Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].Br[C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22])[C:3]([F:19])=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC1(C)OB(c2cc(Cl)c(F)c(Cl)c2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Temperature: 70 °C
Yield: 59.7 %

Procedure:
A mixture of 2-(3,5-dichloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.34 g, 23.75 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (5.82 g, 33.25 mmol), Cs2CO3 (15.5 g, 47.5 mmol) and Pd(PPh3)2Cl2 (400 mg) in THF (30 mL) and water (15 mL) was heated at 70° C. in a sealed tube for 4 h under argon. The mixture was cooled to rt and partitioned between EA and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel eluted with hexanes to give crude compound of 1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.93 g) as a colorless oil. It was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].[Br:12][C:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[N:15]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:14]=1.N1C=CC=C(C)C=1.CS(Cl)(=O)=O>CC#N>[Br:12][C:13]1[CH:17]=[C:16]([C:18]([NH:4][C:3]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])=[O:19])[N:15]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:14]=1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: Cc1cccnc1
Product: Cc1cccc([N+](=O)[O-])c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
2-Methyl-6-nitroaniline (540 mg, 3.54 mmol), 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (1 g, 3.54 mmol), CH3CN (0.3 M, 11.8 mL) and 3-picoline (0.69 mL, 7.08 mmol, 2.0 eq) were introduced to a 50 mL round flask and subjected to a reaction at room temperature. After 10 minutes, the reaction mixture thus obtained was added with methylsulfonylchloride (0.41 mL, 5.31 mmol, 1.5 eq.), subjected to a reaction at 30° C. for 24 hours, and followed by a further reaction at 40° C. for 24 hours. Upon completion of the reaction, CH3CN was removed from the reaction mixture under reduced pressure, and the residue was extracted with 1 M HCl (20 mL) and ethyl acetate (20 mL), and, then, extracted with NaHCO3 (20 mL) and ethyl acetate (20 mL), washed with brine (20 mL). The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (MC:EA=9:1) to obtain the title compound (1.27 g, yield: 82%).
Reaction SMILES: [OH-].[K+].Br[CH:4]1[O:8][C:7]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]1[Br:14].C(O)(=O)C>C(O)C>[Br:14][C:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:7]=2[O:8][CH:4]=1
Reactant: Fc1cccc2c1OC(Br)C2Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Fc1cccc2c(Br)coc12
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of potassium hydroxide (12.7 g) in ethanol (180 ml) was slowly added the product obtained in Step 1 (34 g) and stirred for 3 hours. The resulting solution was neutralized by acetic acid, then extracted with ether. The organic layer was washed with successive water and saturated aqueous NaCl solution. After drying over anhydrous sodium sulfate, ether was removed in vacuo to give 24.1 g of the objective compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(OCC)(=O)C>C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.OS([O-])(=O)=O.O>[Cl:22][C:20]1[CH:19]=[C:18]([S:23]([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:24])=[O:25])[CH:17]=[C:16]([Cl:15])[CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc[nH]1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccn1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
At room temperature, to a stirred solution of tert-butyl pyrrole-2-carboxylate (obtained from Step A) (120 mg, 0.718 mmol) dissolved in benzene (2.5 mL) was added tetra-N-butylammonium hydrogen sulfate (49 mg, 0.144 mmol) followed by 50% aqueous sodium hydroxide solution (0.72 mL). After 10 min, a solution of 3,5-dichlorobenzenesulfonyl chloride (264 mg, 1.08 mmol) dissolved in benzene (1 mL) was added dropwise via a gas-tight syringe over a 25 min period. The reaction mixture was allowed to stir overnight at room temperature. Ethyl acetate and water were added and the phases were separated. The aqueous layer was re-extracted twice with ethyl acetate and the combined organic layers were washed with water (3×) and dried over anhydrous sodium sulfate. The crude product obtained after filtration and removal of solvents by rotoevaporation was purified by flash column chromatography on silica gel eluted with 0.5-2.5% ethyl acetate in hexane to afford the title compound (104 mg), homogeneous by TLC in 10/1 hexane/ethyl acetate; 77% yield, based on starting material consumed) and recovered starting material (58 mg, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:17]([OH:19])=O)[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])[CH3:2].CC[N:22](CC)CC.ClC(OCC(C)C)=O>C1COCC1.N>[CH2:1]([O:3][C:4]([C:6]1([C:17](=[O:19])[NH2:22])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
Azetidine-1,3,3-tricarboxylic acid 1-tert-butyl ester 3-ethyl ester (Example 11b; 21.5 g; 78.9 mmol) and NEt3(17.6 ml; 126 mmol) are dissolved in THF (200 ml) and cooled to 0° C. Isobutyl chloroformate (15.5 ml; 118 mmol) is added dropwise. The thick suspension is stirred for another 10 minutes at 0° C., diluted with THF (200 ml) and NH3-gas introduced for 5 minutes, stirred for 15 minutes at 0° C. followed by a second NH3-gas treatment for 5 minutes. The reaction mixture is warmed to room temperature and stirred for 30 minutes, poured on water and extracted with TBME three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and purified via chromatography (SiO2; TBME ) to yield the title compound as colorless crystals (17.3 g; 80%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH2:19][C:20]4([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][CH2:24][C:20]1([CH2:19][O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C:28]5([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)C1(C=O)CCOCC1
Reactant: OCC1(COc2cccc3onc(OCC4CCNCC4)c23)CCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OCC5(CO)CCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using [1-({[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}methyl)cyclobutyl]methanol (EXAMPLE 49, Step 2) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutane-carboxylate.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:19][O:20][C:21]1[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:19][O:20][C:21]1[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[C:24]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][C@H:12]4[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c2ccsc12
Reactant: O[C@H]1CC[C@H](Nc2ccc3ncc(Br)n3n2)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cnc3ccc(N[C@H]4CC[C@H](O)CC4)nn23)c2ccsc12

