Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:13]O.O>C1COCC1.C(OCC)(=O)C>[C:12]1([CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:5]([OH:6])[CH3:4]
Reactant: CO
Reactant: CCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium borohydride (564 mg) was added to a solution of 2-methylacetophenone (1 g) in a mixture of THF (8 mL) with methanol (32 mL), and the reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 911 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.[Cl:12][CH2:13][CH2:14][CH2:15]I>>[Cl:12][CH2:13][CH2:14][CH2:15][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2]1
Reactant: ClCCCI
Reactant: O=c1[nH]nnc2ccccc12
Product: O=c1c2ccccc2nnn1CCCCl

Procedure:
3-(3-chloropropyl)-1,2,3-benzotriazin-4(3H)one was prepared according to the general procedure outlined in example 6, step 1. Starting from 1,2,3-benzotriazin-4(3H)one (2 g, 13.6 mmol) and 1-chloro-3-iodopropane (1.6 mL, 14.95 mmol), 1.57 g (52%); yellow solid; m.p. 69° C., MS: 223.9 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C:12]2=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:30]Br>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([Br:30])[C:12]2=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2Br
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture intermediate 14, ethyl 3-benzyloxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, (1.00 g, 3.05 mmol) and sodium acetate (1.50 g) in acetic acid (20 ml) was heated at 120° C. and then treated with a solution of bromine (1.5 g, 9.2 mmol) in acetic acid (5 ml). After 1 h at 120° C., the reaction mixture was cooled and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.531 g (43% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (3H, t, J=7.1 Hz, CH3), 2.60 (2H, m, CH2), 4.28 (2H, t, J=7.3 Hz, CH2), 4.38 (2H, q, J=7.1 Hz, OCH2), 5.34 (2H, s, OCH2), 7.05 (1H, t, J=4.8 Hz, CH), 7.3–7.52 (5H, m, aromatics).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[CH:22][C:21]=1I>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:21]1[CH:22]=[C:23]([S:26]([C:29]([F:30])([F:31])[F:32])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccc(Cl)c(I)c1)C(F)(F)F
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Yield: 72 %

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-chloro-2-iodo-4-[(trifluoromethyl)sulfonyl]benzene (Intermediate 186), the title compound was obtained as a white solid in 72% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [I-].[CH2:2]([N+:9]1(C)[CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([O:18][CH3:19])[CH:15]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH3:19][O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:20][CH3:21])[CH2:10][N:9]([CH3:2])[CH2:17]2
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)C[N+](C)(Cc1ccccc1)C2
Agent: [Pd]
Agent: [I-]
Solvent: CO
Product: COc1cc2c(cc1OC)CN(C)C2

Procedure:
1.0 g (2.43 mmol) of N-benzyl-5,6-dimethoxy-N-methylisoindolinium iodide was dissolved in 40 ml of a 50% methanol aqueous solution, and 300 mg of a 10% palladium carbon catalyst was added. Then, the catalytic reduction was conducted at 50° C. for 6 hours in a hydrogen gas stream. After filtering off the catalyst, methanol was distilled off under reduced pressure, and the residual solution was adjusted to strongly alkaline by an addition of a 50% sodium hydroxide aqueous solution. Then, the solution was extracted twice with methylene chloride. The extract solution was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 200 mg of the above identified compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[CH2:6][C:7]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C(Cl)Cl>[C:29]([O:12][C:7]1([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:21])[F:1])[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: OC1(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1
Reaction time: 12 h
Yield: 65 %

