Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(O)C>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 30.3 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.35 g.), conc.hydrochloric acid (0.39 g.), ethanol (5.3 ml.) and tetrahydrofuran (8 ml.) was stirred at room temperature for 4.5 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in an aqueous solution of sodium bicarbonate, treated with activated charcoal and filtered. The filtrate was adjusted to pH 3.5 with 10% hydrochloric acid under ice cooling. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.1 g.).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:12][OH:13])[O:9][N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: OCC1CC(c2ccc(Br)s2)=NO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)s2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
[3-(5-Bromo-thien-2-yl)-4,5-dihydro-isoxazol-5-yl]-methanol (10.7 g, 40.6 mmol) was added to anhydrous dichloromethane (200 ml) followed by addition of triethylamine (7.9 ml, 56.9 mmol). The solution was cooled to 0° C. followed by dropwise addition of methane sulfonyl chloride (3.8 ml, 48.7 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (100 ml) was added. After further extraction with dichloromethane (2×100 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (9 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56]1[N:61]=[CH:60][C:59]([C:62]([NH2:65])([CH3:64])[CH3:63])=[CH:58][CH:57]=1>CN(C=O)C>[O:55]([C:56]1[N:61]=[CH:60][C:59]([C:62]([NH:65][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])([CH3:63])[CH3:64])=[CH:58][CH:57]=1)[CH3:54]
Reactant: COc1ccc(C(C)(C)N)cn1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a stirred solution of Intermediate 1 (see Example 1.1, 100 mg, 0.362 mmol), HATU (165 mg, 0.434 mmol) and DIEA (0.126 mL, 0.724 mmol) in DMF was added 2-(6-methoxypyridin-3-yl)propan-2-amine (72.2 mg, 0.434 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound (138 mg) as white solid. LCMS m/z=425.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.6 and 3.5 Hz, 1H), 1.12-1.15 (m, 1H), 1.76 (s, 3H), 1.77 (s, 3H), 2.08-2.12 (m, 1H), 2.22-2.27 (m, 1H), 2.91 (d, J=16.6 Hz, 1H), 3.00 (dd, J=6.2 and 16.5 Hz, 1H), 3.91 (s, 3H), 6.69 (d, J=8.7 Hz, 1H), 7.00-7.07 (m, 2H), 7.14 (s, 1H), 7.62-7.68 (m, 2H), 8.25 (d, J=2.6 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13]C1C=CC2CCN(C3CCC3)CCC=2C=1)[C:6]([NH:8][CH3:9])=[O:7])#[N:2].[CH3:29][C:30]([O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[CH:44][C:45](B(O)O)=[CH:46][C:39]=2[CH2:38][CH2:37]1)=[O:35])([CH3:32])[CH3:31]>>[C:1]([C:3]1[CH:4]=[C:5]([C:6]([NH:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]=1[O:13][C:45]1[CH:44]=[CH:43][C:40]2[CH2:41][CH2:42][N:36]([C:34]([O:33][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:35])[CH2:37][CH2:38][C:39]=2[CH:46]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(C#N)c1
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(C#N)c1

Procedure:
The title compound was prepared from 3-cyano-4-hydroxy-N-methylbenzamide (E279, Step 3) and (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2), using the method of Example 264 Step 3; MS (ES+) m/e 322 [(M+H)—CO2tBu]+.
