Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(CNc1ccc([N+](=O)[O-])cc1)OC
Reaction time: 12 h
Yield: 95.6 %

Procedure:
To 5.05 g (0.048 mole) of aminoacetaldehyde dimethylacetal were added 5.64 g (0.040 mole) of p-fluoronitrobenzene, 4.03 g (0.048 mole) of sodium hydrogencarbonate and 5 ml of dimethyl sulfoxide and reaction was carried out at 80° C. for 12 hours. After the reaction, the reaction mixture was poured into 100 ml of water to precipitate a yellow solid. The solid was dissolved in 150 ml of benzene, and the solution was washed with a liquid mixture comprising 50 ml of water and 1 ml of hydrochloric acid and with 50 ml of water two times. The residual benzene layer was dried with anhydrous sodium carbonate. After the drying, the benzene layer was concentrated and the obtained yellow solid was washed with hexane and dried under reduced pressure to obtain 8.65 g (the yield was 95.6%) of a crystal of 4-nitrophenylaminoacetaldehyde dimethyl acetal.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].[BrH:31]>C1(C)C=CC=CC=1>[Br:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: Br
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCBr)cn2)CC1

Procedure:
To a solution of 419 mg of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 20 ml of toluene was added 0.60 ml of a 47% hydrobromic acid and the mixture was heated under reflux for one hour. The reaction solution was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue thus obtained was chromatographed over a silica gel column to afford 400 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH3:25][N:26]([C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[O:32])[CH2:27][C:28](O)=[O:29]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:28](=[O:29])[CH2:27][N:26]([CH3:25])[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:32])=[CH:11][C:12]=1[F:17]
Reactant: CN(CC(=O)O)C(=O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: CN(CC(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1)C(=O)c1ccccn1
Product: Cl

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and N-methyl-N-(pyridin-2-ylcarbonyl)glycine, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl)=[O:25]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:29][C:28]2[CH:27]=[C:26]([CH:33]=[CH:32][CH:31]=2)[C:24]([O:23][CH3:22])=[O:25])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: COC(=O)c1cccc(CCl)c1
Product: COC(=O)c1cccc(CN2C(=O)C(CCO)Oc3ccccc32)c1
Yield: 87 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with 3-(methoxycarbonyl)benzyl chloride, and isolated as a white powder in 87% yield, mp 73°-75° C.; 1H NMR (CDCl3) δ 7.92-7.95 (m, 2H), 7.38-7.43 (m, 2H), 6.96-7.03 (m, 2H), 6.91 (dt, J=2.3, 7.3 Hz, 1H), 6.81 (dd, J=1.4, 7.7 Hz, 1H), 5.23 (d, J=16.3 Hz, 1H), 5.16 (d, J=16.3 Hz, 1H), 4.87 (dd, J=5.7, 7.4 Hz, 1H), 3.92-3.95 (m, 2H), 3.91 (s, 3H), 2.21-2.37 (m, 3H containing one exchangeable hydrogen). 13C NMR (CDCl3) δ 166.9, 166.7, 144.2, 136.5, 130.9 (CH), 130.7, 129.1 (CH), 128.7 (CH), 128.5, 127.7 (CH), 124.3 (CH), 122.9 (CH), 117.4 (CH), 115.4 (CH), 75.3 (CH), 58.9 (CH2), 52.2 (CH2), 45.1 (CH2), 33.3 (CH2). IR 3569, 2948, 1709, 1676, 1502 cm-1. MS 342 (MH+). Anal. Calc'd. for C19H19NO5 : C, 66.85; H, 5.61; N, 4.10. Found: C, 66.37; H, 5.62; N, 3.97.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.Cl>ClCC(Cl)(Cl)Cl>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([C:16]1[S:15][C:14]([CH3:13])=[CH:18][CH:17]=1)=[O:5]
Reactant: CCc1ccc(O)c(C(=O)Cl)c1
Reactant: Cc1cccs1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Product: CCc1ccc(O)c(C(=O)c2ccc(C)s2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-5-ethylbenzoyl chloride (6.08g, 0.036 mol) and 2-methylthiophene were mixed together in tetrachloroethane (20 ml), and stannic chloride (18.78g, 0.072 mol) in tetrachloroethane (20 ml) was added dropwise with stirring, the temperature of the mixture being at about 20° C. by cooling with an ice bath. The mixture was then stirred at room temperature for 3 hours and left to stand at room temperature overnight. The resulting pink solution was poured into ice and concentrated hydrochloric acid (10 to 20 ml), stirred until the ice had melted and extracted with chloroform. The chloroform extract was washed firstly with a saturated solution of sodium bicarbonate and secondly with a saturated solution of sodium chloride, was dried (over Na2SO4), filtered and evaporated to leave an oil which distilled to give the pure title product (4.36g), bp 133°-136° C./0.1 mm, nD21 1.6341.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1OC
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (2.24 mL) was added to an ice-cooled mixture of methyl 4-hydroxy-2-methoxybenzoate (2.02 g) and pyridine (0.135 mL) in methylene chloride (15 mL) with stirring. The mixture was stirred at room temperature for 30 minutes, and poured into a mixture of hydrochloric acid and ethyl acetate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford methyl 2-methoxy-4-trifluoromethanesulfonyloxybenzoate (3.49 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[C:10]([NH:12][NH:13][C:14]([NH2:16])=[O:15])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH:10]2[NH:12][NH:13][C:14](=[O:15])[NH:16]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)NNC(N)=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccccc2C2NNC(=O)N2)cc1
Yield: 78.6 %