Procedure:
To a solution of trans-4-(3-bromoimidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol (45 mg, 0.145 mmol, 1.0 equiv) in acetonitrile (1.45 mL) was added 2-(7-methoxybenzo[b]thiophen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (55 mg, 0.188 mmol, 1.3 equiv), bis(triphenylphosphine)palladium(II)dichloride (11 mg, 0.0159 mmol, 0.1 equiv), then sodium carbonate (1.45 mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture was irradiated in the microwave at 150° C. for 10 min. Purification by column chromatography gave 31 mg of the yellow solid, 53%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=O.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C.[NH:77]1[C:85]2[CH:84]=[CH:83][N:82]=[C:81]([NH:86][C:87](=[O:90])[CH2:88][CH3:89])[C:80]=2[CH:79]=[CH:78]1>CC(N(C)C)=O.O>[Cl:15][C:7]1[CH:8]=[C:9]([CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([N:77]1[C:85]2[CH:84]=[CH:83][N:82]=[C:81]([NH:86][C:87](=[O:90])[CH2:88][CH3:89])[C:80]=2[CH:79]=[CH:78]1)=[O:6])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: CCC(=O)Nc1nccc2[nH]ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: C[NH3+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(C(=O)OC)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2,6-dichloro-4-(methoxycarbonyl)benzoic acid (600 mg, 2.3 mmol), in dimethylacetamide (10 mL) was treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1300 mg, 3.45 mmol), 1-hydroxy-7-azabenzotriazole (469 mg, 3.45 mmol), N,N-diisopropylethylamine (1.05 mL, 5.75 mmol) and dimethylaminopyridine (140 mg, 1.15 mmol) were added and the mixture was stirred at room temperature for about 1 hour. This was followed by addition of N-(1H-pyrrolo[3,2-c]pyridin-4-yl)propanamide (450 mg, 2.3 mmol) and stirring at room temperature for about 16 hours. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine (100 mL) and organic layer was separated and dried over anhydrous sodium sulphate to give crude product which was purified by silica gel (100-200 mesh size) column chromatography using ethyl-acetate and hexane as eluting system to give pure methyl 3,5-dichloro-4-{[4-(propanoylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoate. (250 mg, 25%)
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC>C(O)(C)C>[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=[N:6][NH:5][CH:2]([CH3:4])[CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)NN
Reactant: O=CCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)NN=CCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of isopropylhydrazine hydrochloride (92.4 g, 0.84 mol) and (3-oxo-propyl)-carbamic acid benzyl ester (173 g, 0.84 mol) in isopropyl alcohol (1.7 L) was added Et3N (140 mL, 1.0 mol) over 20 min. The resulting slurry was heated at reflux for 3 h, and then was cooled to rt and concentrated. The residue was partitioned between EtOAc (700 mL) and water (700 mL). The organic layer was washed with water (3×500 mL), satd. aq. NaCl (300 mL), dried (MgSO4), and concentrated to afford the title compound. The crude product was used in next reaction without purification. MS (ESI): exact mass calcd. for C14H21N3O2, 263.16; m/z found, 264.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.36-7.25 (m, 5H), 7.02 (t, J=4.5, 1H), 5.10 (br s, 1H), 5.09 (s, 2H), 3.45-3.34 (m, 3H), 2.40-2.34 (m, 2H), 1.11 (d, J=6.4, 6H).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]#[C:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH2:32])[CH2:27]2)=[CH:18][N:17]=1.Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.CN1CCOCC1.ClC(OCC(C)C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]#[C:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:11](=[O:13])[C@@H:9]([N:8]([CH3:14])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:10])[CH2:27]2)=[CH:18][N:17]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COc1nc(Cl)ncc1C#C[C@@H]1CCC[C@H](N)C1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1nc(Cl)ncc1C#C[C@@H]1CCC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1
Reaction time: 0.03 h

