Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([F:50])[CH:46]=2)[N:41]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:39][C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][CH:44]=[C:45]([F:50])[CH:46]=5)[N:41]=4)=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: Fc1ccc2nc(CBr)ccc2c1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (See EP419,049, Example 1, Step C) (322 mg) in acetonitrile (7 mL) were added solid cesium carbonate (456 mg) and 2-bromomethyl-6-fluoroquinoline (190 mg) from Step A. The mixture was stirred at room temperature for 18 hr. The mixture was poured into 25% aqueous NH4OAc (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried (MgSO4) and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetate:toluene (5:95) as eluant to give the title compound as a white solid; m.p. 165°-167° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1cccc(C(=O)c2ccc(Cl)nc2N)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)c2ccc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(3-methoxy-phenyl)-methanone (Example 17) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, 405.1595 observed:, Calcd for (M+H)+: 405.1591.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].Cl[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18].Cl>CN(C)C=O>[C:17]([C:16]1[CH:19]=[CH:20][N:21]=[C:14]([S:3][C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])[CH:15]=1)#[N:18]
Reactant: O=C(O)c1cccc(S)c1
Reactant: N#Cc1ccnc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccnc(Sc2cccc(C(=O)O)c2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
Add sodium hydride (60% dispersion in mineral oil, 635 mg, 15.88 mmol) to a solution of 3-mercapto-benzoic acid (1.11 g, 7.22 mmol) in dimethylformamide (50 mL) chilled to 0° C. and stir. After 10 minutes add 2-chloro-isonicotinonitrile (1.00 g, 7.22 mmol). Warm gradually to ambient temperature. After 18 hours, add 1N aqueous hydrochloric acid (200 mL). Filter the resulting precipitate, washing with water and hexanes to yield the title compound as a tan solid (920 mg, 50%): 1H NMR (DMSO-d6) δ 7.62-7.66 (m, 3H), 7.84 (d, 1H), 8.03-8.08 (m, 2H), 8.62 (d, 1H), 13.26 (bs, 1H).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[O:15]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]([C:26]([Cl:28])=[O:27])[CH2:18][CH2:17]1.[OH-].[Na+]>>[ClH:28].[O:15]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]([C:26]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:8][N:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:27])[CH2:18][CH2:17]1
Reactant: O=C1CCC(C(=O)Cl)c2ccccc21
Reactant: C1CCC(CN2CCCC2)NC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCC(C(=O)N2CCCCC2CN2CCCC2)c2ccccc21
Yield: 76.7 %

Procedure:
From 3.48 g of 2-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride, 4.44 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride and 63.9 ml of 1N aqueous sodium hydroxide solution. 4.17 g of the title compound was obtained, melting at 239°-242° C. (dec). using a procedure similar to that in Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[N+:19]([C:15]1[C:16]([NH2:18])=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[N:22]=[CH:23][N:24]=[C:4]3[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=3)[N:7]=2)=[CH:13][CH:14]=1)([O-:21])=[O:20]
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Nc1nc(NCCNc2nc(-c3ccc(C(F)(F)F)cc3)cc3ncnn23)ccc1[N+](=O)[O-]

Procedure:
In analogy to the procedure described for Example 94, 2.3 mg (4% of theory) of the product are obtained as solid starting from 50 mg (0.133 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo-[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 55A) by coupling with 25.2 mg (0.13 mmol) of [4-(trifluoromethyl)phenyl]boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[NH:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[CH2:30]([O:29][C:27]([C:26]1[N:7]=[C:6]([C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:25]=1)=[O:28])[CH3:31]
Reactant: N=C(NCc1ccccc1Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cn(Cc2ccccc2Cl)c(-c2ccc(Br)cc2)n1
Temperature: 175 °C
Yield: 13.3 %