Procedure:
1-[2-(4-Methylphenyl)benzoyl]semicarbazide (4.6 g) and phosphorus oxychloride (10.3 g) were suspended in benzene (100 ml), and the suspension was heated for 3 hours under reflux. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added water, and resulting crystalline precipitate was collected by filtration. Recrystallization from methanol afforded the title compound as colorless needles (3.4 g, 79%), m.p.245-246° C. (decomp.).
Reaction SMILES: [C:1]([O:7][C:8]1[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:11](=[O:18])[N:10]2[CH:19]([CH2:32][CH2:33][O:34]CC3C=CC=CC=3)[CH2:20][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22](=[O:23])[C:9]=12)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C>[C:1]([O:7][C:8]1[C:13](=[O:14])[N:12]([CH:15]([CH3:17])[CH3:16])[C:11](=[O:18])[N:10]2[CH:19]([CH2:32][CH2:33][OH:34])[CH2:20][N:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:22](=[O:23])[C:9]=12)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)n1c(=O)c(OC(=O)C(C)(C)C)c2n(c1=O)C(CCOCc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CC(C)n1c(=O)c(OC(=O)C(C)(C)C)c2n(c1=O)C(CCO)CN(Cc1ccc(F)cc1)C2=O
Reaction time: 48 h

Procedure:
A mixture of 4-[2-(benzyloxy)ethyl]-2-(4-fluorobenzyl)-7-isopropyl-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl pivalate (918 mg, 1.62 mmol) and 10% Pd(C) (92 mg) in ethyl acetate (32 mL) was stirred under a balloon atmosphere of hydrogen for 24 h. The reaction mixture was filtered through Celite, fresh catalyst was added and the mixture subjected to balloon hydrogenation for an additional 24 h. Analysis by LCMS showed slow conversion to the alcohol, so the mixture was again filtered through Celite and the filtrate was concentrated. The residual solid was taken up in ethanol (32 mL) with a small amount of ethyl acetate added to aid dissolution of the material. 10% Pd(C) was added and the mixture subjected to balloon hydrogenation for 96 h, with fresh catalyst being added after the first 24 h. The reaction still appeared to be progressing slowly, so the mixture was filtered through Celite and Pearlman's catalyst was added to the filtrate. Hydrogenation (balloon) was complete after 48 h (fresh Pearlman's catalyst was added after the first 24 h). Filtration through Celite and concentration afforded the title compound as a foamy white solid. 1H NMR (CDCl3, 400 MHz): δ 7.28-7.26 (m, 2 H), 7.07-7.02 (m, 2 H), 5.21-5.14 (m, 1 H), 4.87-4.74 (m, 2 H), 4.48-4.36 (m, 1 H), 3.89-3.77 (m, 1 H), 3.49-3.25 (m, 3 H), 1.68-1.54 (m, 2H), 1.46 (d, J=6.8 MHz, 6 H), 1.40 (s, 9 H). ES MS (M+1): 476.5.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:19])[C@:15]([NH2:18])([O:16][CH3:17])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:20]([S:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1)[CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:7])(C)(C)C.C(N(CC)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C>C(Cl)Cl>[C:15]([NH:18][C@:15]1([O:16][CH3:17])[C:14](=[O:19])[N:13]2[C:8]([C:6]([OH:5])=[O:7])=[C:9]([CH:20]([S:30][C:31]3[NH:32][N:33]=[N:34][N:35]=3)[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:10][S:11][C@H:12]12)(=[O:16])[C@@H:14]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[OH:19]
