Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12>C1COCC1>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:47]3[C:43](=[O:53])[C:44]4[C:45](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:46]3=[O:48])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
20.3 g (65.6 mmol) 3-(1-diphenylmethylpiperidin-4-yl)-propan-1-ol, 17.2 g (65.6 mmol) triphenylphosphine and 9.7 g (65.6 mmol) phthalimide are suspended in 220 ml THF and a solution of 10.4 ml (65.6 mmol) azodicarbonic acid diethyl ester in 50 ml THF is added dropwise within one hour under protective atmosphere and light cooling (ca. 15-25° C.). After a further three hours, the solvent is removed under vacuum and the residue is crystallized from 60 ml 1-chlorobutane. Yield: 12.9 g (45%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([NH2:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].[CH3:28]C[O-].[Na+].CI>C(O)C>[CH2:24]([O:23][C:21]([C:10]1([CH3:28])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([NH2:27])[N:8]=[C:9]1[NH2:26])=[O:22])[CH3:25]
Reactant: CC[O-]
Reactant: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)C1=C(N)N=C(N)C(C)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 37.5 g of 2,6-diamino-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol was treated with 15 g of methyl iodide at the boil. After a further 60 minutes under reflux, the mixture was concentrated by distillation. The residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water, and the organic phase is concentrated. Recrystallization of the residue from ethanol gave 2.6-diamino-3-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 142° C (18 g, 41.5% of theory).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[C:22]1([CH3:31])[C:23]([N:28]=[C:29]=[O:30])=[CH:24][CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH3:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1
Reactant: Cc1ccccc1N=C=O
Reactant: C#CCN1CCCc2ccc(O)cc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)Nc3ccccc3C)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (250 mg, 1.34 mM) and triethylamine (0.2 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, o-tolyl isocyanate (250 mg/ml, 2.01 mM) was added at once and then the reaction mixture was further stirred for 48 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:19) to give 10a as solid. Yield: 300 mg, 70.13%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][C:24]3[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=3)=[CH:29][CH:30]=2)=[CH:9][CH:10]=1)[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: Ic1ccc(Cc2ccccc2)cc1
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(Cc3ccccc3)cc2)cc1
Yield: 50 %

Procedure:
The title compound was prepared from the product from step 1 (1.3 g, 4.6 mmol) and 4-iododiphenylmethane (2.0 g, 6.9 mmol) using the Step 4 procedure of example 1 with 50% yield (1.1 g). 1HNMR (CDCl3) 1.43 (s, 9H), 3.73 (s, 3H), 3.97 (s, 2H), 5.29 (m, 1H), 5.50 (m, 1H), 6.94 (m, 4H), 7.15 (d, J=6.8 Hz, 2H), 7.20 (m, 3H), 7.30 (m, 4H), MS m/z 448 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-:32].[Na+].O>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]([NH2:25])=[O:32])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(N)=O
Temperature: 70 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (404 mg, 1.00 mmol) obtained in Example 1 was dissolved in ethanol (8 mL), 2 mol/L aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 70° C. for 2 days. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with 2 mol/L aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered to give the title compound (compound 3) (279 mg, 66%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Br>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:19]([Cl:18])[CH:20]=2)[C:5]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(Br)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 73.2 %