Procedure:
A mixture of 4-bromo-N-(2-chlorobenzyl)-benzamidine (1.4 g, 4.3 mmol), sodium bicarbonate (0.72 g, 8.6 mmol) and ethyl bromopyruvate (0.98 mL, 7.8 mmol) in EtOH (14 mL) was heated in a microwave unit (Biotage Initiator™) at 175° C. for 12 min. The resulting mixture was decanted and the solids rinsed with EtOAc. The combined filtrates were concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 40:60) to give the title compound (0.24 g, 13%) as a pale brown residue. 1H-NMR (DCM-d2): 0.5-7.58-7.62 (m, 3H), 7.43-7.49 (m, 3H), 7.34 (m, 1H), 7.28 (m, 1H), 6.96 (d, 1H), 5.30 (s, 2H), 4.32 (q, 2H), 1.35 (t, 3H); MS (ES): 419, 421 [M+H]+.
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)[CH3:2].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:2][O:1][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: COc1ccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-methoxylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1>CO.[Pd]>[OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[CH:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c(CO)nc3c(N4CCOCC4)ccnn23)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2c(CO)nc3c(N4CCOCC4)ccnn23)CC1

Procedure:
To a solution of compound 41a (3.5 g, 8.4 mmol) in methanol (30 mL) was added 10% Pd/C (ca. 50% water, 3.5 g). The resulting mixture was hydrogenated at about 2 to 3 atm overnight, and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain compound 41b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H31N5O4: 418.2 (M+H). found: 418.2.
Reaction SMILES: [CH:1](=[N:8][N:9]([C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:23]([Cl:36])[CH:22]=1)[C:10]([NH:12][CH2:13]C(OCC)OCC)=[O:11])C1C=CC=CC=1>C(#N)C.Cl>[Cl:27][C:25]1[CH:26]=[C:21]([N:9]2[C:10](=[O:11])[NH:12][CH2:13][CH:1]=[N:8]2)[CH:22]=[C:23]([Cl:36])[C:24]=1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1
Reactant: CCOC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1)OCC
Agent: Cl
Solvent: CC#N
Product: O=C1NCC=NN1c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
In 5 ml of acetonitrile was dissolved 0.4 g of 1-benzylidene-2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-4-(2,2-diethoxyethyl)-semicarbazide. To the solution was added one drop of 35% hydrochloric acid. The mixture was stirred for one hour at room temperature. The reaction mixture was cooled, then resulting crystalline precipitate of the titled compound was collected by filtration. The yield was 95%. m.p.199-200° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:60])[C:32]([C:35]3[N:36]=[C:37]([NH:40]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:38][CH:39]=3)=[N:33][OH:34])[C:28](=[O:61])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C(OC(C)C)(C)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:60])[C:32]([C:35]3[N:36]=[C:37]([NH2:40])[S:38][CH:39]=3)=[N:33][OH:34])[C:28](=[O:61])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
The product of Step C was dissolved in 15 ml of pure trifluoroacetic acid and the mixture stood for 15 minutes and was then diluted with 100 ml of isopropyl ether. The mixture was stirred for 5 minutes and was vacuum filtered and the filter was rinsed with isopropyl ether. The product was dried and then dissolved in 2 ml of ethanol containing 0.2 ml of pyridine. The mixture was vacuum filtered and the recovered product was rinsed twice with ethanol to obtain the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:22]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:21]=2)[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.Cl>[CH2:1]([O:8][CH2:9][C:10]1([C:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[N:22]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:21]=2)[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(C3(COCc4ccccc4)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C3(COCc4ccccc4)CCC(=O)CC3)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
To a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazole (Reference Example 90) (458 mg, 0.872 mmol) in tetrahydrofuran (2.2 mL), 6 M hydrochloric acid (4.4 mL) was added, and the obtained solution was stirred at room temperature for 15 hours. The reaction solution was cooled in ice and 50% aqueous sodium hydroxide solution was added dropwise thereto at 0° C. until basic. Thereafter, the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (387 mg, 0.804 mmol, 92%) as a white amorphous product.
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:43][NH:44][C:45]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([C:57]([C:59]3[N:60]=[CH:61][N:62]([C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[CH:63]=3)=[O:58])[CH:53]=2)[CH:48]=1)=[O:46]>C1COCC1.C(OCC)(=O)C.Cl.[Zn]>[OH:58][C@@:57]([C:52]1[CH:51]=[CH:50][C:49]2[C:54](=[CH:55][CH:56]=[C:47]([C:45]([NH:44][CH3:43])=[O:46])[CH:48]=2)[CH:53]=1)([C:59]1[N:60]=[CH:61][N:62]([C:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH:63]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC(C)(C)C)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 108 %