Procedure:
To a solution of N-Boc-N-methyl-L-alanine (195 mg) in N,N-dimethylformamide (2.5 mL), N-methylmorpholine (246 μL) and isobutyl chloroformate (105 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 2 minutes. To the reaction mixture, a solution of (1S,3R)-3-((2-chloro-4-methoxypyrimidin-5-yl)ethynyl)cyclohexaneamine (Q3) hydrochloride in N,N-dimethylformamide (2 mL) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 88 to 40% hexane in ethyl acetate) to obtain tert-butyl ((S)-1-(((1S,3R)-3-((2-chloro-4-methoxypyrimidin-5-yl)ethynyl)cyclohexyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (Q4, 120 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.[Li+].[OH-].COCCOC.Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC(C)CCC1CSc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Product: CC1CCC(CSc2ccc(F)cc2)C(C(=O)O)C1
Temperature: 70 °C

Procedure:
A solution of (1R/S,3R/S,6R/S)-ethyl 2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methyl-cyclohexanecarboxylate and (1R/S,3S/R,6R/S)-ethyl 2-{[(4-fluorophenyl)sulfanyl]-methyl}-5-methylcyclohexanecarboxylate (1:1 mixture, 54 mg, 0.17 mmol) in a mixture of aqueous LiOH (2 M, 1.7 mL, 3.4 mmol), DME (1 mL) and ethanol (0.3 mL) was heated at 70° C. for 7 h. The solution was cooled to room temperature, acidified with aqueous 2 M HCl (0.5 mL) and extracted with ethyl acetate. The organic extracts were concentrated in vacuo to yield (1R/S,3R/S,6R/S)-2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexanecarboxylic acid and (1R/S,3S/R,6R/S)-2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexanecarboxylic acid as a 1:1 mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[OH:19])[CH:3]=1.Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[O:19][CH2:21][CH2:22][OH:23])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCO
Reaction time: 22 h
Yield: 82.2 %

Procedure:
A solution of 4-chloro-2-(3-formyl-2-hydroxyphenoxy)benzonitrile (0.30 g, 1.11 mmol), 2-bromoethanol (0.10 mL, 0.18 g, 1.4 mmol) and cesium carbonate (0.43 g, 1.3 mmol) were heated with stirring in dry DMF (3 mL) at 50° C. After 22 h, 2-bromoethanol (0.19 mL, 0.33 g, 2.7 mmol) was added, and stirring continued for an additional 24 h at 50° C. The reaction mixture was cooled, poured into-water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-[3-formyl-2-(2-hydroxyethoxy)phenoxy]benzonitrile (0.29 g, 83%) as a tan oil, which was used without further purification.
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:16]=1[C:17]#[N:18]>CN(C)C(=O)C.CCOCC>[Br:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([S:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)[C:16]=1[C:17]#[N:18]
Reactant: SC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1c(F)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: N#Cc1c(Br)cccc1SC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of adamantanethiol (1.01 g) in N,N-dimethylacetamide (20 mL) at room temperature was added NaH (0.24 g, 60% in mineral oil) and the reaction was stirred for 10 minutes. 2-Fluoro-6-bromobenzonitrile (1 g) was added and the mixture was heated to 80° C. for 1 hour. The reaction mixture was cooled and diluted with ether (400 mL), and the mixture was washed three times with 1M NaOH solution and once with brine, then dried over sodium sulfate, filtered and concentrated to yield the crude product which was taken on to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[Br:21]Br.O>O>[Br:21][C:18]1[C:17]([Cl:20])=[CH:16][C:5]2[N:6]([C@@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:2]([Cl:1])=[N:3][C:4]=2[CH:19]=1
Reactant: BrBr
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Cl)cc32)[C@H](O)[C@@H]1O
Solvent: O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Br)c(Cl)cc32)[C@H](O)[C@@H]1O
Reaction time: 3 h