Procedure:
43 g of 1-(3,5-bis(trifluoromethyl)benzyl)cyclopentanol and 16.7 g of triethylamine dissolved in 100 mL of methylene chloride was slowly charged into flask equipped with magnetic stirrer and 14.93 mL of methacryloyl chloride in 100 mL of dichloromethane cooled down to 0° C. The resultant mixture slowly warmed up to room temperature and allowed to stir at this temperature for 12 hours. Upon completion of the reaction as confirmed by thin layer chromatography, the mixture was quenched by pouring into 400 mL of deionized water and extracted further into methylene chloride. The methylene chloride extracts were then dried over sodium sulfate, filtered and concentrated in the rotary evaporator affording 34 g of 1-(3,5-bis(trifluoromethyl)benzyl)cyclopentyl methacrylate (˜65%) yield of as an amber oil. The oil was purified further by passing through a silica gel plug eluting with a 60/40 mixture of hexanes/methylene chloride affording 30 g of 1-(3,5-bis(trifluoromethyl)benzyl)cyclopentyl methacrylate (LG1) as pure product. 1H NMR (500 MHz, Acetone-d6): δ 7.97 (s, 1H), 7.76 (s, 2H), 5.99 (s, 1H, vinyl), 5.6 (s, 1H, vinyl), 3.56 (s, 2H), 2.23-1.70 (m, 8H), 1.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[N+:11]([O-])([OH:13])=[O:12].O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 3,5-difluoroanisole (30 g, 208 mmol) in 260 mL dichloromethane was added HNO3 (>90% fuming, 60 mL) dropwise at 0° C. The resulting solution was stirred at 0° C. for 3 hours, then washed water. The aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate and condensed on a rotavap. The residue was recrystallized in hexane and ethyl acetate to provide 28.5 g (72% yield) of 1,5-difluoro-3-methoxy-2-nitrobenzene as an off-white powder. 1H NMR (400 MHz, DMSO) δ ppm 7.20 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[C:10]([Si:14]([CH3:30])([CH3:29])[O:15][CH2:16][CH2:17]/[CH:18]=[CH:19]/B1OC(C)(C)C(C)(C)O1)([CH3:13])([CH3:12])[CH3:11].[F-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[C:10]([Si:14]([O:15][CH2:16][CH2:17]/[CH:18]=[CH:19]/[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1)([CH3:29])[CH3:30])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC1(C)OB(/C=C/CCO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 150 °C
Reaction time: 72 h
Yield: 86.2 %

Procedure:
4-Bromo-1,2-dichlorobenzene (0.9 mL, 7 mmol), (E)-tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyloxy)silane (3.0 mL, 8.3 mmol), KF (1.2 g, 21 mmol), Pd(OAc)2 (0.16 g, 0.70 mmol), and 2-(di-tert-butylphosphino)biphenyl (0.41 g, 1.4 mmol) were combined in a 20 mL microwave tube and the tube was sealed, evacuated and backfilled with argon. Degassed THF (20 mL) and H2O (0.25 mL, 14 mmol) were added under argon, and the mixture was heated to 150° C. for 60 min using microwave irradiation. The reaction mixture was cooled to rt and stirred for 3 days. The reaction mixture was diluted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and brine (100 ml), dried over Na2SO4 and concentrated to give a black oil that was stored overnight at −20° C. The crude product was dissolved in hexanes/DCM and purified by silica gel chromatography (100% hexanes for 10 min, 0-3% ethyl acetate in hexanes over 20 min) to obtain 2.0 g (67% yield) of Intermediate 2A. HPLC/MS (Method C)RT=4.80 min, [M-C6H16OSi]+ 199.1.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:10]([NH:12][C@@H:13]1[C:16](=[O:17])[N:15]2[C:18]([C:27]([O-:29])=[O:28])=[C:19]([CH2:22][O:23][C:24]([NH2:26])=[O:25])[CH2:20][S:21][C@H:14]12)=[O:11])/[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.[Na+].[C:31]([O:34][CH:35](Br)[CH3:36])(=[O:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:36][CH:35]([O:28][C:27]([C:18]1[N:15]2[C:16]([C@@H:13]([NH:12][C:10](/[C:4](/[C:5]3[O:9][CH:8]=[CH:7][CH:6]=3)=[N:3]\[O:2][CH3:1])=[O:11])[C@H:14]2[S:21][CH2:20][C:19]=1[CH2:22][O:23][C:24]([NH2:26])=[O:25])=[O:17])=[O:29])[O:34][C:31]([CH3:32])=[O:33]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of sodium cefuroxime (20 g) in dimethylacetamide (100 ml) was cooled to 14° and (RS) 1-acetoxyethyl bromide (10 ml) was added. The mixture was stirred at 14° for 45 minutes before anhydrous potassium carbonate (0.5 g) was added. After stirring for a further 45 minutes ethyl acetate (200 ml) and 3% sodium bicarbonate solution (200 ml) were added. The mixture was stirred at ambient temperature for 1 hour and the two phases were allowed to separate. The aqueous layer was washed with ethyl acetate (100 ml) and the two organic layers were then washed sequentially with M hydrochloric acid (100 ml) and 20% sodium chloride solution (30 ml). The combined organic layers were stirred with charcoal (2 g) for 30 minutes before filtration. The filtrate was concentrated in vacuo to 176 ml. Water (1.9 ml) was added to the concentrate which was run into stirred 60°-80° petrol (1.76 l) over 15 minutes. The precipitated product was filtered off and washed with a mixture of petrol (105 ml) and ethyl acetate (12 ml) followed by petrol (118 ml). Drying at 40° in vacuo gave cefuroxime axetil 17.9 g: Solvents (GLC), ethylacetate 1.6%, petrol 1.5%; impurities by HPLC 4.1% m/m, isomer ratio 1.06:1; E1 cm1 % (MeOH) 364. The infra-red spectrum in Nujol was typical of the amorphous material.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>O>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH2:9][N:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12][CH:13]=2)[N:7]=1
Reactant: CNc1nc(-c2cccnc2)cs1
Reactant: CCCCCBr
Agent: Cl
Solvent: O
Product: CCCCCN1CCC=C(c2csc(NC)n2)C1
Yield: 53 %

