Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:22][O:23][CH3:24])[C:5]=1[CH3:11]
Reactant: COCCl
Reactant: COC(=O)c1cccc(O)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0° C. under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50% complete by tlc (1:2 ethyl acetate/hexanes, 12) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0° C. and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate/hexanes) affording 0.44 g (69%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Temperature: 27.5 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
Raltegravir (50 gm) was suspended in ethanol (500 ml) and then added potassium hydroxide (8 gm) at 25 to 30° C. The reaction mass was stirred for 18 hours at 25 to 30° C. and filtered. The solid obtained was dried under vacuum at 60° C. for 9 hours to obtain 50 gm of raltegravir potassium crystalline form 1-11.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][CH:8]=2)[N:6]=1.CCN(CC)CC.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[CH2:15][N:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:38]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:39])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(NC(=O)CNCc3ccccc3)cc2)cs1
Reactant: O=C(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1nc(-c2ccc(NC(=O)CN(Cc3ccccc3)C(=O)N3CCOCC3)cc2)cs1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a cooled (0°) suspension of N-{4-(2-amino-4-thiazolyl)phenyl}-2-{(phenylmethyl)amino}acetamide (1.02 g, 3.00 mmol, described in example 2) in CH2Cl2 (30 mL) and Et3N (836 μL, 6.00 mmol), were added DMAP (36.6 mg, 0.30 mmol) and 4-morpholinecarbonyl chloride (350 μL, 3.00 mmol). The reaction mixture was stirred at 0° for 30 min, and then at room temperature for 18 h. The reaction mixture was then dissolved in EtOAc (300 mL). The resulting solution was washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), then dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, EtOAc) to afford the title compound (925 mg, 68% yield) as a white solid: M.p. 105° (decomp.); 1H NMR (400 MHz, DMSO-d6) δ9.94 (s, 1H), 7.71 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.25-7.39 (m, 5H), 6.99 (s, 2H), 6.88 (s, 1H), 4.47 (s, 2H), 3.84 (s, 2H), 3.59 (t, J=4.9 Hz, 4H), 3.19 (t, J=4.9 Hz, 4H); MS (FAB) m/z 452 (MH)+; Anal. Calcd for C23H25N5SO3: C, 61.18; H, 5.58; N, 15.51. Found: C, 60.61; H, 5.60; N, 15.35.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([N:13]1CCC(=O)[CH2:15][CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:9]([O:8][C:6]([N:13]1[CH2:14][CH2:15][C:4](=[CH2:5])[CH2:3][CH2:2]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a cooled suspension of methyl triphenyl phosphonium bromide (47.0 g, 132 mmol) in THF (330 mL) was added n-BuLi (85.0 mL, 136 mmol). 1-Boc-4-piperidone (25.0 g, 125 mmol) was added via cannula as a solution in THF. The resulting mixture was kept at 0° C. and allowed to warm to r.t. over 2 h. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl. The resulting precipitate was filtered off and the layers were separated. The remaining aqueous layer was extracted with Et2O and the combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified (FCC) to give 4-methylene-piperidine-1-carboxylic acid tert-butyl ester (22 g, 91%)
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([NH:22][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NN1CCCCC1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN2CCCCC2)[nH]n1
Yield: 85 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (218 mg, 0.74 mmol) was converted, using 1-aminopiperidine instead of 4-aminotetrahydropyran, to the title compound (228 mg, 85%) which was obtained as a colorless oil. MS: m/e=362.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[C:8]=2[F:13])[N:3]=1.[CH3:15][O:16][C:17]([C:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=1)([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[F:13][C:8]1[C:7]([F:14])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([CH3:12])[C:2]([O:26][C:25]1[C:20]([C:17]([O:16][CH3:15])([CH3:18])[CH3:19])=[N:21][CH:22]=[CH:23][CH:24]=1)=[N:3]2
Reactant: COC(C)(C)c1ncccc1O
Reactant: Cc1nc2c(F)c(F)ccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(C)(C)c1ncccc1Oc1nc2ccc(F)c(F)c2nc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
0.17 g of 2-chloro-5,6-difluoro-3-methylquinoxaline were dissolved in 2 mL of N-methylpyrrolidone. 0.13 g of 2-(1-methoxy-1-methyl-ethyl)-pyridin-3-ol and 0.11 g of potassium carbonate were added thereto followed by stirring for 3 hours at 100° C. Subsequently, the reaction solution was purified by silica gel column chromatography to obtain 0.24 g of 5,6-difluoro-2-[2-(1-methoxy-1-methyl-ethyl)-pyridin-3-yloxy]-3-methyl-quinoxaline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][N:14](CC3C=CC(OC)=CC=3)[C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C1(S)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:14][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(-c3ccnc(Cl)n3)s2)C(=O)c2ccccc2)cc1
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(-c2ccnc(Cl)n2)s1)c1ccccc1

