Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1.CCCCCC.C([Li])CCC.CN(C)[CH:36]=[O:37]>O1CCCC1>[CH:36]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1)=[O:37]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(I)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cn1
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of 5-iodo-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (2.5 g) in tetrahydrofuran (40 ml) was added dropwise, at −65° C. under nitrogen streams, a hexane solution of n-butyllithium (1.6M, 4.61 ml). The mixture was stirred for 15 minutes at the same temperature, to which was added dropwise N,N-dimethylformamide (0.71 ml). The cooling bath was removed, then the reaction mixture was stirred for further 30 minutes, to which was added a saturated aqueous solution of ammonium chloride (6 ml). The reaction mixture was poured into water, followed by extraction with ethyl acetate. The ethyl acetate was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure to leave 5-formyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (1.5 g, 79%). Recrystallization from ethyl acetate-hexane gave colorless crystals, m.p.99-100° C.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[CH2:22][NH2:23])[CH2:2][CH2:3][CH3:4].[NH:24]1[C:28]([CH2:29][C:30](O)=[O:31])=[CH:27][N:26]=[CH:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[CH2:22][NH:23][C:30](=[O:31])[CH2:29][C:28]1[NH:24][CH:25]=[N:26][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1cnc[nH]1
Reactant: CCCCc1c(CN)cnn1-c1ncc(C)c(-c2cccs2)n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCc1c(CNC(=O)Cc2cnc[nH]2)cnn1-c1ncc(C)c(-c2cccs2)n1

Procedure:
A mixture of (5-butyl-1-(5-methyl-4-(thiophen-2-yl)pyrimidin-2-yl)-1H-pyrazol-4-yl)methanamine and 2-(1H-imidazol-5-yl)acetic acid in 1:1 molar ratio was treated with EDC (1 equiv.), HOBT (1 equiv.) and N-methylmorpholine (2 equiv.) in methylene chloride (at a concentration of 0.5 M) at room temperature overnight (20 hours). Upon completion, an additional methylene chloride was added and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography using 10% CH3OH/CH2Cl2 as the eluent to give the title compound 34. 1H NMR (400 MHz, CD3OD) δ 8.79 (s 1H), 8.34 (t, J=5.48 Hz, 1H), 8.10 (s 1H), 7.94 (s 1H), 7.93 (s 1H), 7.62 (s 1H), 7.33 (D, J=4.69 Hz, 1H), 7.10 (s 1H), 4.18 (D, J=5.48 Hz, 2H), 3.49 (s 3H), 3.11 (t, J=7.83 Hz, 2H), 2.60 (s 3H), 1.40 (quint, J=7.43 Hz, 2H), 1.24 (sex, J=7.83 Hz, 2H), 0.77 (t, J=7.43 Hz, 3H). LCMS (ES+) m/z 436 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH2:14][OH:15])[C:12]([CH3:17])([CH3:16])[CH2:11][C:10]([CH3:19])([CH3:18])[CH:9]=2)=[CH:4][C:3]=1[CH3:20]>CS(C)=O.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH:14]=[O:15])[C:12]([CH3:16])([CH3:17])[CH2:11][C:10]([CH3:18])([CH3:19])[CH:9]=2)=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(C2=CC(C)(C)CC(C)(C)C2CO)ccc1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=CC(C)(C)CC(C)(C)C2C=O)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Into a slurry of 61.4 g (0.222 mol) of 1-(4-fluoro-3-methylphenyl)-6-hydroxymethyl-3,3,5,5-tetramethylcyclohexene in 330 ml of DMSO and 194 ml of triethylamine is poured a solution of 106.0 g (0.666 mol) of sulfur trioxide pyridine complex in 330 ml of DMSO. The reaction mixture is then stirred for 30 min. Ice (660 g) is added and the reaction mixture is extracted twice with 300 ml of hexanes. The extracts are then backwashed thrice with 280 ml of 10% HCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at 40° C. to yield 57.1 g (94%) of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-2-enecarboxaldehyde suitable for use in the next step. A pure sample of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohex-2-enecarboxaldehyde can be obtained via column chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([S:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([C:18]3([O:24][CH3:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:27][OH:28]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([C:18]3([O:24][CH3:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[N:27][OH:28]
Reactant: NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C=O)c(Cl)c3)c2)CCOCC1
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(C=NO)c(Cl)c3)c2)CCOCC1
Yield: 83 %

