Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][C@@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[C:7]=1[F:21])[CH3:2].Cl.[NH2:33][OH:34].C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][C@@H:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[C:7]=1[F:21])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[NH:30])[NH:33][OH:34])=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a mixture of 8.85 g (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid ethyl ester described in example 3.6 in 515 ml EtOH were added 20.21 g hydroxylamine hydrochloride and 81.1 ml triethylamine. The solution was stirred over night at 50° C., then evaporated. The crude product was isolated by extraction with EtOAc, then purified by chromatography on silica gel (CH2Cl2/MeOH) to yield 7.64 g (RS)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid ethyl ester as a light brown amorphous solid.
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:20])[NH:5]1)[CH:2]=C.CC([OH:31])(C)C>C1COCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@@:4]([CH2:1][CH2:2][OH:31])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:5][C:6]2=[O:20])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reactant: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CCC[C@@](CCO)(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 1517.5 %

Procedure:
To a stirred solution of (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-phenyl-1,3-diazepan-2-one (51 mg, 0.12 mmol) in THF (2 mL) and water (2 mL) were added NaIO4 (132 mg, 0.62 mmol) and 2.5% OSO4 in t-BuOH (0.032 mL, 0.003 mmol). The mixture was stirred at rt for 5 h and concentrated under reduced pressure. The residue was partitioned between EtOAc (90 mL) and brine (20 mL). The organic layer was concentrated and the residue was dissolved in MeOH (20 mL). The solution was cooled in an ice bath and NaBH4 (50 mg) was added. The mixture was stirred overnight and concentrated. The residue was taken up in EtOAc (90 mL), washed with 5% aq HCl (20 mL) and satd aq NaHCO3 (20 mL), and dried over Na2SO4. Removal of the solvent left an oil (43 mg) which was purified by prep HPLC to afford (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxyethyl)-4-phenyl-1,3-diazepan-2-one (19 mg, 37%) as an oil. LC-MS Method 2 tR=8.7 min, m/z=419, 417; 1H NMR (CDCl3) δ 1.0-1.2 (2H), 1.23 (d, 3H), 1.77 (m, 1H), 2.01 (m, 1H), 2.24 (m, 2H), 2.66 (m, 1H), 2.89 (m, 1H), 3.45 (m, 1H), 3.72 (m, 1H), 4.10 (br s, 1H), 5.50 (q, 1H), 6.79 (s, 1H), 7.24 (3H), 7.37 (2H), 7.43 (4H)
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>ClCCl>[OH:21][N:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:19]
Reactant: O=Nc1ccccc1
Reactant: O=CC1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(C1CCCCC1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of cyclohexanal (112 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([N:14]=[C:15]=[S:16])(=[O:13])[CH3:12].O>CC(C)=O>[C:11]([NH:14][C:15]([NH:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])=[S:16])(=[O:13])[CH3:12]
Reactant: CC(=O)N=C=S
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC(=S)Nc1c(F)cc(Br)cc1F
Temperature: 72 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
4-bromo-2,6-difluorobenzenamine (2.514 g, 12.1 mmol) was dissolved in acetone (75 ml) and ethanoyl isothiocyanate (1.30 ml, 14.8 mmol) was added. The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (70-74° C.) and the reaction was stirred under nitrogen for 90 minutes. The reaction was then cooled to room temperature and poured into water (200 ml), and the resultant suspension was filtered. The solid was washed with water, collected, and dried under high vacuum in water bath (60° C.) to afford 1-acetyl-3-(4-bromo-2,6-difluorophenyl)thiourea (3.435 g, 93% purity, 85% yield). MS (ESI pos. ion) m/z: 309 (MH+, 79Br), 311 (MH+, 81Br). Calculated exact mass for C9H7BrF2N2OS 308 (79Br), 310 (81Br).
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[C:37]([C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=3[CH3:49])[C:43]([OH:45])=[O:44])[CH:38]=2)[O:33][C:32]=1[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1.C[CH2:58][O:59][C:60](C)=[O:61]>CO.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:56][C:53]1[CH:54]=[CH:55][C:50]([C:32]2[O:33][C:34]3=[N:35][CH:36]=[C:37]([C:40]4[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=4[CH3:49])[C:43]([OH:45])=[O:44])[CH:38]=[C:39]3[C:31]=2[C:60]([O:59][CH3:58])=[O:61])=[CH:51][CH:52]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C(=O)O)cc1-c1cnc2oc(-c3ccc(F)cc3)c(Br)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)O)ccc3C)cc12
Reaction time: 8 h
Yield: 67 %