Procedure:
8 mL of THF and 0.15 mL (1.18 mmol) of chlorotrimethylsilane were added to 1.04 g (16 mmol) of zinc powders, and the mixture was stirred at 35˜40° C. for 5 minutes. A solution of 2.36 mL (16 mmol) of tert-butyl bromoacetate in 20 mL of THF was added dropwise at 45˜52° C. over 10 minutes. The mixture was stirred at 65˜67° C. for 1 hour, and cooled to 25° C. 8.5 mL of THF was added to 1.32 g (4.5 mmol, 1.25 eq) of (+)-cinchonine. The above Reformatsky reagent was added dropwise at 4˜6° C. over 15 minutes. 1.16 mL (14.4 mmol, 4 eq) of pyridine was added dropwise at 5˜7° C. over 2 minutes. The mixture was stirred at 5˜6° C. for 30 minutes. A solution of 1.88 g (3.6 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 15 mL of THF was added dropwise at −44˜−39° C. over 7 minutes. The mixture was stirred at −44˜−35° C. for 5 hours and 20 minutes. 10 mL of 1N hydrochloric acid was added, and the mixture was warmed to 0° C. The mixture was diluted with 50 mL of ethyl acetate, 10 mL of 1N hydrochloric acid was added, and the layers were separated. The organic layer was washed successively with 20 mL of 1N hydrochloric acid 2 times, 20 mL of water, and 20 mL of an aqueous saturated sodium bicarbonate solution. To the organic layer were added 10 mL of 0.1N hydrochloric acid, 10 mL of water and 10 mL of ethyl acetate, and the layers were separated. The organic layer was washed with 20 mL of an aqueous saturated sodium chloride solution, and concentrated at 20° C. or lower under reduced pressure. 10 mL of n-hexane was added to the concentration residue, crystals were loosened, filtered, and washed with 10 mL of n-hexane. Air drying to a constant weight afforded 2.48 g of tert-butyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (enantiomer excess 95.0% ee).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: O=C1CCc2cccc(F)c2N1
Agent: O=S(=O)(O)O
Product: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
8-Fluoro-3,4-dihydro-1H-quinolin-2-one [prepared according to the procedure found in EP0524846] (2.62 g, 0.0159 mol) is dissolved in concentrated sulfuric acid (20 ml) and cooled to −5° C. Nitric acid (70%, 1.02 ml, 0.0159 mol) is added dropwise and the reaction stirred at −5° C. for 20 minutes. The mixture is poured onto ice and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum. Purification by flash column chromatography (30% ethyl acetate/hexane) gives the title compound as a light yellow solid (2.50 g, 75%); [M+H]+=211.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[O:19][C:20]([CH3:41])=[C:21]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([C:36]([O:38]CC)=[O:37])([CH3:35])[CH3:34])[CH:27]=4)[N:22]=3)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:36]([C:33]([CH3:35])([O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][CH2:24][CH2:23][C:21]1[N:22]=[C:18]([C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=3)[CH:17]=[CH:16][CH:15]=2)[O:19][C:20]=1[CH3:41])[CH3:34])([OH:38])=[O:37]
Reactant: CCOC(=O)c1ccc(-c2cccc(-c3nc(CCOc4cccc(OC(C)(C)C(=O)OCC)c4)c(C)o3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccc(C(=O)O)cc3)c2)nc1CCOc1cccc(OC(C)(C)C(=O)O)c1
Temperature: 25 °C

