Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)=[O:18])C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][CH:19]2[C:17]([OH:18])=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCC2)c(Cl)c1
Yield: 76 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (52 mg, 0.26 mmol) obtained in Step C of Preparation Example 23 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (70 mg, 0.29 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 84%).
Reaction SMILES: [CH3:1][Li].Cl[C:4]([C@@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@@H:7]1[C:12]([O:14][CH3:15])=[O:13])=[O:5].CO.[Cl-].[NH4+]>CCOCC.[Cu]I>[C:4]([C@@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@@H:7]1[C:12]([O:14][CH3:15])=[O:13])(=[O:5])[CH3:1]
Reactant: [Li]C
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C(=O)Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H]1CC=CC[C@H]1C(C)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1 ml of dry ether was added to 141 mg of copper (I) iodide in a stream of nitrogen gas, and 1.35 ml of ether solution (1.1M) of a methyllithium was added dropwise to the mixture while cooling it by ice. The mixture was cooled down to -78° C. To the reaction mixture was added a solution of (1S, 2R)-2-chloroformyl-1-methoxycarbonylcyclohex-4-ene (50 mg) prepared by a method similar to that of Example 1 in ether (0.5 ml) at -70° C., and the mixture was stirred for one hour. After addition of methanol, the mixture was allowed to stand to return to room temperature, a saturated ammonium chloride solution was then added, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ether, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=15:85) to be purified, and thus 35 mg of the titled compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCc1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cccs1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 4-chlorobenzoyl chloride (0.114 mol) in 50 mL dry CH2Cl2 was added over 30 min to a stirred solution of 2-aminomethyl-thiophene (0.137 mol) and iPr2NEt (0.25 mol) in CH2Cl2 (200 mL) at 0° C. A white solid was formed and the reaction was allowed to warm to room temperature over 1 h. The mixture was diluted with 200 mL of CH2Cl2, washed twice with HCl aq. (0.1N) and dried over MgSO4. Evaporation of the solvents afforded 28 g (98%) of the title benzamide as a white solid: m.p. 153-54° C., 1H NMR (CDCl3) δ 7.9 (d, J=8.67 Hz, 2H), 7.58 (d, J=8.67 Hz, 2H), 7.44 (dd, J=3.77, 1.13 Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 7.16 (dd, J=3.39, 5.27 Hz, 1H), 6.62 (br d, 1H), 4.98 (d, J=5.65 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][CH2:20][SH:21]>CC#N.O>[CH2:20]([S:21][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)[CH3:19]
Reactant: CC(=O)Nc1cccc(CBr)c1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCSCc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of N-(3-(bromomethyl)phenyl)acetamide (6.6 g, 29 mmol) in CH3CN (50 mL) and water (10 mL) was added K2CO3 (6 g, 43 mmol) and EtSH (1.79 g, 29 mmol). The mixture was stirred at r.t. overnight. After removal of the solvent, the residue was extracted with EtOAc, dried and concentrated to give the crude product. The crude was purified by silica gel chromatography (petroleum ether:EtOAc=1:0 to 10:1) to give N-(3-(ethylthiomethyl)phenyl)acetamide (3.4 g, 56% yield) as a light yellow solid. 1H NMR: (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.41 (s, 1H), 7.34 (d, 1H), 7.22-7.17 (m, 1H), 7.01 (d, 1H), 3.61 (s, 2H), 2.41-2.34 (m, 2H), 2.11 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].[C:23](=O)([O-])[O-].[Na+].[Na+].IC>CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:23])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 150 °C
Yield: 65.2 %

Procedure:
A mixture of 10-[(2RS)-1-ethylamino-2-propyl]-2-phenothiazinecarbonitrile (4.4 g), sodium carbonate (2.25 g) and iodomethane (0.9 cc) in dimethylformamide (60 cc) is heated for 6 hours to a temperature in the region of 150° C. The reaction mixture is then concentrated to dryness under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. and the residue is taken up with distilled water (100 cc) and extracted with ethyl acetate (2×100 cc). The combined organic phases are extracted with N-aqueous hydrochloric acid solution (2×50 cc). The combined aqueous phases are alkalinized with sodium hydroxide (d=1.33) to pH 13 and extracted with ethyl acetate (2×100 cc). The combined organic phases are washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40 ° C. 10-[(2RS)-1-(N-Ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbonitrile (3 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[CH:10]=3
Reactant: ClCc1ccncc1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cl
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4ccncc4)cc13)Sc1ccc(Br)cc1-2
Yield: 54.1 %