Reactant: CO[C@@]1(N)C(=O)N2C(C(=O)OC(C)(C)C)=C(C(CCC(=O)OC(C)(C)C)Sc3nnn[nH]3)CS[C@@H]21
Reactant: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: CO[C@@]1(NC(=O)[C@H](O)c2ccccc2)C(=O)N2C(C(=O)O)=C(C(CCC(=O)O)Sc3nnn[nH]3)CS[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.06 g. (2 mmol.) of 7β-amino-7α-methoxy-3-[1-(2-t-butoxycarbonylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 0.30 g. (2 mmol.) of N,N-diethylaniline in 100 ml. of dry methylene chloride is stirred at 0°-5° while 0.56 g. (2 mmol.) of D-O-dichloroacetylmandeloyl chloride in 10 ml. of methylene chloride is added dropwise over 10 minutes. The mixture is stirred in the cold for 30 minutes then warmed to room temperature and stirred for an additional 30 minutes. The solution is washed with 50 ml. of cold dilute hydrochloric acid and 50 ml. of cold 5% aqueous sodium bicarbonate, dried and evaporated to dryness. The residue is dissolved in a mixture of 10 ml. of trifluoroacetic acid and 2 ml. of m-dmethoxybenzene and stirred at ambient temperature for 2 hours. The excess trifluoroacetic acid is evaporated under vacuum and the residue is partitioned between 50 ml. of ether and 50 ml. of water and adjusted to pH 9.3-9.5 with 5% aqueous sodium carbonate. The organic phase is separated and discarded. The aqueous phase is stirred at pH 9.3-9.5 for 30 minutes, extracted with 50 ml. of ethyl acetate which is discarded, layered with fresh ethyl acetate and adjusted to pH 1.5 with dilute hydrochloric acid. The aqueous layer is extracted with three 50 ml. portions of ethyl acetate and the combined extracts are dried and evaporated to a small volume. Petroleum ether is added dropwise to precipitate the title compound which is collected by filtration and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15].[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=1)[C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: CSc1ccc(CCl)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(SC)cc2)c2ccc(OC)cc12
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
To the indole of Example 7, Step 1, (1.00 g, 4.29 mmol) in DMF (15.0 mL) at 0° C. were added NaH 60% in oil (188 mg, 4.72 mmol) and a solution of 4-chloromethylthioanisole (810 mg, 4.7 mmol) in DMF (5.0 mL). After a period of 5 min at r.t., the reaction was quenched by the addition of 25% aqueous solution of NH4OAc. The reaction was extracted with EtOAc, dried over Na2SO4, evaporated in vacuo and purified by flash chromatography (20% EtOAc in hexane) to provide the title compound (770 mg).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]#[CH:20].Cl>C(C(C)=O)C>[CH2:20]([S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])[C:19]#[CH:18]
Reactant: O=C(O)c1ccccc1S
Reactant: C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCSc1ccccc1C(=O)O
Reaction time: 3 h