Procedure:
Powdered sodium hydroxide (0.5 g) was added in a single portion to a vigorously stirred solution of ethyl 3-bromoindole-2-carboxylate (0.3 g), 3,4-dichlorobenzyl bromide (0.32 g) and tetra-n-butylammonium hydrogensulphate (50 mg) in dichloromethane. The reaction was stirred for 3 hours then partitioned between 2M HCl and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-5% ethyl acetate as eluent to give the desired end product as a colourless oil (0.35 g, 73%); NMR δ (CDCl3) 1.42 (t, 3H), 4.41 (q, 2H), 5.73 (s, 2H), 6.84 (d, 1H), 7.18-7.40 (m, 5H), 7.74 (d, 11H); M/z (+) 428 (MH+), 426, 346, 159.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].CO.C(OO)(=[O:28])C>C(Cl)Cl>[CH3:1][C:2]1[CH2:3][S@:4](=[O:28])[C@@H:5]2[C@H:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: CC(=O)OO
Solvent: ClCCl
Solvent: CO
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[S@@](=O)C1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of polymer ester of (6R, 7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid (5.00g, 4.45 mole, from example 8 in methylene chloride (35 ml.) and methanol (10 ml.) cooled to 0° was added peracetic acid (38% w/v, 1.1 ml., 5.50 m.mole) in one portion. Stirring was continued for 30 minutes at 0° and for a further 15 minutes, after removal of the cooling bath. The reaction mixture was filtered and pulled as dry as possible. The product was washed with methylene chloride (2 × 50 ml.) methanol (2 × 50 ml.), and methylene chloride (2 × 50 ml.). The product was dried to constant weight in vacuo at 30° to give the pale yellow polymer ester of (1S, 6R. 7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid 1-oxide (5.00g, which proved to be similar (infra red, nmr., and t.l.c.) with the product obtained in example 9 above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[C:34]([C:37](O)=[O:38])=[CH:33][N:32]([CH2:40][CH3:41])[C:31]2=[O:42])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:37]([C:34]3[C:35](=[O:36])[N:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[C:31](=[O:42])[N:32]([CH2:40][CH3:41])[CH:33]=3)=[O:38])=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc(OC)c2c(Oc3ccc(N)cc3)ccnc2c1
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)cc(OC)c34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(5,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide was synthesized using 4-(5,7-dimethoxyquinolin-4-yloxy)phenylamine and 3-(4-fluorophenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid by the method for example 38. mp=128-9° C.; LCMS m/z=557 (M+1); 1H NMR (DMSO) δ: 10.87 (s, 1H), 8.85 (s, 1H), 8.52 (m, 1H), 7.72 (m, 2H), 7.33-7.41 (m, 4H), 7.07 (m, 2H), 6.99 (m, 1H), 6.63 (m, 1H), 6.49 (m, 1H), 4.01 (m, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 1.28 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[O:6][C:7]=1[NH:8][C:9]1[CH:31]=[CH:30][C:12]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])=[CH:11][CH:10]=1)#[N:2].C(=O)(O)[O-:41].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[NH:20]1[CH2:19][CH2:18][CH:17]([CH2:16][NH:15][C:13]([C:12]2[CH:30]=[CH:31][C:9]([NH:8][C:7]3[O:6][C:5]([C:32]4[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=4[F:39])=[N:4][C:3]=3[C:1]([NH2:2])=[O:41])=[CH:10][CH:11]=2)=[O:14])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(Nc3oc(-c4c(F)cccc4F)nc3C#N)cc2)CC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)NCC2CCNCC2)cc1
Yield: 14 %

Procedure:
A solution of tert-butyl 4-((4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzamido)methyl)piperidine-1-carboxylate (0.028 g, 0.052 mmol) in concentrated sulfuric acid (1 mL) was stirred at room temperature for 1.5 hours. The solution was neutralised by pouring into saturated sodium bicarbonate solution. The aqueous phase was then basified to pH14 with 5M NaOH and extracted with EtOAc. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford 5-(4-((piperidin-4-ylmethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.003 g, 0.007 mmol, 14%) as a yellow solid. 1H NMR (CD3OD) δ 1.51 (2H, m), 2.00 (3H, m), 2.99 (2H, t), 3.35 (2H, m), 3.45 (2H, m), 7.22 (2H, t), 7.53 (2H, d), 7.60 (1H, m), 7.87 (2H, d), 8.55 (1H, br s). LCMS (2) Rt: 1.85 min; m/z (ES+) 456.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([C:31]=3[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=4[O:33][CH3:34])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C[O:36][C:37]([C@H:39]1[CH2:44][CH2:43][C@H:42](C(O)=O)[CH2:41][CH2:40]1)=[O:38].O[Li].O>>[CH3:34][O:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:24][C:23]([C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([C@H:42]4[CH2:43][CH2:44][C@H:39]([C:37]([OH:38])=[O:36])[CH2:40][CH2:41]4)=[O:7])[CH2:13][CH2:12]3)=[CH:19][CH:18]=1)=[O:22])=[C:31]2[CH3:32]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)[nH]c12
Agent: [Li]O
Solvent: O
Product: COc1cccc2c(C)c(C(=O)Nc3ccc(N4CCN(C(=O)[C@H]5CC[C@H](C(=O)O)CC5)CC4)cc3)[nH]c12