Procedure:
According to Example 34, the compound (150 mg) produced in Example 37 was reacted with 4-chloromethylpyridine hydrochloride (84 mg) to obtain the title compound (98 mg; 54%).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](O)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:46][CH2:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][N:64]([CH3:69])[CH2:65][CH2:66][CH2:67]N>CN(C=O)C.CCOC(C)=O>[CH3:63][N:64]([CH3:69])[CH2:65][CH2:66][CH2:67][C:37]1[N:38]=[C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=2[O:46][CH2:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[C:34]2[C:41]([CH3:42])=[C:40]([C:43]([NH2:2])=[O:44])[S:39][C:35]=2[N:36]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OCC3CCOCC3)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(C)CCCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C(N)=O)sc2nc(CCCN(C)C)nc(Nc3ccc(F)cc3OCC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
HATU (36 mg) was added to a solution of 4-(4-fluoro-2-((tetrahydro-2-H-pyran-4-yl)methoxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (36 mg) and DIPEA (17 μl) in DMF (1 ml). The reaction mixture was stirred for 40 min at room temperature. Then 3-(dimethylamino)propylamine (49 μl) was added. The reaction mixture was stirred at room temparture overnight. It was diluted with EtOAc and washed with water and brine. The organic phase was concentrated in vacuo. The residue was suspended in Et2O and filtered and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][CH2:19][CH:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -15 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
(S)-4-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)butyric acid (493 mg, 1.12 mmol) was dissolved in tetrahydrofuran (1 ml), and then isobutyl chloroformate (0.15 ml, 1.14 mmol) and N-methylmorpholine (0.125 ml, 1.15 mmol) were added thereto at −15° C. After stirring for one hour, the precipitate was filtrated and washed with tetrahydrofuran (7 ml). The filtrate was cooled to −15° C., and an aqueous solution (4 ml) of sodium borohydride (127 mg, 3.36 mmol) was dropwise added thereto. After stirring for 30 minutes, water (25 ml) was added to the solution and extracted three times with ethyl acetate (20 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=50:1) to yield [(S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-hydroxybutyl]carbamic acid tert-butyl ester (411 mg) as a colorless oily material.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[NH2:11][C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH:5]([NH:11][C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: Cn1nccc1N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nccc1NC=O
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
A mixture of acetic anhydride (38.86 ml) and formic acid (15.54 ml) was stirred at 45° C. for 45 minutes. To this mixture was added 5-amino-1-methylpyrazole (10 g) under ice-cooling, and the reaction mixture was stirred at the same temperature for 10 minutes. The resultant mixture was poured into a mixture of water and ethyl acetate, and the resultant solution was adjusted to pH 8 with potassium carbonate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate six times. The organic layers were combined, dried over magnesium sulfate, and evaporated in vacuo to give 5-formamido-1-methylpyrazole (12.88 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].CN(C=O)C.CC(C)([O-])C.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>C(=O)=O.CC(C)=O.C(O)(C)(C)C>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: Fc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: O=Cc1cc(O)cc(OCc2ccccc2F)c1
Temperature: -30 °C
Yield: 74.5 %