Procedure:
To thiosalicylic acid (77 g) slurried in methyl ethyl ketone (500 ml) was added 1 equivalent of K2CO3 followed by 3-bromopropyne (1 equivalent). The reaction mixture was stirred for 3 hours and then poured into 1N HCl and the solids filtered and then vacuum dried to afford the subtitle compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>>[I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: CCOC(=O)CC(=O)c1cccc(I)c1
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(I)c1
Yield: 38 %

Procedure:
Ethyl 3-(3-iodophenyl)-3-oxopropanoate (29.3 g, 92.1 mmol) was heated to 120° C. in a sealed tube in t-butanol (80 mL) for 4 hours. The mixture was concentrated in vacuo and purified by column chromatography (0–3% ethyl acetate in hexanes) to provide the titled compound (12.1 g, 38%).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:19][C:20]1[CH:31]=[CH:30][C:23]([CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(CCN(C)C)C.[C:40]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.O>[CH2:12]([O:19][C:20]1[CH:31]=[CH:30][C:23]([CH:24]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[OH:47])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: c1ccc(COc2ccc(Cn3ccnc3)cc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccccc1)(c1ccccc1)C(c1ccc(OCc2ccccc2)cc1)n1ccnc1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 9.4 %

Procedure:
34 ml (53 mmol) of 1,55 molar n-butyllithium/hexane solution were added dropwise to a solution of 6.87 g (26 mmol) of N-(4-benzyloxybenzyl)-imidazole and 3.03 g (26 mmol) of TMEDA in 100 ml of absolute THF at about -70° C., the mixture was stirred for 20 minutes at -70° C., a solution of 4.74 g of benzophenone in 40 ml of absolute THF was then added dropwise at -70° C., stirring was continued for 30 minutes at about -70° C. and for 1.5 hours at -70° C. to room temperature, and 350 ml of water were added, while cooling. The mixture was extracted with CH2Cl2. The residue (12 g) from the CH2Cl2 extract was chromatographed over a silica gel S/CH2Cl2 column (diameter 2.1 cm, height 55 cm) as described in Example 102. Fractions which were shown by thin layer chromatography to have a high concentration of the desired substance were combined and recrystallized from ethyl acetate/diisopropyl ether. 1.09 g (=16.4% yield) of pure 2-(4-benzyloxyphenyl)-2-(1-imidazolyl)-1,1-diphenylethanol of melting point 204° C. were obtained in this manner.
Reaction SMILES: [CH:1]([CH:3]([CH2:8][C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)[C:4]([O:6]C)=O)=O.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]([NH2:40])=[NH:39])=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:45])([F:44])[F:43]>CN1C(=O)CCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]([CH3:41])[C:38]3[NH:40][CH:1]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)[C:4](=[O:6])[N:39]=3)=[CH:31][CH:30]=2)=[CH:24][C:23]=1[C:42]([F:43])([F:44])[F:45]
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Reactant: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cnn(C)c2)c[nH]1
Temperature: 200 °C
Yield: 20.4 %