Procedure:
The procedure of Example 1 was repeated, using the N-methyl-4-(3-pyridinyl)-2-thiazolamine prepared in Example 14 and an excess of 1-bromopentane as the reactants. The title compound was purified by column chromatography (53% yield) and converted to its HCl salt by the procedure of Example 2. The salt obtained (mp 168°-172° C.) contained 1.5 molecules of HCl and one molecule of water.
Reaction SMILES: [CH3:1][CH:2]([C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]([C:3](=[O:12])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C(=O)C=Cc1ccccc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C(=O)CCc1ccccc1)C(=O)CCc1ccccc1
Yield: 73 %

Procedure:
4-Methyl-1,7-diphenyl-1,6-hetpadiene-3,5-dione (6b, 0.96 g, 3.3 mmol) and palladium on activated carbon (0.25 g, 10%) were combined in ethyl acetate (50 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 2 hr at room temperature. The resulting mixture was filtered through celite and the filtrate was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was twice chromatographed on silica gel with ethyl acetate/hexane to give an oil. The oil was distilled bulb to bulb to give 0.71 g (73%) of a clear oil; 1H NMR: δ enol form: 1.66 (s, 3H), 2.73 (m, 8H), 7.17 (m, 10H); keto form: 1.20 (d, 3H, J=7.2 Hz), 2.73 (m, 8H), 3.55 (q, 1H, J=7.0 Hz), 7.17 (m, 10H); 13C NMR: δ 12.3, 29.3, 31.0, 37.6, 42.8, 60.9, 104.2, 125.9, 128.1, 128.2, 140.4, 140.8, 174.6, 191.5, 205.6; Exact mass calcd for C20H22O2: 294.1620, observed (M+H) 295.1693.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[C:14]1([S-:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+]>CS(C)=O.Cl>[F:12][C:10]1[CH:11]=[C:2]([S:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(F)cc(F)c21
Reactant: [S-]c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCCc2cc(Sc3ccccc3)cc(F)c21
Temperature: 50 °C