Procedure:
A solution of N-[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl]-N-(4-methoxybenzyl)-benzamide (25 mg, 0.055 mmol) in 0.25 mL CH2Cl2 was treated with trifluoroacetic acid (0.25 mL) as co-solvent and PS-thiophenol resin (3 eq.) at 40° C. for 15 h. The material was filtered and concentrated to a yellow solid (16 mg, 88%). The crude material was used in the next step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18](O)=[O:19])[C:12]([CH3:21])=[C:11]2[OH:22].Cl>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15]([CH:14]=[C:13]([CH2:18][OH:19])[C:12]([CH3:21])=[C:11]2[OH:22])=[CH:16][CH:17]=1
Reactant: Cc1c(C(=O)O)cc2ccc(Cl)cc2c1O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(CO)cc2ccc(Cl)cc2c1O
Temperature: 60 °C
Yield: 70.7 %

Procedure:
To a slurry of lithium aluminum hydride (4.1 g) in tetrahydrofuran (80 mL) was added a solution of 6-chloro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid (12.7 g, 54 mmol) in tetrahydrofuran (80 mL) at 0° C. under a nitrogen atmosphere. After being heated at 60° C. for 5 hours, the resulting mixture was cooled to 0° C. and treated with 1 N hydrochloric acid to quench the reaction. The aqueous layer was extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine (200 mL×2), dried over sodium sulfate and concentrated in vacuo to give 7-chloro-3-hydroxymethyl-2-methyl-naphthalen-1-ol (8.5 g, 71%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[N:8][C:7]=1[Cl:12])=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[Cl:12][C:7]1[N:8]=[N:9][CH:10]=[CH:11][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccnnc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccnnc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of crude 3-chloro-pyridazine-4-carboxylic acid ethyl ester (565 mg) in THF (5 ml) was added 2N LiOH (3.03 ml, 6.06 mmol) and the mixture was stirred for 15 min at ambient temperature. The pH of the reaction mixture was then adjusted to 2 by addition of 0.1N HCl and the mixture was extracted five times with ethyl acetate. The combined extracts were dried (Na2SO4) and evaporated to give the crude title compound as a brown solid (452 mg, 94%) which was used in the next reaction step without further purification. 1H NMR (d6-DMSO): 8.07 (d, J=5 Hz, 1H), 9.41 (d, J=5 Hz, 1H), 14.52 (s br, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)=O.[CH3:23][CH:24]([CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=1)=[O:26]>>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[CH2:1][N:37]2[CH2:38][CH2:39][CH:34]([C:30]3[CH:29]=[C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:40])[CH3:23])[CH:33]=[CH:32][CH:31]=3)[CH2:35][CH2:36]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1ccc(COc2ccc3ccccc3c2C=O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c(OCc4ccc(C#N)cc4)ccc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-{[(1-formyl-2-naphthyl)oxy]methyl}benzonitrile and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 518.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6](=[O:12])[N:5]3[C@H:13]([CH2:15][N:16]4[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22]C(=O)C(F)(F)F)[CH2:17]4)[CH2:14][N:3]1[C:4]=23.C(=O)([O-])[O-].[K+].[K+]>CO.O.CO.C(Cl)Cl>[NH2:22][CH2:21][C@@H:18]1[CH2:19][CH2:20][N:16]([CH2:15][C@H:13]2[N:5]3[C:4]4[N:3]([C:2](=[O:1])[CH:11]=[CH:10][C:9]=4[CH:8]=[CH:7][C:6]3=[O:12])[CH2:14]2)[CH2:17]1
Reactant: O=C(NC[C@@H]1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NC[C@@H]1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)C1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a 25 mL round-bottomed flask was added N-[((3S)-1-{[(1R)-4,9-dioxo-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridin-1-yl]methyl}-3-pyrrolidinyl)methyl]-2,2,2-trifluoroacetamide (85 mg, 0.214 mmol) in methanol (9 ml) and water (1.00 ml) to give a yellow solution. Potassium carbonate (59.3 mg, 0.429 mmol) was added and the reaction was stirred overnight. LCMS indicated a complete reaction. The reaction was diluted with 20% MeOH/DCM (100 mL), dried over Na2SO4, filtered and concentrated to give the product (60 mg, 0.200 mmol, 93% yield) as an orange solid.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[C:11]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)(=[O:13])[CH3:12]>[O-]CC.[Na+]>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:12][C:11](=[O:13])[C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1nccs1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a sodium ethoxide solution (prepared from 150 ml of ethanol and 4.2 g of sodium) at 0° C., a mixture of diethyl oxalate (22.98 g) and acetylthiazole (20.07 g) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours and concentrated. The residue was treated with 100 ml of water and neutralized with 6N HCl. Filtration afforded 25.8 g of 2,4-diketo-4-(thiazol-2-yl)butyric acid ethyl ester as brown solids. NMR: 1.46 (t, 3H), 4.49 (q, 2H), 7.27 (s, 1H), 7.65, 8.04 (2d, 2H, thiazolyl H's).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:13][C:14]1[C:18]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>C(=O)=O.ClCCl>[CH3:27][C:26]([CH3:29])([CH3:28])[C:25]([C:15]1[O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[C:14]=1[CH2:13][C:12](=[O:11])[C:31]([CH3:32])([CH3:33])[CH3:34])=[O:30]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(O)C(C)(C)C)c2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cool 1.5 mL dichloromethane in dry ice bath under nitrogen. Add 38 mg oxalyl chloride followed by 47 mg DMSO. Stir for 30 minutes. Add a solution of 49.9 mg 1-[3-(2-hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzofuran-2-yl]-2,2-dimethylpropan-1-one from the Step A above in 2.5 mL dichloromethane. After another 25 minutes, 167 μL triethylamine were added. After stirring for additional 25 minutes, the reaction mixture was removed from the cooling bath and allowed to warm to room temperature. After 2 hours, solvents were removed under reduced pressure and the residue was purified directly on RP-HPLC using 70-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. 1H NMR (CDCl3, 500 MHz) 7.43 (d, J=8.9 Hz, 1H), 7.10 (dd, J=2.5 & 8.9 Hz, 1H), 6.90 (d, J=2.6 Hz, 1H), 4.39 (s, 2H), 3.87 (s, 3H), 1.42 (s, 9H), 1.34 (s, 9H). LC-MS: 4.17 min. (m/Z=247.2, 353.3, 331.4).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([CH2:22][C:23]([OH:25])=O)=[CH:14]1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]1>ClCCl>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([CH2:22][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]2)=[O:25])=[CH:14]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)Cc1coc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)Cc2coc3ccccc23)CC1
Reaction time: 1 h