Procedure:
To a suspension of 0.319 g (1.0 mmol) of 2,6-dichloro-1-β-D-ribofuranosylbenzimidazole (67) in 10 mL of H2O, was added dropwise a sat. solution of Br2 /H2O at room temperature. After the addition had been completed, stirring was continued for 3 hr. The reaction mixture was filtered and the solid was washed with portions of H2O, and then recrystallized from MeOH to give 0.335 g (78%, as M MeOH) of 95 as white crystalline needles. MP 140°-142° C. MS (El) m/e 395.9274 (2%, M+ =395.9279). 1H NMR (DMSO-d6): δ 8.88 (s, 1, 7-H), 8.08 (s, 1,4-H), 5.89 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.49 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.40 (t, 5'-OH, J5'-5'OH =4.0 Hz), 5.28 (d, 1, 3'-OH, J3'-3'OH =4.5 HZ), 4.42 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.13 (m, 1, 3'-H, J3'-4' =1.5 Hz), 4.01 (m, 1, 4'-H, J4'-5' =J4'-5" =2.5 Hz), 3.70 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). Anal. Calcd. for C12H11BrCl2N2O4MeOH: C, 36.30; H, 3.51; N, 6.5 Found: C, 35.98; H, 3.60; N, 6.39.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([CH3:37])[C:34]=1[O:35][CH3:36])[NH2:31].[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([F:46])=[CH:41][N:40]=1>>[Cl:38][C:39]1[N:44]=[C:43]([NH:31][C:30]2[CH:32]=[C:33]([CH3:37])[C:34]([O:35][CH3:36])=[C:28]([CH3:27])[CH:29]=2)[C:42]([F:46])=[CH:41][N:40]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1c(C)cc(N)cc1C
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: COc1c(C)cc(Nc2nc(Cl)ncc2F)cc1C

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 3,5-dimethyl-4-methoxyaniline (400 mg, 2.6 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gave 2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 3-(methoxycarbonylmethyleneoxy)aniline (650 mg, 3.6 mmol) gave N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (180 mg, 35%). 1H NMR (CD3OD): δ 2.20 (s, 6H), 3.70 (s, 3H), 3.74 (s, 3H), 4.52 (s, 2H), 6.76 (ddd, J=0.9, 2.4 and 8.4 Hz, 1H), 7.03–7.08 (m, 2H), 7.24 (m, 3H), 7.96 (d, J=5.4 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −162.92; LCMS: ret. time: 23.13 min.; purity: 100%; MS (m/e): 427.04 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29]O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:26][C@H:27]([CH2:29][N:54]4[C:50](=[O:60])[C:51]5[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=5)[C:53]4=[O:55])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a solution of 5 g (12.48 mmol) of trans-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol, which is prepared as described in Example 47(b) of WO 97/28161, in 100 ml of dry THF are added under argon 4.91 g (18.72 mmol) of triphenylphosphine and 2.75 g (18.7 mmol) of phthalimide; 3.36 g (3.02 ml; 18.7 mmol) of diethyl azodicarboxylate (96%) are added dropwise thereto. The reaction mixture is stirred at RT for 27 h. The reaction mixture is concentrated to dryness and the crude compound is purified by flash-chromatography (ethylacetate) to obtain trans-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dione. Analytical HPLC: tR=12.12 min (Grad 1); ES-MS: m/eo=529.9.
Reaction SMILES: [S:1]1[CH:6]=[C:5]([C:7](=[N:34][O:35][CH3:36])[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[S:4][CH2:3][CH2:2]1.O1CCCC1.CO.O>[C].[Pd].C(O)(=O)C>[S:1]1[CH:6]=[C:5]([C:7](=[N:34][O:35][CH3:36])[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([OH:21])=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[S:4][CH2:3][CH2:2]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)C1=CSCCS1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)C1=CSCCS1
Yield: 41.9 %

Procedure:
4-Nitrobenzyl 7-[2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.0 g.), tetrahydrofuran (50 ml.), methanol (30 ml.), 10% palladium-carbon (2 g.), water (7 ml.) and acetic acid (0.7 ml.) were treated in a similar manner to that of Example 19-(2) to give 7-[2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).