Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1[C:11]([C:12]([C:24]([F:27])([F:26])[F:25])([C:20]([F:23])([F:22])[F:21])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[C:8]([OH:28])[CH:7]=1.Cl>N1C=CC=CC=1>[S:2]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([C:11]2[CH:10]=[CH:9][C:8]([O:28][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:6]=2)([C:24]([F:25])([F:26])[F:27])[C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=1)([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(C(c2ccc(OS(C)(=O)=O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
11.8 g (0.1 mol) of methanesulfonyl chloride are added dropwise, at a reaction temperature of 0-5° C., to a solution of 16.8 g (0.05 mol) of bisphenol AF in 100 ml of pyridine. Stirring is then continued for a further hour at 5° C. and overnight at room temperature. The reaction mixture is then acidified with sufficient half-concentrated hydrochloric acid to precipitate the product. Filtering off with suction and washing with water gives 24 g of crude product, and recrystallization from toluene gives 20.2 g (82% yield) of 2,2-bis-(4-mesyloxyphenyl)-hexafluoropropane are isolated. M.p 136-138° C.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[C:28]1([O:34][CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OC(=O)C)C.CO>FC(F)(F)C(O)=O>[CH3:35][O:34][C:28]1[CH:33]=[CH:32][C:31]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:30][CH:29]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)cc1

Procedure:
A mixture of 5 g of 3-acetoxymethyl-7(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and 10 ml of absolute anisole is dissolved in 40 ml of trifluoracetic acid and the clear solution is evaporated to dryness under a water pump vacuum and with repeated addition of toluene. The residue is dissolved in acetone, and the solution is mixed with about 30 g of silica gel and evaporated to dryness. The residue is suspended in methylene chloride and the suspension is applied to a column (diameter: 35 mm) of 150 g of silica gel. Elution is carried out with methylene chloride and mixtures of methylene chloride and acetic acid ethyl ester (fractions of 400 ml). Unreacted anisole is eluted with 2 fractions of pure methylene chloride. 3-(4-Methoxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid mixed with 3-(2-methoxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid, is obtained by elution with 6:1 to 1:1 mixtures of methylene chloride and acetic acid ethyl ester. Additional, impure material is obtained with acetic acid ethyl ester and with acetic acid ethyl ester containing 5% of methanol. The pure product is crystallised from a mixture of acetic acid ethyl ester and cyclohexane and melts at 181.5°-182°C (uncorrected); [α]D20 = +379° ± 1° (c = 0.989 in dioxane); thin layer chromatogram (silica gel G): Rf = 0.61 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.72 (system acetic acid ethyl ester/pyridine/acetic acid/water, 62:21:6:11) and Rf = 0.63 (system n-butanol/pyridine/acetic acid/water, 38:24:8:30); ultraviolet absorption spectrum (in 95% strength ethanol), λmax = 224 mμ(ε = 19200), and shoulder at about 255 mμ (ε = 7200) and at about 279 mμ (ε = 3000); infrared absorption spectrum (in mineral oil): characteristic bands at 3.02μ, 3.19μ (shoulder), 3.30μ, 5.67μ, 5.77μ, 6.05μ, 6.23μ, 6.54μ, 6.61μ, 6.69μ, 7.07μ, 7.49μ, 7.99μ, 8.24μ, 8.52μ, 9.71μ, 13.31μ, 14.41μ and 15.05μ. Further recrystallisation from a mixture of acetone, methylene chloride and cyclohexane results in enrichment of 3-(4-methoxy-benzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid, with the melting point rising to 188°C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][NH:5][C:6]([C:8]1[CH:31]=[CH:30][C:11]2[N:12]([CH3:29])[C:13]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7].[OH-].[Li+]>>[CH3:29][N:12]1[C:11]2[CH:30]=[CH:31][C:8]([C:6]([NH:5][CH2:4][C:3]([OH:32])=[O:2])=[O:7])=[CH:9][C:10]=2[N:14]=[C:13]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Yield: 87 %

Procedure:
{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (4.22 g) was prepared by following General Procedure E starting from {[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid methyl ester (5.0 g) and lithium hydroxide (1.81 g).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]([O:15][CH3:16])[NH:8][CH:9]=[C:10]([C:11]([O:13]C)=[O:12])[C:5]=2[N:4]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[C:6]2[CH:7]([O:15][CH3:16])[NH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:5]=2[N:4]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1
Reactant: COC(=O)C1=CNC(OC)c2c(Br)cn(C3CCCC3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC1NC=C(C(=O)O)c2c1c(Br)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.5 %