Procedure:
1,3-bis(diphenylphosphino)propane (160 mg, 0.387 mmol) was added to a stirring solution of palladium(II) acetate (44 mg, 0.19 mmol) and 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (275 mg, 0.645 mmol) in MeOH (2.1 mL) and DMSO (4.3 mL) at 80° C. in a Parr bomb which was charged with 150 psi CO (g) and allowed to stir overnight. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the expected product 3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoic acid (176 mg, 0.434 mmol, 67% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (1H, br. s.), 8.42 (1H, d, J=2.01 Hz), 8.34 (1H, d, J=2.01 Hz), 8.14-8.21 (2H, m), 7.93 (1H, dd, J=8.03, 1.76 Hz), 7.84 (1H, d, J=1.76 Hz), 7.45-7.53 (3H, m), 3.89 (3H, s), 2.32 (3H, s). LC-MS retention time: 2.16 min; m/z (MH+): 406. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([C:10](=[O:12])[CH3:11])[N:4]2[C:3]=1[CH3:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+]>C1COCC1>[CH3:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([C:10](/[CH:11]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[N:4]2[C:3]=1[CH3:13]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cnc2sc(C)c(C)n12
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1sc2ncc(C(=O)/C=C/c3ccccc3)n2c1C
Temperature: 0 °C

Procedure:
A solution of 1-(2,3-dimethylimidazo[2,1-b]thiazole-5-yl ethanone (See procedures from Preparation 6) (Formula D-1) (0.87 g) in THF (25 mL) was treated with benzaldehyde (0.52 mL) and sodium methoxide (0.11 g). After 18 hours trace 1-(2,3-dimethylimidazo[2,1-b]thiazol-5-yl ethanone remained and additional benzaldehyde (0.2 mL) was added. After an additional 2.5 hours the reaction was diluted with ice water and precipitated 2,3-Dimethyl-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazol-5-yl methanone (FIG. D-2) (1.03 g) was filtered. Crystallization from isopropanol solution gave pure 2,3-Dimethyl-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazol-5-yl methanone (FIG. D-2), m.p. 189-190°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[Cl-:11].[Al+3].[Cl-:13].[Cl-].ClCl>C(Cl)Cl>[Cl:11][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([Cl:13])[C:2]=1[CH3:1])[C:8]([OH:10])=[O:9]
Reactant: [Cl-]
Reactant: Cc1ccc(C(=O)O)cc1
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of p-toluic acid (95.0 g, 0.698 mole) in methylene chloride (1 liter), was added aluminum chloride (260.0 g, 1.948 mole) portionwise keeping the reaction temperature below 10° C. (ice-water bath). When the addition was completed (approx. 30 minutes) chlorine gas was bubbled in at such a rate as to keep the temperature below 10° C. The reaction was followed by gas-liquid chromatography. After about 4 hours, most of the starting material had been converted to the expected compound. The resulting mixture was poured into ice and concentrated hydrochloric acid and then extracted with ethyl acetate several times. The combined organic layers were then washed with water and dried over anhydrous sodium sulfate. Removing the solvent in a rotavap yielded the crude product as a white solid. Recrystallization from acetone/water or ethyl acetate/hexane yielded 3,5-dichloro-4-methylbenzoic acid with minor impurities 115.4 g (81% yield of product).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:19]3[CH3:18])[C:9]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Reactant: CN1CCCCC1=O
Solvent: CCCCCC
Product: CN1CCCCC1=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21

