Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:6]([OH:13])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.CO>O=[Pt]=O.O>[ClH:1].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C:3]2[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=2[OH:17])[CH:6]([OH:13])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:22][CH:21]=1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(N)c1
Reactant: COc1ccc(C=O)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2cc(C(O)CNC(C)(C)C)ccc2O)cc1

Procedure:
A mixture of 3-amino-4-hydroxy-α-(tert.butylaminomethyl)-benzylalcohol hydrochloride (6.53 g, 0.025 mole), p-methoxybenzaldehyde (3.4 g, 0.025 mole), PtO2 (180 mg), and methanol (125 ml) was placed in a hydrogenation apparatus and hydrogenated at normal pressure (20 - 30 cm H2O superatmospheric) for one hour and 50 minutes. During this period of time, the calculated amount of hydrogen was absorbed, and the hydrogenation was interrupted by supplying argon. The platinum catalyst was filtered off with continued supply of argon, but in spite of this, the filtrate quickly became dark due to oxidation. The filtrate was immediately evaporated in vacuum at 40° - 50° C. The residue which was a light brown foam (9.53 g), was recrystallized twice by precipitation from ethanol/ether (1:1). The yield of the analytical pure 3-(4-methoxybenzylamino)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride was 5.2 g (55%), m.p. 196.6° - 197.8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[CH3:22])[S:11][CH:12]=1.[CH:23](OCC)=[O:24].Cl>C(O)=O.C(OCC)(=O)C>[CH3:22][C:14]1[CH:15]=[CH:16][C:17]([NH:19][CH:23]=[O:24])=[CH:18][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:9]=1
Reactant: CCOC=O
Reactant: Cc1ccncc1-c1csc(-c2cc([N+](=O)[O-])ccc2C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Cc1ccncc1-c1csc(-c2cc(NC=O)ccc2C)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
4-Methyl-3-[2-(2-methyl-5-nitrophenyl)-1,3-thiazol-4-yl]pyridine (98 mg) and reduced iron (170 mg) were suspended in a mixture of formic acid (3 ml)-ethyl formate (3 ml). 1N Hydrochloric acid (0.2 ml) was added and the mixture was stirred at 80° C. for 12 hrs. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off. The organic layer was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was separated and concentrated by drying. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1–0:1) for purification. Recrystallization from ethyl acetate gave the title compound (15 mg) as pale-yellow columnar crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH3:16])[C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17](=O)([O:19]CC)[NH2:18]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][CH:5]=[C:6]([CH3:16])[C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:18][C:17]1=[O:19]
Reactant: CCOC(N)=O
Reactant: CNc1scc(C)c1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1csc2c1c(-c1ccccc1)nc(=O)n2C
Temperature: 200 °C

Procedure:
A mixture of 2.0 g of 2-methylamino-3-benzoyl-4-methylthiophene, 2.3 g of ethyl carbamate and 0.18 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is recrystallized from chloroform-ethanol to give 1-methyl-4-phenyl-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 275° - 280°C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([C:17]2[CH:18]=[N:19][C:20](S(CCC)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:19][CH:18]=2)[CH:3]=1
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Reactant: C1CCNCC1
Product: O=C(O)COc1ccc(Cl)cc1-c1cnc(N2CCCCC2)nc1

Procedure:
The title compound was prepared from the product of example 20 step (iv) and piperidine by the method of example 20 step (v).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:25])([CH3:24])[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[C:19](OCC)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:24][C:3]1([CH3:25])[CH2:4][N:5]2[C:9]3[N:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=[CH:13][C:8]=3[CH:7]=[C:6]2[C:19](=[O:20])[NH:1][CH2:2]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)(C)CN)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)nc3n2C1
Temperature: 60 °C
Reaction time: 16 h
Yield: 107.8 %

