Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:10][C:11]([C:13]1[CH:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[C:15]([C:21]([O:23]C)=O)=C(C)[NH:17][C:18]=1[CH3:19])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1>C(O)C>[CH3:2][O:10][C:11]([CH2:13][C:21](/[CH:15]=[CH:14]/[C:25]1[C:26]([N+:31]([O-:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:23])=[O:12].[CH3:1][CH:2]([O:10][C:11](=[O:12])/[CH:13]=[C:18](\[NH2:17])/[CH3:19])[C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)c2ccc(Cl)cc2)C1c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: C/C(N)=C/C(=O)OC(C)c1ccc(Cl)cc1
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid α-methyl-4-chlorobenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid α-methyl-4-chlorobenzyl ester of melting point 206° C (from ethanol).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]2[N:32]=[C:31]3[NH:33][N:34]=[C:35]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([S:42][CH3:43])[N:37]=4)[C:30]3=[CH:29][N:28]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl.CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27]2[N:32]=[C:31]3[NH:33][N:34]=[C:35]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([S:42]([CH3:43])=[O:9])[N:37]=4)[C:30]3=[CH:29][N:28]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
m-CPBA (339 mg, 1.98 mmol) was added slowly to a solution of 4-{[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (from Example 14 supra) (450 mg, 0.99 mmol) in a mixture of dichloromethane and methanol (80 mL, 1:1). The reaction mixture was stirred at room temperature for 20 minutes. The solvent was then removed under reduced pressure and the solid was purified by column chromatography (silica gel, 15 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford 4-{[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 150 mg, 32.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([NH2:29])[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:29][CH2:23][C:24]1[O:28][CH:27]=[CH:26][CH:25]=1)=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: NCc1ccco1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2ccco2)c1
Yield: 115 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (100.3 mg, 0.3 mmol), furfuryl amine (58.3 mg, 0.06 ml, 0.6 mmol), 4-dimethylaminopyridine (73.4 mg, 0.6 mmol) and PyBOP (312.3 mg, 1.0-mmol) in DMF 5.0 mL was stirred. Reaction mixture was separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-furan-2-ylmethyl-benzamide as a white solid (144.6 mg, 90% yield).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]#[C:19][CH3:20])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C(N(CC)CC)C.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[Cl:30][C:31]1[N:36]=[CH:35][C:34]([S:37]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C@@:3]([OH:5])([CH3:4])[C:2]([F:1])([F:21])[F:22])=[CH:11][CH:10]=3)[CH:13]([C:18]#[C:19][CH3:20])[CH2:14]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC#CC1CNCCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of (2S)-1,1,1-trifluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (0.190 g, 0.608 mmol) in DCM (5.0 mL) was added triethylamine (0.254 mL, 1.83 mmol, Aldrich, St. Louis, Mo.). The reaction mixture was cooled to 0° C. and 6-chloropyridine-3-sulfonyl chloride (0.155 g, 0.730 mmol, Organic Process Research & Development 2009, 13, 875) was added in one portion. After the addition, the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was concentrated and the crude product was purified by column chromatography (40 g of silica, 10 to 30% acetone in hexanes) to afford (2S)-2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.240 g) as a white foam.
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[CH2:17][CH2:16][C:15](=O)[CH2:14]1.N1CCCC1.Cl>CO.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:15]1([CH2:16][CH2:17][CH:13]([CH3:12])[CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC1CCC(=O)C1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: C1CCNC1
Solvent: CO
Solvent: O
Product: CC1CCC2(CC(=O)c3cc(Br)ccc3O2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (2.193 g, 10.2 mmol), 3-methylcyclopentanone (2 g, 20.4 mmol) and pyrrolidine (1.67 mL, 19.43 mmol) in MeOH (42 mL) was stirred at room temperature overnight, followed by reflux for 2 days. The mixture was concentrated in vacuo to give the residue, which was added water and HCl (36%) until pH=1. The mixture was extracted with EtOAc and then the organic layer was concentrated to give 6-bromo-3′-methylspiro[chroman-2,1′-cyclopentan]-4-one, which was purified by chromatography (PE:EA 300:1-200:1) (2.3 g, 76%). 1H NMR (CDCl3): 7.94 (d, 1H), 7.52-7.49 (m, 1H), 6.83-6.79 (m, 1H), 2.79 (m, 2H), 2.39-2.22 (m, 0.5H), 2.21-1.95 (m, 3H), 1.91-1.75 (m, 1H), 1.67-1.57 (m, 1H), 1.51-1.41 (m, 0.5H), 1.31-1.15 (m, 1H), 1.08-0.98 (m, 3H).
Reaction SMILES: [C:1]([C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([CH:35]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH3:36][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:14](=[O:16])[C:13]2[CH:17]=[C:9]([CH2:8][NH:7][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])[CH:10]=[CH:11][C:12]=2[Cl:18])=[CH:35][C:24]=1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:26]
Reactant: Cc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to example 7 with 5-(tert-butylcarbonylamino)methyl-2-chloro benzoic acid (50 mg; 0.19 mmol); 5-amino-N-(4-bromo-phenyl)-2-methyl-benzamide (57 mg; 0.19 mmol); HATU (78 mg; 0.2 mmol) in TEA (77 μL; 0.56 mmol) and 5 mL THF.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20](C)C.Cl.CNC1CC1>CS(C)=O.O>[CH:23]1([N:19]([CH3:20])[C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24][CH2:25]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Agent: CNC1CC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (750 mg, 3.14 mmol) in DMSO (5 ml) was added DIEA (812.7 mg, 6.29 mmol), N-methylcyclopropanamine hydrochloride (450 mg, 4.18 mmol) with stirring for 3 h at 75° C. in an oil bath. The resulting solution was diluted with water (200 ml), and the product was collected by filtration to give methyl 3-[cyclopropyl(methyl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a solid (780 mg, 91%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]2[CH2:8][C:9]3[C:14]([CH2:15][CH:3]12)=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][CH:10]=3.[I:18]I.N.CO.CCOC(C)=O>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]2[CH2:8][C:9]3[C:14]([CH2:15][CH:3]12)=[C:13]([O:16][CH3:17])[CH:12]=[CH:11][C:10]=3[I:18]
Reactant: II
Reactant: COc1cccc2c1CC1C(C2)OCCN1C
Agent: CC(=O)O[Hg]OC(C)=O
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(I)c2c1CC1C(C2)OCCN1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
A solution of 4-methyl-6-methoxy-3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][1,4]oxazine (0.37 g, 1.6 mmol) was dissolved in 7 ml of AcOH and heated to 50° C. To the solution of the amine was added a solution of Hg(OAc)2 (0.62 g, 19 mmol) and I2 (1.0 g, 3.8 mmol) in 30 ml of AcOH. The resulting solution was stirred for 1 h at 50° C. and 1.5 h at 25° C. The reaction mixture was filtered to remove mercury salts and concentrated in vacuo, yielding an oily residue which was subjected to column chromatography (5% NH3 sat'd MeOH-EtOAc) to yield 0.25 g (44%) of the desired product. 1H NMR (300 MHz, CDCl3): δ 2.04 (m, 1H), 2.32 (dd, 1H, J=11.0, 18.0 Hz), 2.41 (s, 3H), 2.49 (m, 1H), 2.62 (dd, 1H, J=11.0, 17.0 Hz), 2.76 (m, 1H), 3.12 (dd, 1H, J=6.0, 17.0 Hz), 3.33 (dd, 1H, J=5.6, 17.0 Hz), 3.56 (m, 1H), 3,81 (s, 3H), 3.88 (m, 2H), 6.47 (d, 1H, J=7.8 Hz), 7.66 (d, 1H, J=7.8 Hz).
Reaction SMILES: CN(C)C.[CH2:5]([O:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH2:20][CH2:21][OH:22])[C:14]=1[CH3:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C)C=O.CO>[CH2:5]([O:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH2:20][CH2:21][O:22][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=1[CH3:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1c(OCc2ccccc2)c(=O)ccn1CCO
Agent: CN(C)C
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)C(C)(C)C
Reaction time: 16 h
Yield: 60 %