Procedure:
22 g of carbonyldiimidazole are added in portions to 23.9 g of benzofuran-3-ylacetic acid in 250 ml of dichloromethane. When the evolution of gas has stopped, the reaction mixture is stirred for 1 hour and then 21 ml of ethyl piperid-4-ylcarboxylate are added dropwise. After 12 hours' stirring at room temperature, the reaction mixture is washed with 1N sodium hydroxide solution and then with 1N hydrochloric acid. After decanting and drying, concentration under reduced pressure enables the expected product to be isolated.
Reaction SMILES: [NH:1]([C:8]1([CH3:36])[CH:13]([C:14]([O:16]C(C2CC2)C)=[O:15])[N:12]2[C:22](=[O:35])[CH:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:11]2[S:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH:1]([C:8]1([CH3:36])[CH:13]([C:14]([OH:16])=[O:15])[N:12]2[C:22](=[O:35])[CH:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:11]2[S:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Nc1ccccc1)C1CC1
Solvent: O=C(O)C(F)(F)F
Product: CC1(Nc2ccccc2)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Reaction time: 1 h
Yield: 50.4 %

Procedure:
1-Cyclopropylethyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)-cepham-4-carboxylate (142mg) was dissolved in ice-cooled trifluoroacetic acid (1.5 ml) and the mixture was stirred for 1 hour under ice-cooling. After the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved by adding ethyl acetate and extracted with 5% sodium bicarbonate aqueous solution. The extract was adjusted to pH2 with 5% hydrochloric acid and back-extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue (amorphous) was dissolved in methanol and to this solution was added water little by little. Precifitates were collected by filtration and dried to give powder of 3-anilino-3-methyl-7-(2-phenoxy-acetamido)cepham-4-carboxylic acid (62 mg), mp 119 to 123° C (dec.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][NH:9][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)CBr
Solvent: Cc1ccccc1
Product: COC(=O)CNCCc1ccccc1
Reaction time: 18 h
Yield: 124.2 %

