Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([Cl:32])([Cl:33])[Cl:34])=[O:28])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Reactant: O=C(CCCCCCCCCO)OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Yield: 69.8 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (1.00 g; 4.3 mmol), the product from 12a (1.37 g; 4.3 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 1.03 g; 5.0 mmol), and pyridine (2.0 mL) in dichloromethane (40 mL) using Procedure E. The crude product was purified on a 100×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2), collecting 16×50 mL fractions. From evaporation of fractions 4-9 gave 1.6 g (71%) product was obtained (yellowish oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=S.Cl.[NH:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH2:25].ClCCl>C(O)C>[CH2:30]([O:29][C:27]([CH2:26][NH:24][N:25]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:28])[CH3:31]
Reactant: CCOC(=O)CNN
Reactant: CC(C)(C)CNc1ccc(Cl)cc1C(=S)c1ccccc1Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CNN=C(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
To a solution of 5-chloro-2-neopentylaminophenyl 2-chlorophenyl thioketone (0.54 g) in ethanol (7 ml) was added ethyl hydrazinoacetate hydrochloride (0.11 g). The mixture was stirred for one day at 70° C. To the reaction mixture was added dichloromethane (50 ml), which was washed with water and, then, dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=15:1 v/v as an eluent) to give 0.16 g of an oily product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
1-Benzyl-3-pyrrolidinol (1.1 g) in toluene (10 mL) at 0° C. was treated with triethylamine (1 mL) and methanesulfonyl chloride (0.53 mL), warmed to room temperature, washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous sodium sulfate, and concentrated. 1H NMR (300 MHz, DMSO-d6) δ 7.31 (s, 5H), 5.21 (m, 1H), 3.65 (q, 2H), 2.82 (m, 2H), 2.5 (m, 2H), 2.36 (m, 2H), 2.1 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31].[O:32]1[CH2:35][C:34](=O)[CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH:34]5[CH2:35][O:32][CH2:33]5)[CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31]
Reactant: O=C1COC1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCNCC1)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCN(C2COC2)CC1)C3
Yield: 68.8 %

Procedure:
A mixture of Example 64 (110 mg; 0.25 mmol; 1 eq.), 3-oxetanone (22 μL; 0.37 mmol; 1.5 eq.) and sodium triacetoxyborohydride (53 mg; 0.25 mmol; 1 eq.) in DCE (6 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over sodium sulfate and concentrated in vacuo. Crystallization from EA afforded the title compound (86 mg, 69%) as an off-white solid. 1H NMR (CDCl3) δ 7.34 (td, J=8.1, 6.6 Hz, 1H), 6.80-6.63 (m, 2H), 5.07-4.92 (m, 2H), 4.66 (br s, 2H), 4.61-4.47 (m, 4H), 4.47-4.33 (m, 1H), 3.43-3.28 (m, 1H), 2.92 (s, 1.8H), 2.86 (s, 1.2H), 2.70 (s, 1.2H), 2.63 (s, 1.8H), 2.44-2.28 (m, 2H), 2.23-2.10 (m, 2H), 2.03-1.90 (m, 2H), 1.90-1.73 (m, 2H). HPLC (max plot) 97.1%, Rt 2.90 min. UPLC/MS: (MS+) 500.5 ([M+H]+).
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:42]([O:49][C:50]1[C:51]([CH:56]=O)=[N:52][CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[CH2:42]([O:49][C:50]1[C:51]([CH:56]=[CH:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:10][CH:9]=2)=[N:52][CH:53]=[CH:54][CH:55]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ncccc1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC=Cc2ncccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-(4-Carboxyphenyl)ethyl)triphenylphosphonium bromide (0.58 g, 1.17 mmol) was suspended in THF (7 ml) and lithium bis(trimethylsilyl)amide was added (1M in THF, 2.46 ml). The reaction mixture turned orange and was allowed to stir for 1 hour at ambient temperature. A solution of 3-benzyloxy-2-pyridinecarbaldehyde (0.25 g, 1.17 mmol) in THF (3.5 ml) was added slowly. The reaction was stirred at ambient temperature for 1 hour. The reaction was quenched by the addition of water (8 ml) and ether (8 ml). The layers were separated, the ether layer was washed with water and the as aqueous layers were combined, acidified with 1N HCl and extracted with EtOAc (2×). The organic extracts were dried (MgSO4) and evaporated to give the title product as a mixture of isomers (2.7 g 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1C
Temperature: 25 °C
Yield: 78 %