Reaction SMILES: [OH-].[Na+].Cl.[C:4](=[NH:9])(OCC)[CH3:5].[NH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH2:11]>C(O)C>[C:4]([NH:11][NH:10][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[NH:9])[CH3:5]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(C)=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=N)NNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydroxide (16.0 g, 400 mmol) was dissolved in absolute ethanol (1 L) at 60° C. The solution was cooled to 0° C. and treated portion-wise with ethyl ethanimidoate hydrochloride (50 g, 400 mmol); after 10 minutes, tert-butyl hydrazinecarboxylate (52.9 g, 400 mmol) was added in a single portion. The reaction mixture was stirred at 70° C. for 2.5 hours, then cooled to 20° C. and filtered. The filtrate was concentrated in vacuo and treated with tert-butyl methyl ether (500 mL) and ethanol (20 mL). After seeding, the mixture was allowed to stir for 18 hours, whereupon the precipitated solid was collected via filtration and washed with ice-cold tert-butyl methyl ether (500 mL). The solid was dissolved in 2-methyltetrahydrofuran:methanol (9:1 mixture, 300 mL), and the solution was concentrated to dryness. The residue was washed with diethyl ether (3×200 mL) to afford the product as a very pale yellow solid. Yield; 50.2 g, 290 mmol, 72%. LCMS m/z 174.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 1.88 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C@H:10]([CH3:36])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[NH:22][C:21]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[N:20][C:19]=2[N:18]([CH3:35])[C:16]1=[O:17])#[N:9]>ClCCl>[NH2:27][CH2:26][C:21]1[NH:22][C:23]2[C:24](=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([C:8]#[N:9])[CH3:36])[C:16](=[O:17])[N:18]([CH3:35])[C:19]=2[N:20]=1
Reactant: C[C@@H](C#N)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C#N)CCCCn1c(=O)c2[nH]c(CN)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
To a 50% solution of trifluoroacetic acid in dichloromethane (15 ml) was added (R)-1-(5-cyanohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.21 g, 0.52 mmol). After stirring at room temperature for 3 hours, the solvent and excess reagent were evaporated under reduced pressure. The residue was treated with ammonia-methanol solution (2.0 M, 10 ml) and stirred for 1 hour. After concentration under reduced pressure, the crude product was purified by flash chromatography on silica gel eluting with ammonium hydroxide (37% in water)-methanol-ethyl acetate mixture (1:10:5) to provide (R)-8-aminomethyl-1-(5-cyanohexyl)-3-methylxanthine (0.06 g, 38% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH2:17][NH2:18])=[CH:15][N:14]=[CH:13]1.[N:20]([CH3:23])=[C:21]=[O:22]>ClC(Cl)Cl>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:12]1[C:16]([CH2:17][NH:18][C:21]([NH:20][CH3:23])=[O:22])=[CH:15][N:14]=[CH:13]1
Reactant: CN=C=O
Reactant: CC1(C)CCc2ccccc2C1n1cncc1CN
Solvent: ClC(Cl)Cl
Product: CNC(=O)NCc1cncn1C1c2ccccc2CCC1(C)C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a stirred mixture of 5.1 parts of 1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazole-5-methanamine and 75 parts of trichloromethane were added 1.2 parts of isocyanatomethane. After stirring for 1 hour, the reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.9 parts (46.4%) of N-[[1-(1,2,3,4-tetrahydro-2,2-dimethyl-1-naphthalenyl)-1H-imidazol-5-yl]-methyl]-N'-methylurea; mp. 120.1° C. (compound 2.54).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
138.1 g (1.0 mol) of para-hydroxybenzoic acid were first dissolved in 400 ml of water and 600 ml of isopropanol and this solution was admixed at 0 to 5° C. with 235.7 g of KOH solution (50% strength by weight aqueous solution, 2.1 mol). The resulting pH was 14. Metered into this solution over the course of one hour, then, at 0 to 5° C., were 140.4 g (1.0 mol) of benzoyl chloride, and the batch was stirred for 30 minutes at 0 to 5° C. thereafter. At the end of the after-stirring, the pH of the reaction mixture was 9.3. The reaction mixture was subsequently adjusted to a pH of 8 at 0 to 5° C. using 25.0 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 100 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 220.5 g (91.0% of theory). According to HPLC and NMR measurement, the product was free from benzoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[NH:14][C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[C:1]1([S:7]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:15](=[O:18])[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCCl
Reactant: O=C1COc2cc(S(=O)(=O)c3ccccc3)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCN1C(=O)COc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 3 h
Yield: 50 %

Procedure:
A suspension of 7-benzenesulfonyl-4H-benzo[1,4]oxazin-3-one (0.09 g., 0.3 mmol), (2-chloro-ethyl)-dimethyl-amine hydrochloride (0.056 g., 0.39 mmol) and potassium carbonate (0.095 g., 0.69 mmol) in 0.7 mL ethyl acetate was refluxed for 1 hour. To the reaction mixture was added 0.75 mL water, and reflux was continued for 3 hours. 30 mL Ethyl acetate was added, and the reaction mixture was washed three times with 15 mL water, dried over magnesium sulfate and concentrated in vacuo. The residue was purifed by flash chromatography (0 to 5% methanol in dichloromethane) to afford 0.055 g (0.15 mmol, 50%) of 7-benzenesulfonyl-4-(2-dimethylamino-ethyl)-4H-benzo[1,4]oxazin-3-one. MS: 361 (M+H)+, mp: 232.9-235.3° C. (HCl salt).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.Cl>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
4.9 g of 4-(3-phenylpropyloxy)benzaldehyde were dissolved in 30 ml of ethanol, and 0.39 g of sodium borohydride were added to the resultant solution, then the solution was stirred for 1 hour at room temperature. After completed the reaction, the solvent used was distillated under reduced pressure, and the residue obtained was dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. After washing the ethyl acetate layer with dilute hydrochloric acid, dilute alkaline aqueous solution and water in series, the organic layer was then dried with anhydrous magnesium sulfate, and the solvent used was distillated under reduced pressure, thereby affording 4.1 g of 4-(3-phenylpropyloxy)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([NH2:72])=[O:71])=[C:68]([Cl:75])[CH:67]=1>C(Cl)Cl>[C:70]([C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:67][C:68]=1[Cl:75])(=[O:71])[NH2:72]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)c1ccc(N)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)c(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 4-amino-2-chloro-benzamide (Chembridge, 58 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 6 mg.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([OH:34])[CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:13]1[CH:14]=[N:15][C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([S:2][CH3:1])[CH:4]=2)=[C:8]([CH:12]=1)[C:9]([NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([OH:34])[CH2:29]1)=[O:11]
Reactant: N[C@H]1CCC[C@H](O)C1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CCC[C@H](O)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid (345 mg, 1.26 mmol) was dissolved in dimethylformamide (10 ml) and triethylamine (865 μl, 11.8 mmol) was added followed by (1S,3S)-3-aminocyclohexanol hydroformate (200 mg, 1.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (715 mg, 3.73 mmol) and 1-hydroxybenzotriazole (185 mg, 1.37 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between 10% aq. citric acid solution (50 ml) and diethyl ether (50 ml). The organic was washed with sat. sodium bicarbonate solution (50 ml), water (25 ml) and brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 70:30) as eluant to give 5-fluoro-N-[(1S,3S)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (212 mg) as a colourless gum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[C:20]([C:21]4[CH:26]=[C:25](S(C)=O)[N:24]=[C:23]([CH3:30])[N:22]=4)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH3:31]>O1CCOCC1>[NH2:31][C:25]1[N:24]=[C:23]([CH3:30])[N:22]=[C:21]([C:20]2[C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:26]=1
Reactant: N
Reactant: Cc1nc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)cc(S(C)=O)n1
Solvent: C1COCCO1
Product: Cc1nc(N)cc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)n1
Temperature: 100 °C
Yield: 31.3 %

Procedure:
A glass microwave reaction vessel was charged with N-(1H-indazol-4-yl)-3-(2-methyl-6-(methylsulfinyl)pyrimidin-4-yl)quinoxalin-2-amine (36 mg, 0.087 mmol) in dioxane (2 mL), ammonia was bubbled in for 5 minutes. The reaction mixture was stirred and heated at 100° C. for 4 h. More NH3 was bubbled in and the mixture was heated for an additional 2 h. The mixture was cooled to room temperature and concentrated in vacuo. Prep TLC purification (5% MeOH in DCM as developed reagent) gave 3-(6-amino-2-methylpyrimidin-4-yl)-N-(1H-indazol-4-yl)quinoxalin-2-amine (10 mg, 0.027 mmol, 31.3% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.22 (s, 2H); 8.52 (d, J=7.07 Hz, 1H); 8.31 (s, 1H); 7.95 (d, J=8.09 Hz, 1H); 7.82 (d, J=9.10 Hz, 1H); 7.72-7.80 (m, 1H); 7.64 (s, 1H); 7.55-7.62 (m, 1H); 7.34-7.46 (m, 2H); 7.26 (d, J=9.10 Hz, 1H); 2.70 (s, 3H). m/z (ESI, +ve ion) 369 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27](Cl)=[O:28]>>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:28]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc5ccccc5s4)nc23)CC1
Yield: 45.5 %

Procedure:
Beginning with 0.41 gm (1.8 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.46 gm (2.33 mMol) 2-benzothiophenecarbonyl chloride, 0.32 gm (46%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH:4]=[CH:3]1.[C:11]([C:15]1[C:20]([O:21][SiH:22]([CH3:24])[CH3:23])=[C:19]([Br:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH2:28]C1C(=O)C=CCC1(C)C)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[C:20]([O:21][SiH:22]([CH3:23])[CH3:24])=[C:19]([Br:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH2:28][C@@H:6]1[C:5](=[O:10])[CH:4]=[CH:3][C@@H:2]([CH3:1])[C:7]1([CH3:9])[CH3:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Reactant: CC1C=CC(=O)CC1(C)C
Product: COc1cc(C[C@@H]2C(=O)C=C[C@@H](C)C2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br

Procedure:
This compound was prepared from 4,5,5-trimethylcyclohex-2-en-1-one (10) (169 mg, 1.22 mmol) in the manner previously described for benzylated enone 11, affording 0.337 g (59%) of the less polar trans diastereomer as a colorless, oily solid, along with 22 mg (4%) of the more polar cis diastereomer as a colorless, oily solid, separable by flash column chromatography. The relative stereochemistry of each respective diastereomer was confirmed by nOe NMR experiments. 1H NMR (400 MHz, CDCl3) δ 0.21 and 0.23 [2s, 2×3H, Si(CH3)2 ], 0.98 [s, 9H, SiC(CH3)3 ], 0.90 and 1.10 (2s, 2×3H, geminal-CH3 's), 1.11 (d, 3H, CHCH3), 2.45 (dd, 1H), 2.53 (ddd, 1H), 2.72 and 2.97 (d of ABq, 2H, benzylic-H's), 3.81 (s, 3H, OCH3), 5.87 (dd, 1H, 2-H), 6.55 (dd, 1H, 3-H), 6.64 (s, 1H, Ar--H), 6.93 ppm (s, 1H, Ar--H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C:4]([C:5]#[N:6])=[C:21]([OH:22])[C:20]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CN(C)C(=O)CC#N
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(C#N)=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a well stirred solution of 5.0 g of N,N-dimethylcyanoacetamide, 8 ml of triethylamine, and 0.05 g of p-dimethylaminopyridine dissolved in 8 ml of dry THF was added 10 g of 2-nitro-4-trifluoromethylbenzoyl chloride dissolved in a min. amount of THF at such a rate that the reaction temperature did not exceed 45° C. The reaction was stirred overnight, at which time TLC analysis indicated that the reaction was complete. The reaction was worked up by removing the solvents under reduced pressure, diluting the residue with 15% NaOH, and extracting well with ether. The aqueous phase was acidified and extracted with 2×100 ml of CH2Cl2. The combined CH2Cl2 extracts were washed once with saturated brine, dried over molecular sieves, filtered, and then passed through a short column of silica gel. The eluate was concentrated under reduced pressure to yield 9.8 g of an orange oil that solidified upon standing. The impure solid was crystallized from ether/hexane to yield 4.24 g of the product, m.p. 104°-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([CH3:18])=[CH:20][CH:21]=1)=[O:9]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(Cl)c1
Reactant: Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccnc2Oc2cccc(Cl)c2)cc1

Procedure:
In the same manner as in Example 1(b), 1.1 grams (0.01 mole) 2(3-chlorophenoxy) nicotinoyl chloride, 1.0 grams (0.01 mole) 4-methylaniline, 1.0 grams (0.01 mole) triethylamine and 125 milliliters toluene were combined to yield 2.4 grams (70.9% of theoretical yield) of the desired product, m.p. 140°-143° C. The structure was confirmed by mass spectrometry.