Procedure:
To a solution of methyl 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (874 mg) in methanol (8 mL) was added 1N aqueous sodium hydroxide solution (8 mL), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the precipitate was collected by filtration, and dried to give the title compound (894 mg).
Reaction SMILES: [CH:1]([N:3]1[CH:7](C(O)=O)[CH2:6][S:5][CH:4]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl[C:30](=[CH2:33])[C:31]#[N:32]>ClCCl.O>[C:31]([C:30]1[CH:33]=[CH:1][N:3]2[C:7]=1[CH2:6][S:5][CH:4]2[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:32]
Reactant: C=C(Cl)C#N
Reactant: O=CN1C(C(=O)O)CSC1c1cccnc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccn2c1CSC2c1cccnc1
Yield: 74.4 %

Procedure:
3-Formyl-2-(3-pyridyl)-4-thiazolidinecarboxylic acid (10 g) is suspended in dichloromethane (15 cc) in a 50 cc three-necked flask equipped with a condenser, a dropping funnel, a magnetic stirrer, a thermometer and a gas-holder. Then triethylamine (4.8 g) is added at 20° C. A homogeneous colourless solution is obtained. This solution is added dropwise in the course of 50 minutes and at 25° C. to a stirred mixture of methanesulphonyl chloride (5.29 g) and dichloromethane (17 cc). 2-Chloroacrylonitrile (4.04 g) is then added quickly, followed at 20°-35° C. and over the course of one hour, by triethylamine (9.35 g) and dichloromethane (5 cc). The mixture is then refluxed for 50 minutes. After cooling, it is hydrolysed with water (12 cc). The organic phase is decanted and the aqueous phase extracted with dichloromethane. The organic extracts are combined and dried overnight over sodium sulphate. After filtering, the solvent is evaporated off under reduced pressure 20 mm Hg; 2.7 kPa) at 20° C. A crude product (9 g) is obtained, and is purified by chromatography on a column diameter 4.5 cm) containing silica (100 g) (0.063-0.2 mm), eluting with a mixture of ethyl acetate and dichloromethane. 7-Cyano-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole (7.10 g) is thereby obtained in the form of light beige-coloured crystals m.p. 108° C. (yield 82.5% relative to the acid used).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCCOC1CCCCO1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCOC2CCCCO2)CC1

Procedure:
In analogy to the procedure described in example 5A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 2-(3-bromo-propoxy)-tetrahydro-pyran gave the title compound as white solid. MS: 455.3 (MH+, 2Cl).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:4]([C:5](=[O:7])[CH2:6]1)[CH2:3][C:2]2=[O:10].[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:7]1[CH2:11][CH2:12][O:13][C:5]21[CH2:6][CH:1]1[CH2:9][CH2:8][CH:4]2[CH2:3][C:2]1=[O:10]
Reactant: O=C1CC2CCC1CC2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1CC2CCC1CC21OCCO1
Temperature: 25 °C

Procedure:
To 4.0 g of rac-(1R*,4R*)-bicyclo[2.2.2]octane-2,5-dione (intermediate K1A.1), dissolved in 120 mL of toluene, 1.7 mL of ethylene glycol and 0.27 g of TsOH were added and the solution was heated under vigorous stirring to reflux for 3.5 h. The reaction mixture was cooled to rt, quenched with saturated aq. NaHCO3, extracted with Et2O, and the organic phase was evaporated. The crude product was purified by CC with Hex-EtOAc (7:3) to yield 2.41 g of rac-(1R*,4R*)-spiro[bicyclo[2.2.2]octane-2,2′-[1,3]dioxolan]-5-one as yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].N12CCCN=C1CCCCC2.C1(P([N:57]=[N+:58]=[N-:59])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([N:57]=[N+:58]=[N-:59])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(OCc2ccc(C(N=[N+]=[N-])c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Temperature: 50 °C
Yield: 55.7 %