Procedure:
5-Fluoro-2-methyl-benzoic acid (0.29 g, 1.9 mmol) was dissolved in anhydrous MeOH (7 mL) and c. H2SO4 (0.12 mL, 2.3 mmol) was added, heating to reflux for 16 hours. The solution was cooled to room temperature and partitioned between EtOAc (15 mL) and brine (10 mL). After separating, the aqueous phase was extracted with EtOAc (2×10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford 5-fluoro-2-methyl-benzoic acid methyl ester as a pale brown liquid (0.25 g, 78%).
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:15][CH:16]([CH3:20])[C:17](Cl)=[O:18].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:17](=[O:18])[CH:16]([Cl:15])[CH3:20])=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCc2ccccc21
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCCCc2cc(C(=O)C(C)Cl)ccc21

Procedure:
Analogously to Example 1, 5-(2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)-6-methyl-3,6-dihydro-1,3,4-thiadiazin-2-one ("E"), m.p. 142°, is obtained from 7-(2-chloropropionyl)-2,3,4,5-tetrahydro-1H-1-benzazepin [obtainable by reaction of 1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-chloropropionyl chloride/AlCl3 to give 1-acetyl-2,3,4,5-tetrahydro-7-(2-chloropropionyl)-1H-1-benzazepine (in addition, the 8-(2-chloropropionyl) isomer is obtained, which can be separated chromatographically) and subsequent removal of the acetyl group with HCl].
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:22]([O:33][CH3:34])(=[O:32])[C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([C:22]([O:33][CH3:34])=[O:32])[CH:31]=[CH:30][C:28]=1[O:29][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(B(O)O)cc2CC1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
(3-{[(1,1-Dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)boronic acid (E264, Step 2) (500 mg, 1.72 mmol) was dissolved in dry dichloromethane (15 ml) and treated sequentially with methyl vanillate (313 mg, 1.72 mmol), molecular sieves (4A, 1.0 g), copper acetate (467 mg, 2.58 mmol) and triethylamine (1.20 ml, 8.60 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane, filtered through celite and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic portion was dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of (0.1:9.9) to afford the title compound (240 mg). MS (ES+) m/e 328 [(M+H)—CO2tBu]+.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[NH:11][C:10](=[O:13])[CH2:9][N+:8]([O-])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C.[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>>[C:29]([O:32][CH:9]1[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:12]=2[NH:11][C:10]1=[O:13])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C[N+]([O-])=C(c2ccccc2F)c2cccc(Cl)c2N1
Solvent: CC(C)OC(C)C
Product: CC(=O)OC1N=C(c2ccccc2F)c2cccc(Cl)c2NC1=O
Yield: 50 %