Procedure:
With a procedure similar to the example above, trans-4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester and trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester, followed by a standard LiOH—H2O saponification procedure to remove the methyl ester. LCMS calcd for C29H34N4O5 (m/e) 518, obsd 519 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:4][C:3]=1[F:16].C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25].Cl>C(Cl)Cl.CO>[N+:24]([C:27]1[CH:28]=[C:29]([S:33]([O:14][CH2:13][C@@H:11]2[O:10][C:9](=[O:15])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:16])[CH:4]=3)[CH2:12]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(Br)c(F)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1O[C@@H](COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1c1ccc(Br)c(F)c1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
To a slurry of 907 g (3.13 mol) of (5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one in 4.5 L of CH2Cl2 in a 22 L round bottom flask was added 654 mL (4.69 mol, 1.50 equiv.) of triethylamine. The mixture was cooled to 0° C., and a solution of 832 g (34.75 mol, 1.20 equiv) of m-nitrobenzenesulfonyl chloride in 2 L of CH2Cl2 was added, keeping the temperature below 6° C. The mixture was sampled for HPLC, and an additional 55 g of solid m-nitrobenzenesulfonyl chloride was added to drive the reaction to completion. Hydrochloric acid (1M, 4.5 L) was added to the slurry. The solids were collected by filtration and washed with water. The phases in the filtrate were separated, and the aqueous later was extracted with 2×500 mL of CH2Cl2. The combined organic layers were concentrated and combined with the solids previously isolated, 2 L of CH2Cl2 and 2 L of methanol. This slurry was distilled on a rotary evaporator, keeping the volume at ˜5 L by adding methanol. The solids were collected by filtration, washed with 1 L of MeOH, and air dried to afford 1415 g (95%) of [(5R)-3-(4-bromo-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl 3-nitrobenzene sulfonate: TLC Rf=0.15 (50% EtOAc.hexanes); HPLC rt=5.68 min; mp 153-156°; [α]D=−76.6° C.=1, MeOH/CH2Cl2), 1H NMR (DMSO) δ8.77 (d, 1H, J=8.2 Hz), 8.71 (s,1H), 8.52 (d, 1H, 7.9 Hz), 8.14 (t, 1H, J=8.1 Hz), 7.85 (t, 1H, J=8.5 Hz), 7.73 (dd, 1H, J=2.3, 11.4 Hz), 7.40 (d, 1H, J=8.9 Hz), 5.12 (m, 1H), 4.68 (m, 2H), 4.28 (t, 1H, J=9.4 Hz), 3,89 (m, 1H); 13C NMR (DMSO) δ157.3 (s, JCF=242 hz), 152.4 (S), 147.2 (S), 138.3 (S, JCF=10 hz), 135.4 (S), 132.7 (D), 132.6 (D), 131.1 (D), 128.2 (D), 121.7 (D), 114.2 (D), 105.3 (D, JCF=29 Hz), 100.6 (s, JCF=20 Hz), 70.4 (t), 69.0 (d), 44.8 (t); Anal. calc'd for C16H12BrFN2O7S: C, 40.44; H, 2.55; N, 5.89; Br, 16.81; found: C. 40.22; H, 2.45; N, 5.86; Br, 16.60.
Reaction SMILES: C([O:8][C:9](=[O:37])[C@H:10]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:31]1([O:30][C:27]2[CH:26]=[CH:25][C:24]([S:21]([NH:20][C@H:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:9]([OH:37])=[O:8])(=[O:22])=[O:23])=[CH:29][CH:28]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCOCC1)NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H](CC(=O)N1CCOCC1)NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A mixture of the title C compound, (2R)-(4-phenyloxybenzenesulfonylamino)-4-morpholin-4-yl-4-oxobutyric acid benzyl ester (430 mg, 0.82 mmol) and 10% Pd on carbon (100 mg) in 10 mL of EtOAc is stirred under hydrogen (H2) atmosphere (1 atm) for 2 h. The catalyst is removed by vacuum filtration though celite, and the filtrate is concentrated to afford 330 mg (100%) of (2R)-(4-phenyloxybenzenesulfonylamino)-4-morpholin-4-yl-4-oxobutyric acid as a white solid: m.p. 147-149° C.; ESI-MS 433 (M−−1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:8][CH2:7]2.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.N>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]3)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Brc1cccc2c1CC1(CC2)OCCO1
Agent: CC(C)(C)[O-]
Agent: N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc3c2CC2(CC3)OCCO2)CC1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
8'-Bromo-3',4'-dihydrospiro-[1,3-dioxolane-2,2'(1H)-naphthalene] (6.0 g, 22 mmol; described in Sunkyung L.; Stewart P. F.; David E. N. Synth. Commun. 1995, 25 (18), 2775-2780) was dissolved in toluene (180 mL) and flushed with argon. N-Methylpiperazine (3.0 mL, 27 mmol), R(+)-bis(diphenylphosphino)-1,1'-binaphthyl (830 mg, 1.3 mmol), tetrakis(dibenzylideneacetone)dipalladium (0) (510 mg, 0.45 mmol) and sodium t-butoxide (3.0 g, 31 mmol) were added and the reaction mixture was stirred at 85° C. for 2.5 h. After cooling to room temperature ethyl acetate (400 mL) and 2 M ammonia (60 mL) were added. The phases were separated and the organic layer was washed with 2 M ammonia (30 mL), brine (40 mL) and dried (MgSO4). Evaporation of the solvent gave 7.5 g of a crude product. Purification by column chromatography on silica using chloroform/methanol/conc. NH3 (180:5:0.5) as eluent afforded 5.5 g (84% yield) of the title compound as a yellowish solid: mp 127-128° C.; EIMS (70 eV) m/z (relative intensity) 288 (43, M+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH2:12][N:13]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]1=[O:26])C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[C:22]([O:21][C:19]([NH:18][C@@H:15]1[CH2:16][CH2:17][N:13]([CH2:12][C:11]2[CH:27]=[CH:28][CH:29]=[C:9]([OH:8])[CH:10]=2)[C:14]1=[O:26])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(OCc3ccccc3)c2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(O)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-1-(3-benzyloxybenzyl)-3-(tert-butoxycarbonylamino)-2-oxopyrrolidine, as described above in Step L, (500 mg, 1.26 mmol) in EtOH (75 mL) was added 20% Pd(OH)2 on carbon (75 mg) and the reaction mixture was stirred under an atmosphere of hydrogen (ca. 1 atm) at ambient temperature for 18 hours. The mixture was filtered through a pad of celite, washing with EtOH, and the filtrate was concentrated in vacuo to give a crude product. This was purified by flash column chromatography on silica, eluting with CHCl3—3% MeOH—0.3% NH4OH, to yield the titled product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]>[Pd]>[CH3:22][C:2]([CH3:1])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C(C)(C)CCCCCOC1CCCCO1
Agent: [Pd]
Product: CCOC(=O)CCC(C)(C)CCCCCOC1CCCCO1
Reaction time: 8 h