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (3 g, 7.22 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 mL, 15.2 mmol), diphenylphosphoryl azide (3.3 mL, 15.2 mmol) and tetrahydrofuran (20 mL) is stirred at 50° C. 2 hr. The mixture is concentrated and the crude residue is purified via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to give the title compound 1.77 g, 56% as a white solid. LCMS M−1 439.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:28])(=[O:27])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[N:30]([CH2:33][C@@H:34]([C:36]1[CH:37]=[CH:38][C:39]([Cl:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:41]=1)[OH:35])=[N+]=[N-]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([NH:30][CH2:33][C@@H:34]([C:36]4[CH:37]=[CH:38][C:39]([Cl:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:41]=4)[OH:35])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)(=[O:27])=[O:28])=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1Cl
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(Cl)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from {4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acid methyl ester (which was obtained in Example 232) and N-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-chloro-phenyl]-methanesulfonamide (which was obtained in Example 25) according to the procedure of Example 95 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.80 (m, 5H), 2.97 (s, 3H), 3.40-3.55 (m, 2H), 3.69 (s, 3H), 4.63 (dd, J=8.0, 3.8 Hz, 1H), 4.87 (s, 2H), 6.77 (d, J=9.0 Hz, 2H), 6.87 (d, J=9.0Hz, 2H), 7.03 (d, J=9.0Hz, 2H), 7.17 (dd, J=8.3, 1.7 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.43 (d, J=1.7 Hz, 1H), 7.62 (d, J=9.0 Hz, 2H); MS (ES) m/z: 667.0 (MH+); HRMS Calcd. for C29H36ClN4O8S2 (MH+): 667.1657. Found: 667.1651.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Sn](CCCC)(CCCC)CCCC)[CH:11]=[CH:10][C:9]=2[O:27][CH2:28][CH3:29])[N:5]=[C:4]([NH2:30])[N:3]=1.[I-:31].[Na+].[OH-].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([I:31])[CH:11]=[CH:10][C:9]=2[O:27][CH2:28][CH3:29])[N:5]=[C:4]([NH2:30])[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OCC)c(-c2cc(Cl)nc(N)n2)c1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(I)cc1-c1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 4-chloro-6-(5-tributylstannyl-2-ethoxy-phenyl)pyrimidin-2-ylamine (79 mg, 0.13 mmol) in a 3% solution of acetic acid in ethanol (1 ml) was added a solution of sodium iodide (24 mg, 0.16 mmol) in a 0.1 M aqueous sodium hydroxide solution (0.2 ml) followed by a solution of chloramine-T (15.0 mg, 0.065 mmol) in water (0.15 ml). The orange solution was stirred at room temperature for 1 hour, treated with saturated aqueous sodium thiosulfate solution (0.3 ml), and extracted with ethyl acetate (2×1 ml). The combined extracts were concentrated under reduced pressure. The residue was purified by preparative TLC eluting with 20% ethyl acetate-hexane to provide 4-chloro-6-(5-iodo-2-ethoxy-phenyl)pyrimidin-2-ylamine (39 mg, 71% yield) as a white powder. 1H NMR (CDCl3) δ 8.24 (d, J=2.3 Hz, 1H), 7.67 (dd, J=2.3, 8.70 Hz, 1H), 7.38 (d, J=8.70 Hz, 2H), s, 1H), 6.76 (d, J=8.70 Hz, 1H), 5.23 (s, 1H), 4.13 (q, J=7.0 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([O:15]C)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>Br>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([OH:15])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Cc2ccccc2)c(Br)cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1cc(Cc2ccccc2)c(Br)cn1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
250 ml of 47% hydrobromic acid was added to 62 g of 4-benzyl-5-bromo-2-methoxypyridine, followed by heating under stirring for 3 hours in an oil bath kept at 100° C. After cooling as it was, the reaction solution was added to an aqueous potassium carbonate solution little by little and neutralized. The resulting precipitates were collected by filtration, to give 59 g of the target compound.
Reaction SMILES: [C:1]([CH:5]1[CH2:26][CH2:25][C:8]2([O:12][CH:11]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([CH:5]1[CH2:26][CH2:25][C:8]2([O:12][CH:11]([CH2:13][NH2:14])[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CN1C(=O)c3ccccc3C1=O)O2
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1CCC2(CC1)OCC(CN)O2
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a warm (50° C.) solution of 8-t-butyl-2-(phthalimidomethyl)-1,4-dioxaspiro (4,5)decane (12.5 g, 35 mmol) in ethanol (100 ml) was 25 added hydrazine hydrate (3.6 g, 72 mmol). The reaction mixture was kept at 50° C. for 1 hour. Light petroleum 200 ml was added and insoluble material was filtered off. The solvent was evaporated in vacuo. The residue was dissolved in toluene (100 ml) washed with brine (100 ml) and dried (MgSO4). Evaporation of the solvent yielded the title compound as a yellow oil (7.2 g). GC analysis indicated the compound as existing as a mixture of two diastereoisomers (cis, cis and cis, trans) in a ratio of 48:52. The NMR spectra are in agreement with the assigned structure.
Reaction SMILES: [Tl].C([O-])(=O)C.[F:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH:10]=[CH:9][C:8]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C.CCCCCC>[F:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH:10]=[CH:9][C:8]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Agent: CC(=O)[O-]
Agent: [Tl]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
Following the procedure of Example 2, the enol ether of the formula ##STR2## is reacted with thallium (lll) acetate in an aqueous acetic acid/hexane mixture at 25° to 50° C. until methyl 2-(2-fluoro-4-biphenylyl)propionate is formed. This ester is isolated from the reaction mixture and hydrolyzed to 2-(2-fluoro-4-biphenylyl)propionic acid (generic name, flurbiprofen) by the described procedure.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](Br)=[C:26]([C:28]([O:30][CH2:31]C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC([I:72])=C(C([O-])=O)N=1)CC2)=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([I:72])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)[O-])c(I)s1)CC2
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I