Procedure:
To a solution of diethyl 1-(3-amino-2,2-dimethylpropyl)-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (3.30 g, 9.50 mmol) in ethanol (45 mL) is added potassium carbonate (3.94 g, 28.5 mmol). The mixture is stirred at 60° C. for 16 h and is then cooled to room temperature. The ethanol is evaporated and the aqueous mixture is acidified to pH 5 with 1N hydrochloric acid. The resulting solid is collected by filtration and dried in vacuo to afford the title compound as a pale yellow solid (2.80 g, quantitative). LCMS: 274.70 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[S:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([OH:17])=O)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[CH2:48]([O:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C:8]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:20])=[O:21])[S:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:56][O:55][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:17])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)N(CC(=O)O)C2=O)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)N(CC(=O)NOCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
To a solution of 2-[5-Benzyl-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-3-yl]-acetic acid (Example 27) (0.400 g, 0.92 mmol) in 13 mL of dichloromethane was added 1-hydroxybenzotriazole (0.126 g, 0.93 mmol), 4-methylmorpholine (0.506 g, 5.00 mmol), O-benzylhydroxylamine hydrochloride (0.440 g, 2.76 mmol), and 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.232 g, 1.21 mmol) and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. The mixture was diluted with 50 mL of dichloromethane and washed with 2×100 mL of water. The combined aqueous washings were back extracted with 100 mL of dichloromethane and the combined organic phases were washed with 100 mL of brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Column chromatography provided 0.280 g of 2-[5-Benzyl-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-3-yl]-N-benzyloxyacetamide as a colorless foam. This material was dissolved in 25 mL of dioxane and stirred at room temperature under a hydrogen atmosphere with an excess of 10% Pd on carbon for 2 days. The mixture was filtered through a celite pad washing with dioxane, followed by ethyl acetate, then methanol. The combined filtrates were concentrated in vacuo and column chromatography provided 0.050 g of the title compound as a white powder. m.p. 81-85° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][O:37][C:34]1[N:33]=[CH:32][C:31]([C:27]2[CH:26]=[C:25]([C:23]3[CH2:22][C:21](=[O:39])[NH:20][C:9]4[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3ccc(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)ccc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M151) (245 mg, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (101 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH2:17](Br)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:13][CH2:12]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: Cc1ccc(N2CCNCC2)cc1[N+](=O)[O-]
Product: CCCCN1CCN(c2ccc(C)c([N+](=O)[O-])c2)CC1

Procedure:
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and 1-butylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 277 (M+, 23), 234 (bp), 191 (17), 70 (64), 56 (33).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O)([O-:28])=[O:27].[OH-].[Na+]>ClCCCl>[OH:11][C:4]1[CH:3]=[C:2]([NH:1][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(O)c1ccc(NCc2cccc([N+](=O)[O-])c2)cc1O
Yield: 55.5 %

Procedure:
To a solution of 4-amino salicylic acid (153 mg; 1 mmol) in 1,2-dichloroethane (4 mL) under argon atmosphere was added sodium triacetoxyborohydride (317 mg; 1.5 mmol) and 3-nitrobenzaldehyde (226 mg; 1.5 mmol). The mixture was stirred at room temperature under argon overnight after which time 1 M NaOH (sq.; 5 mL) was added and the two layers separated. The aqueous layer was acidified with 2 M HCl (aq) and the precipitate formed filtered off and dried to yield 160 mg (55%) of a yellowish powder with satisfactorily purity. Mp. 189° C. (decomposes); MS (ESI−): 287 (MH−).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]4[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=4[O:20][C:21]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:13][CH:12]=2)[C:8]2[C:31]([C:35]([O:37]C)=[O:36])=[CH:32][CH:33]=[CH:34][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]4[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=4[O:20][C:21]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:15][CH:16]=2)[C:8]2[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH:33]=[CH:34][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2c(-c3nnn[nH]3)oc3ccccc23)cc1
Solvent: CO
Product: CCCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2c(-c3nnn[nH]3)oc3ccccc23)cc1