Procedure:
Using an analogous procedure to that described in Example 68, 2-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4yl)phenylthio]benzaldehyde was reacted with hydroxylamine hydrochloride to give 2-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzaldehyde oxime in 83% yield as a gum.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH3:34][NH2:35]>O>[CH3:34][NH:35][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: CN
Reactant: Oc1ccc2ccccc2c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CNc1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
288 parts of β-naphthol, 3 parts of triphenyl phosphite and 80 parts of methylamine gas are heated for 10 hours under pressure at 200° C in a pressure autoclave. The pressure is 40 atmospheres. When the two-phase mixture has cooled, water is added, the batch is stirred for 30 minutes at 70° C and the lower oily phase is separated off and distilled. 305 parts of N-methyl-β-naphthylamine, boiling at 165° - 166° C/12 mm Hg, are obtained. This corresponds to a yield of 97% of theory.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(N(CC)CC)C.[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[C:12]1([S:22]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NCCN
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NCCNS(=O)(=O)c1cccc2ccccc12
Reaction time: 1 h
Yield: 3.5 %

Procedure:
To a solution of ethylenediamine (1.06 g, 17.6 mmol) in dimethylformamide (10 ml), triethylamine (1.79 g, 17.7 mmol) was added, followed by stirring. With stirring at room temperature, a solution of 1-naphtalenesulfonyl chloride (4.00 g, 17.6 mmol) in dimethylformamide (15 ml) was dropwise added thereto, and the reaction was carried out in an ice bath for 1 hour. Insoluble materials were removed by filtration, and the filtrate was concentrated. To the residue, chloroform and water were added, and insoluble materials were filtered off. Furthermore, the aqueous layer was separated, washed with ethyl acetate twice and adjusted to pH 11 with potassium carbonate, followed by extraction with ethyl acetate three times. The extracts were collected, washed with water twice, dried over anhydrous sodium sulfate and concentrated. The residue was allowed to stand in a refrigerator overnight, and the precipitate was collected and recrystallized from ethyl acetate to give Compound (10) (153 mg). Yield, 4%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:18]1[C:23]([C:24]#[N:25])=[N:22][CH:21]=[CH:20][N:19]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:4][C:5]([NH:8][C:20]2[N:19]=[CH:18][C:23]([C:24]#[N:25])=[N:22][CH:21]=2)=[N:6][CH:7]=1
Reactant: CN1CCC(Nc2cc(N)ncc2Cl)CC1
Reactant: N#Cc1nccnc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CN1CCC(Nc2cc(Nc3cnc(C#N)cn3)ncc2Cl)CC1
Temperature: 90 °C
Yield: 30.4 %

Procedure:
A solution of 5-chloro-N4-(1-methylpiperidin-4-yl)pyridine-2,4-diamine (0.080 g, 0.33 mmol), 2-bromo-cyanopyrazine (0.040 g, 0.22 mmol), BINAP (0.005 g, 0.02 mmol), sodium tert-butoxide (0.030 g, 0.31 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.009 g, 0.01 mmol) in dioxane (1.6 mL) was stirred at r.t. under nitrogen for 10 min before being heated under microwave irradiation for 30 min at 90° C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography eluting with methanol/dichloromethane (1/9) to give the title compound as a yellow solid (0.023 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([NH:18]C(=O)C3C=CC=CC=3)=[S:17])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: COc1ccnc(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccnc(-c2cccc(NC(N)=S)c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a suspension of N-(3-(4-methoxypyridin-2-yl)phenyl)-N′-benzoylthiourea (429 mg) in methanol (5 ml) was added an aqueous sodium hydroxide solution (1N, 1.42 ml) dropwise. The mixture was stirred at 60° C. for 1 hour and cooled to ambient temperature. The pH was adjusted to 8.0 with 1N hydrochloric acid. The mixture was diluted with water (50 ml) and extracted with dichloromethane-methanol (4:1). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give N-(3-(4-methoxypyridin-2-yl)phenyl)thiourea (294 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH:12]=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)(C)CO)cc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C=O)cc1OC

Procedure:
A solution of 100 mg (0.476 mmol) 2-(3,4-dimethoxy-phenyl)-2-methyl-propan-1-ol in 1 ml dichloromethane is treated with 202 mg (0.476 mmol) Dess-Martin reagent at rt. After 1 h aqueous sodium bicarbonate and sodium thiosulphate solutions are added and the product is extracted with dichloromethane. The organic layers are evaporated and the aldehyde is obtained in a sufficient purity to be used in reductive aminations.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:5][C:4]=1[CH3:10]
Reactant: COc1c(C)cccc1C
Reactant: O=S(=O)(O)Cl
Product: COc1c(C)cc(S(=O)(=O)Cl)cc1C
Yield: 62.6 %