Procedure:
To a clean, dry 1L flask were added 3,5-dihydroxy benzaldehyde (10 g, 70.9 mmole, 1 eq) and anhydrous DMF (70.9 mL). The mixture was cooled to −70° C. in dry ice/acetone bath while stirring under nitrogen gas. A solution of 1 M tert-butoxide in tert-butanol (70.9 mL) was slowly added drop-wise over 30 min. to the solution while the mixture was allowed to warm to −30° C. The mixture was stirred for ten minutes, then 2-fluorobenzylbromide (13.7 g, 70.9 mmole, 1 eq) was added over 10 min at −30° C. The mixture was stirred at −10° C. for one hour prior to warming to room temperature. The mixture was quenched with 200 mL of saturated ammonium chloride solution. This is an exothermic reaction and the mixture warmed to 45° C. The mixture was filtered by suction onto a 150 mL coarse fritted buchner funnel. The filtrate was added to the material on the funnel. The solid is dried and is a tan to off-white solid (13.0 g, 74.4% yield) of a 1:1 mixture of desired mono-adduct (217a) to undesired bis-adduct (217b). Recrystallization of this material from 1-butanol yields clean product (217a) in the filtrate. Alternatively, flash chromatography can be used to obtain pure product. A white solid (5.2 g, 30% overall yield), was obtained of the desired product (217a). 1H NMR (400 MHz, CDCl3) δ ppm 10.04 (s, 1H), 9.87 (s, 1H), 7.56 (dt, 1H, J=2, 8 Hz), 7.41 (m, 1H), 7.25 (dq, 2H, J=2,8 Hz), 7.04 (dd, 1H, J=1.1, 2.4 Hz), 6.92 (dd, 1H, J=1.1, 2.4 Hz), 6.72 (t, 1H, J=2.3 Hz), 5.17 (s, 2H); Calc'd for C14H11FO3(M+H+)=247; Found 247.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2.Cl.[C:22](=[O:25])([O-])[O-:23].[K+].[K+].[CH3:28]C(Cl)(Cl)Cl>CN(C=O)C>[CH3:28][O:23][C:22](=[O:25])[N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: CC(Cl)(Cl)Cl
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Desipramine hydrochloride (1 equivalent, 0.3 gram) was added drop wise to a stirred solution of potassium carbonate (2 equivalents, 0.27 gram) in dry DMF at 0° C. Methyl chloroform (1.2 equivalents, 0.1 ml) which had been dissolved in dry DMF was added drop wise to this mixture and stirred for 6 hours at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic layer separated, washed with brine solution and dried over anhydrous sodium sulfate. The dried material was concentrated and purified by column chromatography to provide a pale yellow liquid (yield: 0.18 gram) and analyzed by HPLC (purity 97.7%). The FTIR, MS and 1H NMR spectra were consistent with the assigned with the empirical formula of C20H24N2O2.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[C:13]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=3)(=[O:31])=[O:30])[N:12]=2)[CH:8]=[CH:7][N:6]=1)=[NH:4].[C:39](OC(=O)C)(=O)[CH3:40]>C(O)(=O)C>[CH3:18][O:17][C:15]1[N:16]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]3[N:4]=[C:39]([CH3:40])[O:1][N:2]=3)[CH:10]=2)[N:12]=[C:13]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)(=[O:31])=[O:30])[C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=N)NO)c2)nc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(-c3noc(C)n3)c2)nc1OC

Procedure:
A solution of 108 mg of N-hydroxy-4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxamidine, product of example 34, in acetic acid (3 ml) was treated at RT with 0.057 ml of acetic anhydride then and refluxed for 12 h. The reaction mixture was partitioned between CH2Cl2 and diluted aqueous KHCO3, the organic layer was dried over Na2SO4 and the solvent was removed in a vacuo. The residue was purified on a silica gel chromatography column (eluted with AcOEt). Combination of the purified fractions and evacuation in vacuo afforded 5-methyl-pyridine-2-sulfonic acid {6-methoxy-5-(2-methoxy-phenoxy)-2-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide as a light yellow solid. ISN mass spectrum, m/e 560.1 (M−1 calculated for C26H23N7O6S: 560).
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.C(I)I.[C:16]([O:19][C@H:20]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@H:23]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([CH2:50][O:51][CH3:52])=[CH2:49])=[CH:44][CH:43]=3)[CH:35]=2)[O:22][C@@H:21]1[CH2:53][O:54][C:55](=[O:57])[CH3:56])(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([O:19][C@H:20]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([O:30][C:31](=[O:33])[CH3:32])[C@H:23]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]4([CH2:50][O:51][CH3:52])[CH2:2][CH2:49]4)=[CH:46][CH:47]=3)[CH:35]=2)[O:22][C@@H:21]1[CH2:53][O:54][C:55](=[O:57])[CH3:56])(=[O:18])[CH3:17]
Reactant: C=C(COC)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1(c2ccc(Cc3cc([C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)cc2)CC1
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) solution of ZnEt2 (0.16 mL, 0.16 mmol) in CH2Cl2 (0.4 mL) was added a solution of TFA (12 μL, 0.16 mmol) in CH2Cl2 (0.2 mL). After stirring for 20 min, a solution of CH2I2 (43 mg, 0.16 mmol) in CH2Cl2 (0.2 mL) was added. After stirring for an additional 20 min, a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(3-methoxyprop-1-en-2-yl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate BC) (32 mg, 0.053 mmol) in CH2Cl2 (0.4 mL) was added. The mixture was stirred overnight prior to quenching with a saturated solution of NaHCO3. The mixture was extracted 3× with CH2Cl2, and the organic portion was washed with brine prior to drying over Na2SO4. Concentration of the solution gave crude intermediate BC (25 mg).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.[NH2:11][C:12]1[C:22]([Cl:23])=[CH:21][C:15]2[CH:16]([CH3:20])[C:17](=[O:19])[O:18][C:14]=2[CH:13]=1>O1CCOCC1>[Cl:23][C:22]1[C:12]([N:11]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[CH:13][C:14]2[O:18][C:17](=[O:19])[CH:16]([CH3:20])[C:15]=2[CH:21]=1
Reactant: COC1CCC(OC)O1
Reactant: CC1C(=O)Oc2cc(N)c(Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1C(=O)Oc2cc(-n3cccc3)c(Cl)cc21
Reaction time: 1 h