Procedure:
Compound 47D was prepared in a similar manner to the synthesis of compound 34C by substituting compound 34B with compound 8C in step 3 of Example 34: APCI (+)/LC/MS: 707 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:17]=2[O:16][CH3:15])[N:3]=1
Reactant: COc1cccc(CN)c1OC
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCN(CC)CC
Product: COc1cccc(CNc2nc(Cl)nc3c2ncn3C(C)C)c1OC

Procedure:
2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 for preparation), 2,3-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][CH:5]1[NH:9]C(=O)N[C:6]1=[O:11].[OH-:14].[Na+]>>[F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][C@@H:5]([C:6]([OH:14])=[O:11])[NH2:9]
Reactant: O=C1NC(=O)C(CCC(F)(F)F)N1
Reactant: [OH-]
Agent: [Na+]
Product: N[C@@H](CCC(F)(F)F)C(=O)O

Procedure:
5-(3,3,3-trifluoropropyl)imidazolidine-2,4-dione (0.9 g, 4.59 mmol) was dissolved in a 10 mL solution of aqueous NaOH (0.734 g in 10 mL H2O, 18.35 mmol). The solution was divided in 2 special vessels for microwave technology. The solution was heated by microwave in sealed vessels for 1 h. Microwave conditions: 15 min at about 100% power, 150° C., 50 psi, then 5 min at rest, 0% power. Repeat sequence twice or until reaction is done. Water and ammonia were removed from the reaction mixture in vacuo and the resulting crude 5,5,5-trifluoronorvaline (1.1 g, 140%) and NaOH mixture was used in the next reaction without further purification. Mass Spectrum (+ESI): 172 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C[O:27][CH2:26]C1.[Li]CCCC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH:26]=[O:27])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cncn1-c1ccc(F)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(C=O)n1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (770 mg, 2.2 mmol) in anhyd THF (10 mL) at −78° C. was added n-BuLi (1.4 mL, 2.0M in hexane, 2.8 mmol) dropwise. After stirring 1 h at −78° C., anhyd DMF (0.85 mL) was added in one portion. After stirring another 3 h at −78° C., the reaction was quenched with water. After warming to ambient temperature, the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by column chromatography (silica gel, 0-90% EtOAc/Hex) to give 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-carbaldehyde as a white solid (740 mg, 89% yield).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:17][CH2:18][S:19][CH3:20])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:29])C=1>ClCCl>[C:1]([O:4][CH:5]([CH2:17][CH2:18][S:19]([CH3:20])=[O:29])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCNC(=O)C(CCSC)OC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a solution of 4-(methylthio)-1-(octylamino)-1-oxobutan-2-yl acetate (6.33 g, 20.86 mmol) in dichloromethane (200 mL) at 0° C. was added mCPBA (77%, 4.67 g, 20.86 mmol). The resulting mixture was allowed to warm to room temperature with stirring overnight. The reaction was washed with saturated sodium bicarbonate (3×100 mL), 1N HCl (1×100 mL), and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give a yellow oil (6.7 g, 100%). m/z 320 (MH+).