Procedure:
With 2.81 g of 1-naphthyl bromide 4.34 g, 5-chloroisatin as starting material, 4.30 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH:30]=1)=[O:5])[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(C=Cc4ccccc4)cc3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(CCc4ccccc4)cc3)c2c1

Procedure:
Five-percent palladium on carbon was added to a solution of 0.320 g of 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole in 10 ml of ethanol in a nitrogen atmosphere, and the mixture was stirred in a hydrogen atmosphere for 23 hours. The solid material was separated through filtration, and the filtrate was concentrated to give 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]benzimidazole (368). This compound was used in the subsequent reaction at once.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[O:12][CH3:13].[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:15]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[O:16])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(CN)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)n2ccnc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To a mixture of 4-aminomethyl-2-methoxy-benzoic acid methyl ester (149 mg, 0.763 mmol) in N,N-dimethyl formamide (4.0 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 127 mg, 0.762 mmol). After it was stirred at rt for 16 hrs under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-{[(imidazole-1-carbonyl)-amino]-methyl}-2-methoxy-benzoic acid methyl ester (224.3 mg, 101% crude) which was used without further purification.
Reaction SMILES: COC1N=C2C(=CC=1)N[C@@H](C)C[C@H]2NC(=O)C.[CH2:18]([CH:20]1[CH:29]([CH3:30])[CH:28]([NH:31][C:32]2[CH:33]=[N:34][C:35]3[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=3[CH:41]=2)[C:27]2[N:26]=[C:25]3[CH2:42][CH2:43][CH2:44][CH2:45][C:24]3=[CH:23][C:22]=2[NH:21]1)[CH3:19].Cl[C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH:50]([O:49][C:47]([N:21]1[CH:20]([CH2:18][CH3:19])[CH:29]([CH3:30])[CH:28]([NH:31][C:32]2[CH:33]=[N:34][C:35]3[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=3[CH:41]=2)[C:27]2[N:26]=[C:25]3[CH2:42][CH2:43][CH2:44][CH2:45][C:24]3=[CH:23][C:22]1=2)=[O:48])([CH3:52])[CH3:51]
Reactant: CC(C)OC(=O)Cl
Reactant: CCC1Nc2cc3c(nc2C(Nc2cnc4c(c2)CCCC4)C1C)CCCC3
Agent: CN(C)c1ccccn1
Agent: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2
Solvent: c1ccncc1
Product: CCC1C(C)C(Nc2cnc3c(c2)CCCC3)c2nc3c(cc2N1C(=O)OC(C)C)CCCC3
Yield: 31 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 46, Step 2, by replacing (+/−)-cis-N-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide, with (2-ethyl-3-methyl-1,2,3,4,6,7,8,9-octahydro benzo [b][1,5]napthyridin-4yl)-(5,6,7,8-tetrahydro-quinolin-3-yl)-amine (0.575 g, 1.52 mmol), and using isopropyl chloroformate, pyridine, and dimethylaminopyridine. Purify using silica gel column chromatography (gradient eluent, neat ethyl acetate) to provide the title compound (0.218 g, 31%). MS (ES+): 463 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:9]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:10]([NH:46][CH2:45][C:44]1[CH:47]=[CH:48][C:41]([F:40])=[CH:42][CH:43]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
To a solution of 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (335.4 mg, 1 mmol) and triethylamine (404.8 mg, 4 mmol) in THF (5 mL) at −5° C., isobutyl chloroformate (143.5 mg, 1.05 mmol) was added dropwise. After 20 minutes, 4-fluorobenzylamine (137.5 mg, 1.1 mmol) was added and the reaction mixture was allowed to warm up to room temperature. The mixture then was diluted with ethyl acetate and washed with water, 0.5 N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated with silica gel and purified by column chromatography, eluting with 10-20% ethyl acetate in hexanes, to give 2-dibenzylamino-3-difluoromethoxy-N-(4-fluorobenzyl)propionamide (395 mg, 89.2%) as a colorless oil. 1H NMR (300 MHz, CDCl3): (ppm) 7.56 (t, 1H), 6.98-7.32 (m, 14H), 6.35 (wt, 1H), 4.61 (dd, 1H), 4.41 (m, 3H), 3.86 (d, 2H), 3.70 (d, 2H) and 3.68 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:21][C:20]3=[O:32])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH2:33].[OH-].