Procedure:
The title compound was prepared from 2-methoxy-1,3-dimethylbenzene (6.81 g, 50 mmol) and chlorosulfonic acid (6.65 mL, 100 mmol), according to the procedure and in the same manner as described in Example 58, step b to yield 4-methoxy-3,5-dimethylbenzenesulfonyl chloride (7.43 g, 31.3 mmol, 63%) as a white solid;
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[NH:14][C:13]2=[O:20])=[C:4]([F:21])[CH:3]=1.[H-].[Na+].Cl[CH:25]([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH:25]([F:27])[F:26])[C:13]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: FC(F)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C(F)F
Reaction time: 0.5 h

Procedure:
A solution of 2.00 g of 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6 -methyl-2,4(1H,3H)-pyrimidinedione in 20 ml dimethylformamide is added dropwise at room temperature while stirring within 30 minutes to a suspension of 0.28 g of a 55% sodium hydride dispersion in 10 ml of dimethylformamide. The mixture is subsequently stirred for 30 minutes and thereafter 5.26 g of chlorodifluoromethane are introduced at 55° C. while stirring during 18 hours. The reaction mixture is cooled, poured into a solution of 20 ml of 2N hydrochloric acid in 300 ml of water and extracted with 150 ml of ethyl acetate. The organic phase is washed twice with 100 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of diethyl ether and the solution is treated with active carbon and filtered. The filtrate is evaporated to dryness and the residue is recrystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1-difluoromethyl-6 -methyl-2,4(1H,3H)-pyrimidinedione, m.p. 97°-99° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].Cl[CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:22]([I:36])=[C:23]([CH2:29][CH:30]([CH2:34][CH3:35])[C:31]([OH:33])=[O:32])[C:24]([I:28])=[CH:25][C:26]=1[I:27])=[O:19])=[O:11]>>[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[C:22]([I:36])=[C:23]([CH2:29][CH:30]([CH2:34][CH3:35])[C:31]([OH:33])=[O:32])[C:24]([I:28])=[CH:25][C:26]=1[I:27])=[O:19])=[O:11]
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CCl)c1I)C(=O)O
Reactant: NCCNCCN
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CNCCNCCN)c1I)C(=O)O
Yield: 48 %

Procedure:
According to the procedure described in Example 1, 123 g of diethylenetriamine (0.16 mol) are reacted with 121.7 g of compound (A) 3-[[6-[(chloroacetyl)amino]-1-oxohexyl]amino]-α-ethyl-2,4,6-triiodobenzene propanoic acid. 64 g of 3-[6-[[[2-[(2-aminoethyl)amino]ethyl]amino]acetyl amino]-1-oxohexyl]amino-α-ethyl-2,4,6-triiodobenzenepropanoic acid (0.077 mol) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=2[CH3:33])=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:36])[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.2 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 4-(3-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 70%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH3:16])[CH:11]=2)[O:8][C@@H:7]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[Cl:26])[C@@H:6]1[O:28][C:29](=[O:31])[CH3:30])(=[O:3])[CH3:2].[NH2:32][C@@H:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:34][OH:35].CCN(C(C)C)C(C)C.Cl>ClCCCl>[ClH:26].[C:1]([O:4][C@@H:5]1[C@@H:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][CH3:16])[CH:11]=2)[O:8][C@@H:7]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[NH:32][C@@H:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][OH:35])[C@@H:6]1[O:28][C:29](=[O:31])[CH3:30])(=[O:3])[CH3:2]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(N[C@H](CO)Cc5ccccc5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1

Procedure:
A mixture comprising acetic acid (2R,3R,4R,5S)-4-acetoxy-2-(2,6-dichloro-purin-9-yl)-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3-yl ester (WO 99/38877) (1 g, 2.13 mmol), (S)-2-amino-3-phenyl-propan-1-ol (0.321 g, 2.13 mmol) and DIPEA (0.275 g, 2.13 mmol) in DCE (5 mL) is stirred under an inert atmosphere of argon overnight. After cooling to room temperature (RT), 1 M HCl is added, the organic portion is separated and concentrated in vacuo to afford the title compound which is used in the next step without further purification. (MH+585.1)
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.8 %