Procedure:
A solution of methyl 2-butyl-1-[[4-[2-(1H-tetrazol-5-yl)benzo[b]furan-3-yl]phenyl]methyl]benzimidazole-7-carboxylate (1.1 g) 1N aqueous NaOH (12 ml) in methanol (50 ml) was stirred at room temperature for 24 hours. After evaporation of methanol, the residue was neutralized with 1N aqueous hydrochloric acid to precipitate crystals. Recrystallization from DMF-methanol afforded colorless crystals (0.82 g, 77%), m.p. 194°-195° C.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].OO.[Cl:9][C:10]1[CH:11]=[C:12]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([F:38])[CH:31]=2)[CH:13]=[C:14]([Cl:29])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:18]1=[O:28]>CS(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH2:37])=[O:2])=[C:32]([F:38])[CH:31]=2)[CH:13]=[C:14]([Cl:29])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:18]1=[O:28]
Reactant: N#Cc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1F

Procedure:
Add potassium carbonate (83 mg, 0.6 mmol) and hydrogen peroxide (30% in water, 0.5 mL) to a solution of Preparation 13 (3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-3-fluoro-biphenyl-4-carbonitrile) (88 mg, 0.2 mmol) in DMSO (3 mL). Stir the reaction at room temperature for 12 h. Partition the mixture between ethyl acetate (20 mL) and water (20 mL). Separate the organic layer, wash three times with water (15 mL each) then brine (15 mL). After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 1:1 ethyl acetate/hexane to afford the title compound: MS (m/z): 463 (M+).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])=O)C1C=CC=CC=1.[N:23]1[C:32]2[C:27](=[N:28][C:29]([CH:33]=O)=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.N1CCCCC1>CC(O)C>[N:28]1[C:27]2[C:32](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:31]=[CH:30][C:29]=1[CH:33]=[C:15]1[NH:11][C:12]([NH:17][C:18]([CH:20]2[CH2:21][CH2:22]2)=[O:19])=[N:13][C:14]1=[O:16]
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NC(=O)C2CC2)=N1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1N=C(NC(=O)C2CC2)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 2-(cyclopropanecarbonyl-amino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (109.6 mg, 0.36 mmol), 1,5-naphthyridine-6-carboxaldehyde (47.4 mg, 0.30 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3.5 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give cyclopropanecarboxylic acid (5-[1,5]naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-amide as a light brown solid, 32.6 mg (35.4%). HR-ES (+) m/e calcd. for C16H13N5O2: (M)+ 307.1069. Found: 307.1066.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[C:21]([O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH:9][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:17][CH:16]=1)(=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NCCc1ccc(O)cc1)c1cccnc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1
Temperature: 0 °C

Procedure:
To an ice cold suspension of 4.84 g (0.02 mol) N-nicotinoyltyramine in 100 ml chloroform, 3.6 g (0.03 mol) of trimethylacetyl chloride were dropped while stirring. The mixture was refluxed overnight and the non-reacted nicotinoyltyramine was filtered off. The filtrate was washed with water until free from chloride ions, washed once with 5% solution of NaHCO3 and then with water. Chloroform was evaporated on rotavap and the residue was crystallized from ether/pet. ether. Yield 3.9 g (60%), m.p. 80°-82° C. PMR (CDCl3) δ 8.66-6.93 (m, 8H, C5H4N+C6H4), 3.56 (q, 2H, J=7 Hz, ##STR1536## 2.86 (5, 2H, J=7 Hz, CH2), 1.33 (s, 9H, C--(CH3)3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:5]([CH3:9])[C:6]([OH:8])=O.[C:19]([O-])(=[O:21])[CH3:20].[Na+]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:9])=[C:6]([O:8][C:19](=[O:21])[CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[CH:10]=1)=[O:18]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: 150 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of crude 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester (approximately 49 g, 0.196 mol) in acetic anhydride (490 mL) was added sodium acetate (32.15 g, 0.392 mol) in one portion. The reaction mixture was stirred at 150° C. for 3 hours. After this time, the reaction mixture was cooled to room temperature, then stirred overnight. Acetic anhydride was removed in vacuo, providing a viscous brown oil. This crude product was dissolved in ethyl acetate. The resulting solution was washed with a saturated, aqueous ammonium chloride solution. The organic phase was dried over Na2SO4, filtered, and concentrated. Flash chromatography (Analogix SuperFlash™ 10% ethyl acetate in hexane) gave 18.4 g (34%) of 4-acetoxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[O:37][C:38]([CH3:54])=[C:39]([CH2:41][CH2:42]OS(C4C=CC(C)=CC=4)(=O)=O)[N:40]=3)[CH:31]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:42][CH2:41][C:39]2[N:40]=[C:36]([C:32]3[CH:31]=[C:30]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=4)[CH:35]=[CH:34][CH:33]=3)[O:37][C:38]=2[CH3:54])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4ccc(F)cc4)c3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid 2-[2-(4′-fluorobiphenyl-3-yl)-5-methyloxazol-4-yl]ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.18–8.17 (m, 1H), 7.96–7.94 (m, 1H), 7.62–7.57 (m, 3H), 7.51–7.47 (m, 1H), 7.23–7.11 (m, 2H), 7.16–7.11 (m, 3H), 6.98–6.94 (m, 1H), 6.84–6.81 (m, 4H), 6.78–6.75 (m, 1H), 4.24 (t, J=6.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 2.99 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) 580.2 (M+)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:30][CH2:31][OH:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:51](OC(=O)C)(=[O:53])[CH3:52].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:51]([O:32][CH2:31][CH2:30][C@:22]([OH:33])([C@@H:21]([C:19](=[O:20])[NH:18][C@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])(=[O:53])[CH3:52]
Reactant: CC(=O)OC(C)=O
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reaction time: 1.5 h
Yield: 76 %