Procedure:
A mixture of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one (1.0 gram, 5.5 moles) and potassium thiophenolate (0.81 gram, 5.5 mmole) in 4 mL DMSO was heated at 50° C. for 0.5 hour. The mixture was diluted with 30 mL 0.1N hydrochloric acid and then it was extracted with 50 mL diethyl ether. The organic phase was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. 8-Fluoro-6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one was obtained by recrystallization of the residue from ethyl acetate/hexane, 0.871 gram (58%), m.p. 112-113° C., M+H=273.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.CO.[OH-].[Na+].Cl>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([OH:26])=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
Methyl 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxylate (156 mg, 0.39 mmol) was added into the mixture of methanol (5 mL) and sodium hydroxide (5 M, 2 mL). The reaction mixture was stirred at room temperature overnight. After that, the reaction was diluted with 20 mL of water, acidified with 2 M of hydrochloric acid to pH 6 and diluted with ethyl acetate (30 mL). The organic layer was separated and washed with water. The solvent was dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel to give 135 mg of product. MS obsd. (ESI+) [(M+H)+] 387.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18]([C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])(=[O:20])=[O:19])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:30]([O:29][CH2:28][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]1[S:18]([C:21]([F:25])([F:26])[CH:22]([F:24])[F:23])(=[O:20])=[O:19])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(c1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(F)(F)C(F)F
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1nc(-c2ccccc2)c(-c2ccccc2)n1COCc1ccccc1)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1.92 g (5 mmole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole, 1.6 g (10 mmole) of benzyl chloromethyl ether, 2.8 g (20 mmole) of potassium carbonate in 20 ml DMF was stirred at RT for six hours, then poured into ice water. The aqueous mixture was extracted three times with ether. The ether extracts were backwashed three times with water, then dried and concentrated. The residue was chromatographed on 150 g SilicAR CC-7, eluting with toluene to give, after recrystallization from hexane, 2.5 g (100%) of white product, mp 97.5°-98.5°.
Reaction SMILES: C([NH:11][CH:12]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:13]([O:15][CH3:16])=[O:14])(OCC1C=CC=CC=1)=O.[H][H]>CO.[Pd]>[NH2:11][CH:12]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)C(CN1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)CN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title material from Step A was dissolved in methanol with catalytic amount of 10% Pd on C. The reaction mixture was hydrogenated for 2 hours at room temperature in methanol under 25 psi of hydrogen. After filtration of the crude reaction mixture through a pad of Celite, the solvent was evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH2:53][CH2:54]N2CCC(C3C=CC=CC=3[S@](C)=O)CC2)[CH2:35][N:36]([CH3:52])[C:37]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[C:41]([N+:49]([O-:51])=[O:50])[CH:40]=2)=[O:38])=[CH:30][CH:29]=1>O>[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH2:53][CH2:54][N:11]2[CH2:12][CH2:13][CH:8]([N:3]3[CH2:4][CH2:5][CH2:6][NH:7][C:2]3=[O:1])[CH2:9][CH2:10]2)[CH2:35][N:36]([CH3:52])[C:37]([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[C:41]([N+:49]([O-:51])=[O:50])[CH:40]=2)=[O:38])=[CH:32][CH:33]=1
Reactant: CN(CC(CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)cc1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12
Reactant: O=C1NCCCN1C1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: CN(CC(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)cc1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12

Procedure:
Using standard reductive amination conditions 4-(tetrahydro-2-oxo-1(2H)-pyrimidinyl)piperidine (Miller, S C; Jacobs, R T; Shenvi, A B. EP 739891) was reacted with N-[2-(4-chlorophenyl)-4-oxobutyl]-N-methyl-3-nitro-1-naphthamide [Example 3] and converted to the citrate salt. MS m/z 578 (M+H). Analysis for C31H36ClN5O4.1.0 C6H8O7.0.8 H2O: calculated: C, 56.64; H, 5.86; N, 8.92; found: C, 56.60; H, 5.74; N, 8.69.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>>[OH:36][CH:34]1[CH2:35][N:32]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]4[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]4=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:33]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Reactant: OC1CNC1
Agent: Cl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CC(O)C4)c3)nc12

Procedure:
1-[2-[3-(3-Hydroxy-azetidin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and azetidin-3-ol hydrogen chloride following the same procedure of RO5364753. M+H=481.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH3:9])[CH:5]=[N:4][C:3]=1[C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]([CH2:7][CH2:8][CH3:9])[CH:5]=[N:4][C:3]=2[C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=2)=[CH:21][C:20]=1[F:28]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CCCn1cnc(-c2cc(C#N)ccn2)c1Br
Product: CCCn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-propyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H14ClFN4, 342. Found, 341, 343.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[C:28]([O:31][CH2:32][CH2:33]O)(=[O:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:28]([O:31][CH2:32][CH2:33][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])[N:10]=2)=[CH:14][CH:15]=1)(=[O:30])[CH3:29]
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(F)cc1
Reactant: CC(=O)OCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)OCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(F)cc3)[nH]2)cc1

Procedure:
5-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-hydroxyethyl acetate, triphenylphosphine and diethylazodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-acetoxyethyloxy)phenyl)-5-(4-fluorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.