[Li+]>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:33])[CH2:24][NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]([OH:21])=[O:32])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CNc4ccccc4)OC3=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CNc3ccccc3)C(=O)O)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of 3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(phenylamino)methyl]-tetrahydrofuran 19a (0.19 g, 0.42 mmol) in water (3 mL) and THF (3 mL) is added slowly lithium hydroxide monohydrate (180 mg, 4.2 mmol). The reaction mixture is stirred for 4 h, and then concentrated to dryness. The resulting mixture is diluted with water, and then the mixture is extracted twice with Et2O. The Et2O layer is discarded and the aqueous layer is neutralized carefully with 1N HCl to pH 6, then extracted three times with EtOAc. The combined EtOAc layer is washed with brine, dried over MgSO4 and concentrated to a solid which is recrystallized from EtOAc/hexane (3:7) to give the desired product as a white solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@H:8]1[CH2:25][C:24]2[CH2:23][C:22](=O)[CH2:21][CH2:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[CH2:27])[CH2:12][CH2:11]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:7][C@@H:8]1[CH2:25][C:24]2[CH2:23][C:22](=[CH2:1])[CH2:21][CH2:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[CH2:27])[CH2:12][CH2:11]1
Reactant: CC(C)(C)[O-]
Reactant: C=C1CC[C@H]2[C@@H]3[C@H](C)CC4=C(CCC(=O)C4)[C@H]3CC[C@]12C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCC2=C(C1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)C(=C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Methyltriphenylphosphonium bromide (2.2 g, 6 mmol) was added to a stirred solution of potassium t-butoxide (680 mg, 6 mmol) in 25 ml dry THF under a nitrogen atmosphere. The yellow suspension was stirred for 30 minutes at room temperature. A solution of (7α)-7-methyl-3-keto-17-methyleneestr-5(10)ene (850 mg, 3 mmol) in 25 ml dry THF was added rapidly (approx. 30 seconds) to the suspension, resulting in a slightly exothermic reaction. The reaction mixture was stirred for 30 minutes at room temperature, poured on ice-water (100 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), dried (Na2SO4) and evaporated to dryness to give (7α)-7-methyl-3,17-dimethyleneestr-5(10)ene (680 mg, 80%) as a colorless oil. [α]D +115° (c 0.185 in ethanol).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH3:30])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:21]>CN(C=O)C.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[CH:19]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH3:30])=[CH:28][CH:27]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CC(Br)C(=O)Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccnc2ccccc12)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
To a solution of 4-hydroxyquinoline (100 mg, 0.69 mmol) in anhydrous DMF under N2 was added K2CO3 (286 mg, 2.10 mmol) and a solution of 2-bromo-N-(4-chlorophenyl)propanamide (218 mg, 0.83 mmol) in DMF. The reaction mixture was stirred for 12 h at room temperature before being diluted with water (50 mL) and extracted with chloroform (3×50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate/n-hexane (a gradient of 10%) to furnish 114 (207 mg, 92% yield) as a white solid. mp. 170-172° C., 1H NMR (CDCl3, 400 MHz) δ 1.83 (d, J=6.4 Hz, 3H), 5.06 (q, J=6.8, 13.6 Hz, 1H), 6.76 (d, J=5.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.61 (t, J=8.0 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 8.09 (d, J=7.2 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.76 (d, J=5.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 18.72, 75.83, 102.05, 122.27, 121.32, 121.58, 126.61, 129.34, 129.60, 130.34, 130.51, 135.40, 149.74, 151.48, 159.47, 169.20; ESI-HRMS for C18H16N2O2Cl (M+H)+calcd. 327.0900. found 327.0901.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17](=O)[C:18]([CH3:21])([CH3:20])[CH3:19])(=O)OC.O.[NH2:24][NH2:25]>>[C:18]([C:17]1[N:25]=[N:24][C:4]2[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=2[CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COP(=O)(CC(=O)C(C)(C)C)OC
Reactant: NN
Reactant: CC1(C)CC(=O)C(=O)C1
Solvent: O
Product: CC1(C)Cc2cc(C(C)(C)C)nnc2C1

Procedure:
white crystalline solid. MS (ESI): 205.0 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, (3,3-dimethyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.