Procedure:
No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate, Compound D (13.7 g, 19.6 mmol) was dissolved in dichloromethane (274 mL), and then acetic anhydride (4.64 mL, 49.1=mop, triethylamine (2.74 mL, 19.7 mmol), and dimethylaminopyridine (240 mg, 1.96 mmol) were added at 0° C. After stirring for 1.5 hours, the mixture was quenched with water (195 mL) and then separated. The aqueous layer was extracted with dichloromethane (195 mL). The dichloromethane layers were combined, then washed with a saturated aqueous solution (140 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 11.0 g (14.8 mmol, yield 76%) of No. 5318799 (Compound R).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:2]=[CH2:3].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[S:20].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:19]([NH:18][C:12]1[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:17])=[S:20])[CH:2]=[CH2:3]
Reactant: Cc1cccc(C)c1N=C=S
Reactant: C=CCNCCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CCC(=O)O)C(=S)Nc1c(C)cccc1C
Yield: 39.7 %

Procedure:
A mixture of the 3-allylaminopropionic acid (21.9 g), 2,6-dimethylphenyl-isothiocyanate (19 g), triethylamine (20 g) and methylene chloride (200 mL) was heated at reflux for 3 hours. The cooled reaction mixture was extracted with 1N NaOH (150 mL). The aqueous layer was separated and acidified with 2N HCl. The solid was collected by filtration. 13.5 g of the title compound was obtained and used without further purification for the reaction in step 3.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][C:8]2(C)C)[CH2:3]1.[OH:12][CH2:13]CC1NC(=O)C1.C(OC)(OC)OC>>[O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][CH:8]2[O:12][CH3:13])[CH2:3]1
Reactant: O=C1CC(CCO)N1
Reactant: CC1(C)OCCC2CC(=O)N21
Solvent: COC(OC)OC
Product: COC1OCCC2CC(=O)N21

Procedure:
Following the procedure described for the preparation of 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane from 4-(2'-hydroxyethyl)-2-azetidinone and using trimethyl orthoformate instead of 2,2-dimethoxypropane one obtains 8-oxo-2-methoxy-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [OH:1][CH:2]1[CH:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH2:3]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](Cl)=[O:22])=[CH:13]1>>[CH:2]1([O:1][C:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][CH:13]=2)=[O:22])[CH:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: OC1CCCN2CCCCC12
Product: O=C(OC1CCCN2CCCCC12)c1c[nH]c2ccccc12

Procedure:
eq-1-Hydroxyquinolizidine (H. S. Aaron et al, J. Org. Chem. 1964, 29, 2248) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ether to afford the title compound (E11a) as a white solid, mp 230°-232° C.