Procedure:
7 ml (0.045 mole) of 2,5-dimethoxytetrahydrofuran and 5 ml of 5 N HCl are added to a solution of 6.7 g (0.035 mole) of 6-amino-5-chloro-3-methylbenzofuran-2(3H)-one in 100 ml of dioxane. After 1 hour, the aqueous phase that has formed is removed and the upper dioxane-containing phase is concentrated to dryness by evaporation in vacuo. The dark-brown residue is filtered with methylene chloride through silica gel. After evaporating the methylene chloride, 5-chloro-3-methyl-6-(pyrrol-1-yl)-benzofuran-2(3H)-one is obtained in the form of colourless prisms having a melting point of 100°-101°.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2[S:11][CH:10]=[N:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:15]1[N:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1.[NH2:22][CH2:23][CH2:24][N:25]1[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[NH:27][C:26]1=[O:33]>>[F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2[S:11][C:10]([C:17]3[C:18]([F:21])=[CH:19][N:20]=[C:15]([NH:22][CH2:23][CH2:24][N:25]4[C:29]([CH3:30])([CH3:31])[C:28](=[O:32])[NH:27][C:26]4=[O:33])[N:16]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: Fc1cnc(Cl)nc1
Reactant: Fc1ccc(Cc2cncs2)cc1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(F)c(-c2ncc(Cc3ccc(F)cc3)s2)n1

Procedure:
5-(4-Fluorobenzyl)thiazole was condensed with 2-chloro-5-fluoropyrimidine and subsequently aminated with 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione using procedures analogous to those in Example 24. MS (M+H)+ 459.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][O:14][CH:15]3[CH:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[O:39][CH3:40])=[CH:23][CH:22]=4)[CH2:19][CH2:18][N:17]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:16]3)[CH:11]=2)[C:6]([CH3:49])([CH3:48])[CH2:5]1.C(N(CC)CC)C.[C:57]1([CH3:67])[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:48][C:6]1([CH3:49])[C:7]2[C:12](=[CH:11][C:10]([CH2:13][O:14][CH:15]3[CH:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[O:39][CH3:40])=[CH:23][CH:22]=4)[CH2:19][CH2:18][N:17]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:16]3)=[CH:9][CH:8]=2)[N:4]([CH2:3][CH2:2][O:1][S:63]([C:60]2[CH:61]=[CH:62][C:57]([CH3:67])=[CH:58][CH:59]=2)(=[O:65])=[O:64])[CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCO)CC3(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCOS(=O)(=O)c2ccc(C)cc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 0.457 g of tert-butyl 3-[1-(2-hydroxyethyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.274 ml of triethylamine and 0.008 g of 4-dimethylaminopyridine in 10 ml of dichloromethane is admixed with stirring at 0° C. with 0.301 g of p-toluenesulphonyl chloride and stirred at room temperature over 18 hours. The reaction mixture is admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:1 EtOAc-heptane); Rt=6.46.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11]C(=O)CCl)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.NC(N)=S.C(O)(=O)C.O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:11])([CH3:9])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)CCl)c1cccc(Br)c1
Agent: NC(N)=S
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(N)c1cccc(Br)c1

Procedure:
The mixture of N-[1-(3-bromo-phenyl)-1-methyl-ethyl]-2-chloro-acetamide (1.0 g, 3.5 mmol), thiourea (0.32 g, 4.2 mmol), acetic acid (1.5 mL) in ethanol (7 mL) was heated to reflux for 10 h and brought to room temperature. Water was added to the mixture until a precipitate was formed which was filtered. The filtrate was made basic pH 7-8 with 15% NaOH. The product was extracted with ethyl acetate and concentrated to afford a yellow solid. M+1=214.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12](=[S:20])[O:13][C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O.CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([S:20][CH3:1])[O:13][C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(O)CCc1oc(=S)[nH]c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Methyl iodide (0.34 ml) was dropwise added to a mixture of 3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid (1.42 g), an aqueous solution of 2 N sodium hydroxide (5.5 ml) and N,N-dimethylformamide (15 ml), with cooling with ice. After the reaction mixture was stirred for 30 minutes, water was added to the resulting reaction mixture, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated w ere collected by filtration to obtain 4-(4-chlorophenyl)-2-methylthio-5-oxazolepropionic acid (1.45 g, 97%). This was recrystallized from ethanol to give colorless needles. mp 183-184° C.