Procedure:
To a suspension of NaH (240 mg, 60–72%) in tetrahydrofuran (5 ml) was added 2,2,2-trifluoroethanol (500 mg, 5 mmol) at 0° C. After the mixture was stirred for 45 minutes at room temperature, t-butyl bromoacetate (0.9 ml, 6 mmol) was added and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crude t-Butyl 2,2,2-trifluoroethoxyacetate (1.08 g, quant.).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([NH:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=[CH:19][C:17]=2[N:18]=1)[CH3:12].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:11]([N:13]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=[CH:19][C:17]=2[N:18]=1)[CH:1]=[O:3])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1nc2ccc(CCc3ccco3)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Product: CCN(C=O)c1nc2ccc(CCc3ccco3)cc2o1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A mixture of acetic anhydride (1.13 ml) and formic acid (0.45 ml) was stirred at 50° C. for 40 minutes. Tetrahydrofuran (10 ml) and 2-ethylamino-6-[2-(2-furyl)ethyl]benzoxazole (1.02 g) was added thereto and the mixture was stirred at the same temperature for further 6 hours. After cooling, the mixture was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water dried over magnesium sulfate and evaporated in vacuo to give 2-(N-ethylformamido)-6-[2-(2-furyl)ethyl]benzoxazole (1.18 g).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][O:15][C:16]2=[O:19])=[CH:12][CH:11]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[C:1]1([S:7][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([CH2:8][CH3:9])=[CH:18][C:17]=2[C:16]([OH:19])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CCc1ccc2c(c1)C(=O)OC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(CSc2ccccc2)c(C(=O)O)c1
Temperature: 110 °C

Procedure:
Thiophenol (0.128 ml) was added to a mixture of 6-ethyl-3H-isobenzofuran-1-one (Intermediate 18, 0.202 g) and potassium carbonate (0.344 g) in dry DMF (1.3 ml). The resultant mixture was stirred and heated at 110° C. for 2 hours. After cooling, the mixture was diluted with water and acidified by addition of hydrochloric acid (1M). The resultant solid was collected by filtration, washed with water and dried under vacuum to give 2-(phenylthiomethyl)-5-ethylbenzoic acid (0.288 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C([O:20][CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23]Br)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[Br-]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][OH:20])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCC(C)(C)CBr
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OCC(C)(C)CO)cc(C(C)=O)cc1C(C)(C)C
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 42.2 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 2.00 g) and 3-bromo-2,2-dimethylpropyl acetate (2.54 g) were dissolved in DMF (15 ml), and cesium carbonate (3.69 g) was added. After stirring at 150° C. and max. 15 bar in a microwave for 2.5 h, a further 0.5 eq. of the bromide was added and the mixture was placed into the microwave at 150° C. for a further 2 h. Then the mixture was concentrated by rotary evaporation and the residue was partitioned between DCM and water. The DCM phase was removed, dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MtB ether gradient of 0-50% within 60 min). 1.17 g of the title compound were obtained.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][CH:16]=[N:15][C:14]=3[CH:18]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[F:27][C:28]([F:33])([F:32])[C:29](=[O:31])[CH3:30]>O1CCCC1>[F:27][C:28]([F:33])([F:32])[C:29]([C:16]1[S:17][C:13]2[CH:12]=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[CH:18][C:14]=2[N:15]=1)([OH:31])[CH3:30]
Reactant: CC(=O)C(F)(F)F
Reactant: O=S(=O)(c1ccccc1)c1ccc2scnc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)(c1nc2cc(S(=O)(=O)c3ccccc3)ccc2s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To a stirred solution of 5-phenylsulfonylbenzothiazole (0.845 g) in dry tetrahydrofuran (50 mL) at -78° C. was added lithium diisopropylamide (3.5 mmol in 3 mL tetrahydrofuran) dropwise over approximately 10 minutes. A deep red solution formed. Trifluoroacetone (0.63 g) was added. After stirring for 20 minutes at -78° C., the reaction mixture was quenched with saturated ammonium chloride solution. The reaction mixture was then extracted with ether (75 mL and 25 mL) and dichloromethane (25 mL). The combined organic layers were dried, filtered and purified by chromatography, eluting with ethyl acetate:hexane (gradient of 10 to 30% ethyl acetate), to give the title compound as a white solid (0.558 g); m.p. 126.5°-128.5° C.; NMR: 8.62 (d,1), 8.43 (d,1), 8.01-8.07 (m,4), 7.60-7.70 (m,3), 1.84 (s,3); MS: m/z=388(M+1). Analysis for C16H 12 F3NO3S2 : Calculated: C,49.61; H,3.12; N, 3.62: Found: C, 49.43; H, 3.23; N, 3.56.