Procedure:
A solution of (E)-Ethyl 4,4-dimethyl-9-(tetrahydro-2H-pyran-2-yloxy)non-2-enoate (example 285, step d) (0.89 g) in IMS (industrial methylated spirits) (10 mL) was treated with palladium on carbon (spatula tip) under nitrogen then the flask was purged with hydrogen (×3) then stirred under an atmosphere of hydrogen overnight. A further portion of palladium on carbon was added and hydrogenation resumed for a further 24 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated to afford the subtitled compound as a colourless oil. Yield 0.86 g.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8](Cl)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[OH-].[K+]>>[N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([N:17]2[CH:18]=[CH:19][C:14](=[O:13])[CH:15]=[CH:16]2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Oc1ccncc1
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Nc1cc(-n2ccc(=O)cc2)c(F)cc1[N+](=O)[O-]
Yield: 22.6 %

Procedure:
First, 3.811 g of 2-nitro-4-fluoro-5-chloroaniline, 2.473 g of 4-hydroxypyridine, and 1.827 g of powdered potassium hydroxide were allowed to react at 130° C. for 3 hours in a nitrogen atmosphere in the same way as in Reference Example 1 to give 1.125 g of 2-nitro-4-fluoro-5-(4-oxo-4H-pyridin-1-yl)-aniline.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][C:16]([CH3:21])([CH2:19]O)[CH2:17]O>>[CH3:15][C:16]1([CH3:21])[CH2:19][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:17]1
Reactant: CC(C)(CO)CO
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Product: CC1(C)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
With 4-nitrobenzylphosphonic acid and 2,2-dimethyl-1,3-propanediol, the same procedure as in Reference Example 11 was followed, to yield 5,5-dimethyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless plates having a melting point of 176° to 177° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:14][CH2:15][C:16](O)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(O)COCc1ccccc1
Product: O=C(COCc1ccccc1)N1CCOCC1
Yield: 90 %

Procedure:
Using the mixed anhydride procedure described in Example 2, morpholine was coupled to benzyloxyacetic acid to give the desired product in 90% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:37])[CH2:35][CH3:36]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and propionyl chloride the title compound is obtained as colorless solid.