Procedure:
A suspension of 9-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-4-oxide (1.475 g) in acetic anhydride (12 ml) was refluxed for 0.5 hour. The resultant clear solution was cooled in an ice-bath to afford precipitate. To the cooled suspension was added diisopropyl ether (20 ml) and the mixture was cooled further. The resultant precipitate was collected by filtration and washed with diisopropyl ether to give (3RS)-3-acetoxy-5-(2-fluorophenyl)-9-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one (0.84 g, 50.0% yield) as a colorless crystalline powder.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:12]1[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]2[CH:26]3[CH2:27][CH2:28][CH:23]2[CH2:24][CH2:25]3)=[O:18])=[CH:15][N:16]=1)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]3[CH:26]4[CH2:25][CH2:24][CH:23]3[CH2:28][CH2:27]4)=[O:18])=[CH:15][N:16]=2)[CH2:3]1
Reactant: CCS(=O)c1ncc(C(=O)NCCC2C3CCC2CC3)s1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC1C2CCC1CC2)c1cnc(OCC2CO2)s1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
This example illustrates the process of the invention for preparing 1,2-epoxy-3-(5-substituted aminocarbonylthiazole-2-yloxy)propane. In this example 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for 10 minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfinyl-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained for 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazol-2-yloxy)propane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C#N)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
The ester from Step 2 (0.51 g 1.5 mmol) was dissolved in THF (5 mL) and ethanol (5 mL), treated with 2.5N sodium hydroxide (1.2 mL, 3.0 mmol), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl extracted with ethyl acetate, washed with water, brine, dried over MgSO4, concentrated in vacuo, and recrystallized from diethyl ether/hexane to give a white powder (0.10 g, 21%): mp 238.1–239.7° C. 1H NMR (acetone-d6/300 MHz) 7.97 (s, 1H), 7.92 (d, 1H, J=2.4 Hz), 7.89 (d, 1H, J=2.4 Hz), 6.14 (q, 1H, J=6.6 Hz). FABLRMS m/z 302 (M−H). ESHRMS m/z 301.9819 (M−H, Calc'd 301.9832). Anal. Calc'd for C12H5ClF3NO3: C, 47.47; H, 1.66; N, 4.61. Found: C, 47.41; H, 1.70; N, 4.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].ClC1C=CC=C(C(OO)=[O:39])C=1.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)=[O:39])=[N:12][CH:13]=1)=[O:6]
Reactant: COC(=O)CCc1ccc(Sc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCc1ccc(S(=O)c2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-{4-[5-(3,4-dichlorobenzoylamino)pyridin-2-ylsulfanyl]phenyl}propionate (1.00 g, 2.17 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (0.620 g, 2.60 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0° C. To the reaction solution was added methanol and stirred for some time. To the resulting solution was then added water, and extracted with dichloromethane. The dichloromethane layer was washed with water, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The obtained residue was recrystallized from ethanol 3 times, to thereby yield 0.790 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[CH3:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][C:24]([NH2:26])=[O:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:4][CH:3]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.917 min, m/z=444.4; 1H NMR (CDCl3) 1.51 (d, 3H), 1.92 (m, 1H), 2.13-2.32 (m, 5H), 2.44 (m, 1H), 2.82 (s, 3H), 2.93 (m, 1H), 5.50-5.68 (m, 3H), 7.06 (d, 2H), 7.19-7.35 (m, 5H), 7.39 (d, 2H), 7.58 (s, 1H), 7.65 (d, 1H), 8.74 (d, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:5])C>CO.[OH-].[K+]>[CH3:17][O:16][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[CH:15][C:6]([C:4]([OH:5])=[O:3])=[C:7]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1ccc2ccc(OC)cc2c1-c1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(-c2c(C(=O)O)ccc3ccc(OC)cc23)c1
Yield: 103.8 %

Procedure:
A solution of crude 7-methoxy-1-(3-methoxyphenyl)-2-naphthalenecarboxylic acid ethyl ester (4.1 g) in a mixture of methanol (20 mL) and 4N potassium hydroxide (5 mL) was heated at reflux for 3 hours. After the methanol was evaporated off, the reaction was diluted with water and extracted with ether (2×25 mL). The aqueous layer was acidified, extracted with dichloromethane (3×25 mL) and the dried (MgSO4) extracts evaporated to give 3.9 g of crude 7-methoxy-1-(3-methoxyphenyl)-2-naphthalenecarboxylic acid. Crystallization from toluene-hexane provided 3.05 g of acid, mp 164°-168° C. Anal. Calcd for C19H16O4 : C, 74.01; H, 5.23 Found: C, 73.58; H, 5.49
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17](F)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:27])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]2[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([CH3:28])[CH2:34]2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:27])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]2[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Solvent: c1ccncc1
Product: CC1CN(c2cc3c(c(NCc4ccccc4)c2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Yield: 79.5 %