Procedure:
Trimethylamine (4.7 ml) was added with stirring to a solution of 3-benzyloxy-1-(2-hydroxyethyl)-2-methylpyridin-4-one (2 g) in dimethylformamide (40 ml) and the solution was then heated under reflux while pivaloyl chloride (1 ml) was added dropwise. The mixture was refluxed at 78° C. for two hours whilst monitoring by thin layer chromatography (1:1 v/v ethyl acetate:methanol) when very little change of the mixture was obtained. Further trimethylacetylchloride (3 ml) was therefore added and refluxing continued for another 16 hours. The solution was evaporated to dryness, the resultant solid was dissolved in dichloromethane (100 ml) and this solution was washed with sodium bicarbonate solution (0.05M, 4000 ml) and the organic phase was then dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The resultant crude product was flash chromatographed (silica gel, Kieselgel 60,7754, 20 mm×300 mm column; eluting with acetonitrile:ethyl acetate, 1:9 v/v) to provide the title compound in 60% yield as a colourless solid, m.p. 103°- 105.8° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:30])[CH2:28][SH:29]>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][S:29][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 30 %

Procedure:
{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid methyl ester (130 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol), and mercapto-acetic acid methyl ester (212 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]([C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[C:39]=1[NH2:40])([CH3:37])[CH3:36].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:38]([CH:35]([CH3:37])[CH3:36])[C:39]=1[NH:40][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33])([CH3:47])[CH3:46]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4c(C(C)C)cccc4C(C)C)cc3)c2cc1OC
Yield: 76 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was suspended in toluene (5 ml), after the addition of triethylamine (1 ml), triphosgene (53 mg) was added, and the admixture was refluxed with heat for 8 minutes. 2,6-Diisopropylaniline (0.05 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 15 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 69 mg of the title compound (yield: 76%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:50])[C:7]([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[C@H:28]([CH2:44][N:45]3[CH:49]=[CH:48][N:47]=[CH:46]3)[CH2:27]1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:3].[Br:51][CH2:52][C:53](=[O:55])[CH3:54]>O1CCCC1>[Br-:51].[CH2:52]([N:47]1[CH:48]=[CH:49][N+:45]([CH2:44][C@@H:28]2[CH2:27][C@H:26]([S:25][C:7]3[C@H:6]([CH3:50])[C@H:5]4[N:9]([C:10](=[O:11])[C@@H:4]4[C@H:2]([OH:1])[CH3:3])[C:8]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[CH2:30][N:29]2[C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:32])=[CH:46]1)[C:53]([CH3:54])=[O:55]
Reactant: CC(=O)CBr
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](Cn4ccnc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: CC(=O)Cn1cc[n+](C[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Product: [Br-]