Procedure:
By the procedure of Example B1, but using 1:1 hexane:ethyl acetate as chromatography eluant and pentane for crystallization, 1-(3-chlorophenyl-2-(1H,3H)-indolone (2.0 g, 8.2 mmoles) and N-methyl-2-piperidone (1.3 ml, 11.5 mmoles) were converted to title product, 180 mg (6.5%) m.p. 162°-165°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:10])=[O:9])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(CBr)cc1
Yield: 71.7 %

Procedure:
To a solution of 1-p-tolylethanone (600 mg, 4.47 mmol) in carbon tetrachloride (15 mL) was added N-bromosuccinimide (955 mg, 5.37 mmol) and BPO (31 mg, 0.13 mmol). The mixture was refluxed for 3 h; then it was cooled, and filtered. The filtrate was concentrated to give 1-(4-(bromomethyl)phenyl)ethanone (683 mg, 71%) as a brown oil. LCMS MH+ 213.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]2[O:7][C:8]([CH3:31])([CH3:30])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:28])[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:13][C:12]3=[O:29])[C:5]=2[CH:4]=1)#[N:2].[O:34]([C:41](Cl)=[S:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])O.[Na+]>C(#N)C.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:33]=[CH:32][C:6]2[O:7][C:8]([CH3:31])([CH3:30])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([O:28][C:41]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[S:42])[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:27])[CH3:25])([CH3:23])[CH3:22])=[CH:13][C:12]3=[O:29])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(C(O)CCO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)C=C(n2ccc(C(CCO[Si](C)(C)C(C)(C)C)OC(=S)Oc3ccccc3)cc2=O)c2cc(C#N)ccc2O1

Procedure:
In 30 ml of anhydrous acetonitrile, is dissolved 1.46 g of 6-cyano-2,2-dimethyl-4-{2-oxo-4-(1-hydroxy-3-t-butyldimethylsilyloxypropyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 38. Then, 0.73 g of 4-dimethylaminopyridine and 0.79 ml of phenoxythiocarbonyl chloride are added at room temperature, and reacted at that temperature for 6 hours. After stopping the reaction by adding 0.1M aqueous solution of sodium hydrogen carbonate, the reaction mixture is extracted with ether. The organic layer is washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/2 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 1.20 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-phenoxythiocarbonyloxy-3-t-butyldimethylsilyloxypropyl)-1-pyridinyl}-2H-benzo[ b]pyran is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[CH2:11][CH:12]=[CH2:13])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[CH2:11][CH:12]2[CH2:13][O:23]2)=[CH:5][CH:4]=1
Reactant: C=CCC(=O)Nc1ccc(OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)CC2CO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of N-(4-methoxyphenyl)but-3-enamide (9) from the previous reaction was treated with m-chloroperbenzoic acid (2 eq.) and stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and washed with 1N sodium hydroxide. The organic phase was separated, dried over magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give crude N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide, a compound of formula (10).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(Cl)cc3)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 4-chlorobenzoyl chloride (11 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.Cl[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1)=[O:30]
Reactant: NC1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Reactant: COC(=O)Cl
Product: COC(=O)NC1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 43.6 %