Procedure:
To the mixture of methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (68.6 mg, 0.350 mmol) and K2CO3 (112 mg, 0.807 mmol) in NMP (5 mL) was added neat N-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-N-methylguanidine (100 mg, 0.269 mmol). The reaction mixture was heated with a microwave reactor at 200° C. for 2 h. Purification via MDAP then afforded the title compound as a white solid (35 mg, 0.055 mmol, 20.5% yield). LCMS: rt=3.00 min, [M+H+]=518.0
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:44][CH:45]1[C@H:49]2[C@H:50](OC3CCCCO3)[N:51](C(OC(C)(C)C)=O)[C:52]3[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:53]=3[C:54](=[O:55])[N:48]2[CH2:47][CH2:46]1)[CH2:9][CH2:10][CH2:11][O:12][CH:13]1[C@H:17]2[C@H:18](OC3CCCCO3)[N:19](C(OC(C)(C)C)=O)[C:20]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=3[C:22](=[O:23])[N:16]2[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:44][CH:45]1[C@@H:49]2[CH:50]=[N:51][C:52]3[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:53]=3[C:54](=[O:55])[N:48]2[CH2:47][CH2:46]1)[CH2:9][CH2:10][CH2:11][O:12][CH:13]1[C@@H:17]2[CH:18]=[N:19][C:20]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=3[C:22](=[O:23])[N:16]2[CH2:15][CH2:14]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 78.6 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8b (134 mg, 0.14 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9b (60 mg, 0.11 mmol, 78%) as a solid: [α]20D=+477° (c=0.09, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.88-2.06 (m, 8H, 2-H, 2′-H, 13-H, 13′-H), 2.16-2.36 (m, 4H, 1-H, 1′-H), 3.46-3.57 (m, 2H, 3-H, 3′-H), 3.63-3.69 (m, 2H, 11a-H, 11a′-H), 3.60-3.69 (m, 2H, 3-H, 3′-H), 3.82 (s, 6H, 7-OMe, 7′-OMe), 3.98-4.19 (m, 4H, 12-H, 12′-H), 6.72 (s, 2H, 9-H, 9′-H), 7.44 (s, 2H, 6-H, 6′-H), 7.59 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 29.65, 46.6, 53.7, 56.0, 68.6, 109.6, 112.6, 120.2, 140.6, 147.0, 151.7, 162.8, 164.6; IR (neat): 3354, 2950, 1622, 1600, 1506, 1447, 1387, 1262, 1216, 1092, 1026 cm−1;MS (FAB) m/z (relative intensity) 611 ([M+2×MeOH]+., 9), 579 ([M+MeOH]+., 19), 547 (M+., 100).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:14]([NH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCN
Product: COC(=O)CCNS(=O)(=O)c1ccccc1

Procedure:
N-(phenylsulfonyl)-β-alanine, methyl ester (23) was prepared from methyl β-alaninate and phenylsulfonyl chloride on a 32 mmol scale in the manner described above in Example 13 to yield 6.76 g (86%) product. Analysis calculated for C10H13NO4S (M.W. 243.28): C, 49.37; H, 5.39; N, 5.76; S, 13.18. Found: C, 49.06; H, 5.46; N, 5.78; S, 12.95.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C:3](=[O:47])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[C@H:30]([C:31]([O:33]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:32])[CH2:29][C:24]2([S:28][CH2:27][CH2:26][S:25]2)[CH2:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:49])([CH3:48])[C:3](=[O:47])[O:4][CH2:5][O:6][P:7]([CH2:19][C:20]([N:22]1[C@H:30]([C:31]([OH:33])=[O:32])[CH2:29][C:24]2([S:25][CH2:26][CH2:27][S:28]2)[CH2:23]1)=[O:21])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:8]
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Reaction time: 1 h

Procedure:
(S)-7-[[[(2,2-Dimethyl-1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester (2.4 g) in dry dichloromethane is treated with 3.0 ml of trifluoroacetic acid under argon at room temperature. After 1 hour, the trifluoroacetic acid and dichloromethane are removed in vacuo and the resulting oil partioned between ethyl acetate and water. The layers are separated and the organic phase is washed with brine, dried (MgSO4) and evaporated. The residue (4.0 g) is chromatographed on 130 g of silica eluting with dichloromethane/acetic acid/methanol (18:1:1) to give (after azeotropic removal of acetic acid with toluene) 1.5 g of the title compound.