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.80 g) and bromoacetone (0.3 ml) in tetrahydrofuran (8 ml) was stirred at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure to give crude 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(3-acetonyl-1-imidazolio)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate bromide (1.20 g).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C)C=O>[CH3:13][O:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: Cc1ccc2c(c1O)CCC2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1c(C)ccc2c1CCC2=O
Temperature: 62.5 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a suspension of 4-Hydroxy-5-methyl-indan-1-one (50.0 gm, 0.308 mole) and Potassium carbonate (127.0 gm, 0.928 mole) in Dimethylformamide (250 ml), Dimethyl sulphate (90 ml, 0.928 mole) was added at 0° C. The reaction mixture was heated at 60-65° C. and stirred for 16 hours. The reaction mixture was poured into water (1 liter) and extracted with Ethylacetate (3×250 ml). The organic layer was dried over Sodium sulphate and distilled under vacuum to give 10.0 gm of crude product which was purified by column chromatography using Hexane as a mobile phase. The collected fractions were distilled under vacuum to give 45.0 gm of desired product as a viscous oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:44][CH2:45][CH3:46])[N:18]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[C:19](=[O:28])[C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:44][CH2:45][CH3:46])[N:18]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[NH:3][C:4](=[O:7])[O:5][N:43]=3)=[CH:32][CH:31]=2)[C:19](=[O:28])[C:20]=1[CH2:21][N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)[CH3:14]
Reactant: CCCc1nc(CC)c(CN2CCOCC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(CN2CCOCC2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.77 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(morpholin-4-ylmethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.21 g) was added, and the mixture was stirred at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 61%).
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]>>[CH2:9]([O:8][P:4]([O:5][CH2:6][CH3:7])([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])=[O:3])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: C=CCCCCCCCCCI
Product: C=CCCCCCCCCCP(=O)(OCC)OCC

Procedure:
Triethylphosphite (12.2 mL, 71 mmol, 10 equiv) was added to 3 (2.0 g, 7.1 mmol, 1.0 equiv) and the mixture was stirred at reflux for 15 h. The excess triethylphosphite was removed by distillation and the remaining residue submitted to flash chromatography (SiO2, 5×15 cm, 25-50% ethyl acetate-hexanes gradient elution) to afford 4 (1.30 g, 2.1 g theoretical, 62%) as a colorless oil: 1H NMR (CDCl3, 250 MHz) δ 5.95-5.75 (m, 1H, RCH═CH2), 5.03-4.90 (m, 2H, RCH═CH2), 4.05 (m, 4H, CH3CH2OP), 2.02 (m, 2H, CH2CH═CH2), 1.80-1.20 (m, 20H); MALDI-FTMS (DHB) m/z 291.2088 (C15H31O3P+H+ requires 291.2089).
Reaction SMILES: C[O-].[Na+].CS(C)=O.[C:8]([O:16]C)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>CO.O1CCOCC1>[C:21]1([C:18](=[O:20])[CH2:19][C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.88 h

Procedure:
An apparatus as described in Example 1 is charged with 18.0 g of sodium methylate (97%), 100 g of DMSO, 100 g of dioxane and 6 g of methanol and the mixture is cooled to 0° C. Then a mixture of 45 g of methyl benzoate and 36 g of acetophenone are added dropwise over 35 minutes. The reaction mixture is then stirred for ca. 45-60 minutes at 30° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:29]#[N:30])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:31])([CH3:32])[C:4]([OH:33])=[O:3])=[O:9])[N:11]=[C:12]3[C:29]#[N:30])=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{[7-(4-Chloro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (20 mg, 0.04 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 11 mg. MS: (−) m/z 437.95 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20](OCCCC)=[O:21])[O:17][C:16]2=[O:27])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:28][NH2:29]>CO>[CH3:28][NH:29][C:20]([C@@H:18]1[O:17][C:16](=[O:27])[N:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[C:6]([F:14])[CH:5]=2)[CH2:19]1)=[O:21]
Reactant: CN
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The butyl (5R)-3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 17, Step 1) is treated with 2M methylamine in MeOH (0.1 M in starting material), and the reaction mixture is stirred at ambient temperature for 30 mins and then concentrated under reduced pressure. The residue is purified by radial chromatography [4000 micron silica gel rotor; MeOH/CH2Cl2 (3/97) eluent] to give the title compound, mp 179–181° C.; MS (ESI+) for C15H17N3O4F2 m/z 342 (M+H)+; [α]25D−40 (c 0.95, DMSO).