Procedure:
A stirred solution of 3′-(4-{2-[3-(1-ethoxycarbonyl-1-methylethoxy)phenoxy]ethyl}-5-methyloxazol-2-yl)-biphenyl-4-carboxylic acid ethyl ester (0.711 mmol) in ethanol (8.9 mL) was treated with NaOH(aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to a white, crystalline solid: mp 184° C.; MS (EI) 525.2 (M+Na)+, 502.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH:12]=[O:13].[CH3:14][C:15]([CH3:20])([CH2:18]O)[CH2:16][OH:17]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH:12]1[O:17][CH2:16][C:15]([CH3:20])([CH3:18])[CH2:14][O:13]1
Reactant: Cc1cc(C)c(/C=C/C=O)c(Br)c1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C)c(/C=C/C2OCC(C)(C)CO2)c(Br)c1
Yield: 96.9 %

Procedure:
A mixture of 1.00 g (4.19 mmol) of (E)-3-(2-bromo-4,6-dimethylphenyl)-2-propenal, 1.32 g (12.6 mmol) of 2,2-dimethyl-1,3-propanediol and a catalytic amount (65 mg) of p-toluenesulfonic acid monohydrate in 100 mL of dry benzene was heated at reflux in a Dean-Stark apparatus for 2 hours. The solution was washed with 1N sodium hydroxide, water (3 times), and the solvent removed under reduced pressure to give 1.32 g (97%) of (E)-2-[2-(2-bromo-4,6-dimethylphenyl)ethenyl]-5,5-dimethyl-1,3-dioxane as a white crystalline material. Purification by HPLC (70% CH2Cl2 -Hexane) gave an analytically pure sample: mp 54°-56° C.; IR (KBr) 2960, 2860, 1670 and 1610 cm-1 ; NMR (CDCl3) δ 0.77 (3H, s), 1.25 (3H, s), 2.28 (3H, s), 2.37 (3H, s), 3.58 (2 H, d, J=12 Hz), 3.74 (2H, d, J=12 Hz), 5.09 (1H, d, J=6 Hz), 5.90 (1H, dd, J=6, 15 Hz), 6.78 (1H, d, J=15 Hz), 6.96 (1H, s), 7.30 (1H, s).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:11](O)=[N:12][CH:13]=1.IC>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[C:1](=[O:4])[N:12]([CH3:11])[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Reaction time: 18 h

Procedure:
Cesium carbonate (44.6 g, 137 mmol) was added to a solution of 5-bromo-2-hydroxy-3-nitropyridine (20.0 g, 91.3 mmol) and iodomethane (19.4 g, 137 mmol) in N,N-dimethylformamide (500 mL). After 18 h, the reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. MS 233.1 (MI).
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH:29]2[O:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:24][CH:23]=1.ClCCl>O.C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:31]2[C:30](=[O:35])[CH:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=3)[O:33][C:32]2=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)O1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1OC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 60.3 %

Procedure:
0.33 g (1.18 mmole) triphenylmethyl chloride was added to a solution of 0.245 g (1.18 mmole) 5-([4-hydroxyphenyl]methyl)oxazolidine-2,4-dione, 0.165 ml (1.18 mmole) triethylamine, 5 ml dichloromethane and 5 ml dimethylformamide on an icebath. The temperature of the reaction mixture was allowed to reach room temperature. After 1.5 hours 0.05 ml more triethylamine was added. After 2 hours ethyl acetate and water were added and the phases were seperated. The organic phase was dried (sodium sulfate), the solvent was evaporated and the crude product was purified by chromatography on silica gel using heptane:ethyl acetate (3:2) as eluent to give 0.32 g (yield 60%) 3-triphenylmethyl-5-([4-hydroxyphenyl]methyl)oxazolidine-2,4-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[S-:19][C:20]#[N:21].[K+].BrBr>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[N:6]=2
Reactant: COC(=O)c1cccc(Oc2ccc(N)cn2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1cccc(Oc2ccc3nc(N)sc3n2)c1
Yield: 47 %

Procedure:
In the same manner as in Example 98 and using methyl 3-[(5-aminopyridin-2-yl)oxy]benzoate (12.5 g, 51.2 mmol), potassium thiocyanate (34.8 g, 358 mmol), bromine (8.2 mL) and acetic acid (125 mL) as starting materials, the title compound (7.25 g, 47%) was obtained as a yellow solid.