Procedure:
A mixture of 3.0 g of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 2.5 g of 2-methylpiperazine and 30 ml of pyridine was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the solution was acidified with acetic acid and treated with activated charcoal. It was then neutralized with aqueous ammonia. The crystals which precipitated were collected by filtration to give 2.9 g of 5-benzylamino-1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 129°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH:12]2[C:17](=O)[CH2:16][CH2:15][O:14][CH2:13]2)[NH:8][N:7]=1)=[O:5])[CH3:2].CS(O)(=O)=O>C(O)(=O)C.C1(C)C=CC=CC=1>[N:7]1[N:8]2[C:9]([O:11][C:12]3[CH2:13][O:14][CH2:15][CH2:16][C:17]=32)=[CH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc(OC2COCCC2=O)[nH]n1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2oc3c(n2n1)CCOC3
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A mixture of ethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)oxy]-1H-pyrazole-3-carboxylate (254 mg, 1 mmol) and methane sulfonic acid (192 mg) in 7 ml of acetic acid and toluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap to remove water. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate aqueous bicarbonate solution. The organic layer was washed with water and dried over MgSO4. After removal of the ethyl acetate, the residue was purified by silica gel chromatography eluting with ethyl acetate/hexane to give 120 mg (51%) of the desired product as white solid. Mp; 116–118° C.; Electrospray-MS m/z 237.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:15]([O:18][C:19](Cl)=[O:20])[CH:16]=[CH2:17]>O>[CH2:15]([O:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)=[O:20])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)Cl
Reactant: Nc1ccc(OCC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)Nc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.9 g of 4-aminophenoxyacetic acid is suspended in 15 ml of water, and 2.4 ml of 5N NaOH solution are added. After cooling with ice, 0.63 ml of chloroformic acid allyl ester is added over a period of 5 minutes. After removing the cooling bath, the reaction mixture is stirred for 20 minutes at room temperature. The reaction mixture is then washed twice with ethyl acetate, and the aqueous phase is adjusted to pH 2 with 4N HCl and extracted with ethyl acetate. The organic solution is washed with brine and dried over sodium sulphate. The title compound is obtained after evaporating off the solvent.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9][C:7]=2[N:8]=1.C[OH:15]>ClCCl>[CH3:1][S:2]([C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9][C:7]=2[N:8]=1)=[O:15]
Reactant: CO
Reactant: CSc1ncc2ccc(N)nc2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(N)nc2n1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A suspension of 10.63 g (55.3 mmol) of 2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine (Example 7) in 300 mL of dichloromethane and 300 mL of methanol is treated with 18.06 g (69.1 mmol) of (±)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine and stirred overnight. The suspension is filtered to remove a small amount of solid, concentrated to approximately 25 mL, and diluted with ethyl acetate. The solid is collected by filtration to give 9.27 g (80.5%) of the product, mp 180° C. (dec).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:28])[CH2:12][CH:13]([OH:27])[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:1]([O:27][CH:13]([CH2:12][N:11]([CH3:10])[CH3:28])[CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CN(C)CC(OC(=O)c1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 99 %

Procedure:
Benzoyl chloride (1 49g) was added to 3-dimethylamino-1,1-diphenyl-propan-2-ol (2,55g) in dry pyridine (10 ml.) and the solution allowed to stand for 4 hours. Pyridine was removed by evaporation and the residue dissolved in dilute hydrochloric acid and ether. Basification of the acid extract and isolation through ether in the usual manner gave 2-benzoyloxy-3-dimethylamino-1,1-diphenyl-propane (3.47g . 99%), m.p. 90°- 91°.