Procedure:
To a stirred solution of 2-phenylethylamine (9.68 g, 40 mmol) in toluene (50 mL) was added methyl bromoacetate (6.12 g, 20 mmol) dropwise at room temperature and was left stirring for 18 hours. The reaction mixture was filtered before removing the solvent in vacuo and the residue was purified by chromatography over silica gel to yield 4.8 g (61%) of the title compound as an oil. NMR (250 MHz, CDCl3) δ(1H, s), 2.92 (4H, m), 3.43 (2H, s), 3.71 (3H, s), 7.27 (5H, m).
Reaction SMILES: [CH2:1]([CH:4]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]2[C:6]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:7][C:8]3[C:13]2=[CH:12][CH:11]=[C:10]([O:19]COC)[CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([CH:4]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]2[C:6]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:7][C:8]3[C:13]2=[CH:12][CH:11]=[C:10]([OH:19])[CH:9]=3)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1CC2(CCCC)Cc3cc(OCOC)ccc3C2=C(C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC1CC2(CCCC)Cc3cc(O)ccc3C2=C(C)C1=O
Temperature: 50 °C

Procedure:
A solution of (2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (5 mg, 0.015 mmol) in THF (0.5 mL) was treated with 6N HCl (0.5 mL) and the resulting solution was heated at 50° C. overnight. The mixture was diluted with EtOAc (30 mL), washed with 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to a yellow oil. The crude product was purified by PLC on a 0.025×20×20 cm silica gel GF plate using 2:1 hexanes-EtOAc as developing solvent. The UV visible band at Rf 0.43-0.57 afforded (2SR,9aSR)-2-allyl-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:19])[C:12]([C:20]2[C:24]([F:25])=[C:23]([Si](C)(C)C)[O:22][C:21]=2[CH2:30][O:31][Si](C(C)(C)C)(C)C)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:19])[C:12]([C:20]2[C:24]([F:25])=[CH:23][O:22][C:21]=2[CH2:30][OH:31])=[CH:11][CH:10]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2c(CO[Si](C)(C)C(C)(C)C)oc([Si](C)(C)C)c2F)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2c(F)coc2CO)c1O
Yield: 78.8 %

Procedure:
A solution of methyl 6-bis-(tert-butoxycarbonyl)amino-3-[2-(-tert-butyldimethylsilanyloxymethyl)-4-fluoro-5-trimethylsilanylfuran-3-yl]-2-hydroxybenzoate (Intermediate 100, 3.66 g) in a 1M solution of tetrabutylammonium fluoride in THF (30 mL) was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 10-50% to give methyl 6-bis-(tert-butoxycarbonyl)amino-3-(4-fluoro-2-hydroxymethylfuran-3-yl)-2-hydroxybenzoate (2.08 g) as a white solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=[O:23].IC>C1COCC1.O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:1])[C:22]([OH:24])=[O:23]
Reactant: CC(C)NC(C)C
Reactant: COc1ccccc1CC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COc1ccccc1C(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85 %

Procedure:
As shown in step 4-i of Scheme 4, to a solution of diisopropylamine (6.70 g, 9.28 mL, 66.2 mmol) in THF (60 mL) at −78° C. under N2 was added n-butyllithium (33.1 mL of 2.0 M in cyclohexane, 66.2 mmol) and the solution was stirred for 40 minutes. A solution of 2-(2-methoxyphenyl)acetic acid (5.00 g, 30.1 mmol) in THF (30 mL) was added dropwise, then the reaction was allowed to warm to room temperature over one hour. The reaction was then cooled to −78° C. and iodomethane (4.27 g, 1.87 mL, 30.1 mmol) was added to the reaction in one portion. The reaction was warmed to room temperature 18 hours, 15 mL of water was added, and the organics were collected and the volatiles removed under reduced pressure. The residue was acidified with 1N HCl and the crude product extracted with Et2O (3×). The combined organics were dried over MgSO4, filtered, concentrated under reduced pressure, and the residue purified by medium pressure chromatography on silica gel (25 to 50% EtOAc in hexanes) to give 2-(2-methoxyphenyl)propanoic acid as a white solid (Compound 2008, 4.86 g, 85% yield): 1H NMR (CDCl3) δ 7.31-7.21 (m, 2H), 7.01-6.84 (m, 2H), 4.09 (q, J=7.2 Hz, 1H), 3.84 (s, 3H), 1.49 (d, J=7.2 Hz, 3H).