Procedure:
Using essentially the technique of Example 94, starting with 3-(4-(4-aminopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (249 mg, 0.66 mmol) and methyl chloroformate (70 mg, 0.74 mmol) in place of methanesulfonyl choride, gave the desired product (125 mg) after chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH2:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)[C@H]1CC[C@H](CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)[C@H]1CC[C@H](CNc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, (6-bromo-4-{[trans-4-(dimethylamino)cyclohexyl]methylamino}quinolin-3-yl)(cyclopropyl)methanone (66 mg, 0.153 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.230 mmol) to afford the desired product (38 mg, 50%) as a yellow solid: 1H NMR (300 MHz, CD3OD+Acetic Acid-d4) δ 9.24 (s, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.10 (dd, J=8.8, 1.8 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.68 (s, 2H), 3.90 (d, J=6.5 Hz, 2H), 2.85 (d, J=11.2 Hz, 6H), 2.15 (t, J=11.3 Hz, 4H), 2.01-1.74 (m, 2H), 1.61 (dd, J=21.6, 12.1 Hz, 2H), 1.46-1.07 (m, 7H); ESI MS m/z 512 [C28H31Cl2N3O2+H]+; HPLC 99.0% (AUC), tR=10.65 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.CN1C(N)=CC(C2C=CC=CC=2)=N1.[F:38][C:39]([F:49])([F:48])C1C=C(C#C)C=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:39]([F:49])([F:48])[F:38])[CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: Cn1nc(-c2ccccc2)cc1N
Product: Cn1nc(-c2ccccc2)c2c(Cl)c(-c3cccc(C(F)(F)F)c3)nnc21

Procedure:
Compound 29 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 1-methyl-3-phenyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine and 3-(trifluoromethyl)-phenylacetylene instead of phenyl acetylene in Step 4.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C(O)(=O)C>C1COCC1>[C:1]1([N:7]2[C:11]([B:17]([OH:22])[OH:18])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OB(O)c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 1-phenyl-1H-pyrazole (20.0 g) in THF (700 mL) was added dropwise n-butyllithium (2.5 M hexane solution, 58.3 mL) at −78° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added triisopropyl borate (52.2 g) at −78° C., and the mixture was stirred at the same temperature for 1 hr, gradually warmed to room temperature, and stirred at room temperature for 20 hr. The reaction mixture was adjusted to pH 5 with acetic acid (20 mL) and concentrated to give the title compound (25.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][C:15](=O)[CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:15]1([CH2:16][CH:17]([CH3:19])[CH2:18][CH:13]([CH3:12])[CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC1CC(=O)CC(C)C1
Solvent: CO
Solvent: C1CCNC1
Product: CC1CC(C)CC2(CC(=O)c3cc(Br)ccc3O2)C1
Reaction time: 8 h
Yield: 110.5 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (6 g, 28 mmol), 3,5-dimethylcyclohexanone (7.12 g, 56 mmol) and pyrrolidine (3.8 g, 53.3 mmol) in methanol (120 mL) was stirred overnight. The reaction mixture was concentrated in vacuo, and H2O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6-bromo-3′,5′-dimethylspiro[chroman-2,1′-cyclohexan]-4-one (10 g, 100%). 1HNMR (CDCl3): 0.51 (m, 1H), 0.71 (m, 4H), 0.72 (m, 3H), 0.91 (m, 3H), 1.11 (d, 1H), 1.19 (t, 1H), 1.50 (s, 1H), 1.64 (t, 1H), 1.79 (m, 3H), 1.90 (m, 2H), 2.0 (m, 3H), 2.24 (t, 1H), 2.53 (s, 1H), 2.79 (s, 1H), 6.75 (t, 1H), 7.49 (t, 1H), 7.89 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])O.[Na+:38].O.[H][H]>C1COCC1.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)[CH3:2].[Na+:38]
Reactant: CCOc1ccc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reaction time: 3 h
Yield: 42 %

Procedure:
4-Nitrobenzyl (5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.39 g) prepared in accordance to the method described in Tetrahedron Letters, 34, 3211-3214 (1993)] was dissolved in THF (28 mL), and thereto were added under ice cooling sodium hydrogencarbonate in ion-exchange water (28 mL), and 10% palladium-carbon [50% water] (0.14 g). Then the atmosphere was changed with a hydrogen gas, and the mixture was stirred at the same temperature for 3 hours. After filtration of the insoluble materials with Celite, to the filtrate was added chloroform (80 mL). The organic layer was separated, and extracted with ion-exchange water (20 mL). The organic solvent in the aqueous solution separated and extracted was removed over one hour period in vacuo, purified with C18 reverse column chromatography (Wakosil C18 reverse column, mobile phase; ion-exchange water/THF) and lyophilized to give sodium (5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.44 g, yield 42%).