Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-])=O)=[C:4]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.Cl>CO.O.[Zn]>[NH2:14][C:5]1[C:6](=[O:13])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]([CH3:1])=[CH:3][C:4]=1[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)Cn1c(C)cc(Sc2ccccc2)c([N+](=O)[O-])c1=O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)Cn1c(C)cc(Sc2ccccc2)c(N)c1=O
Yield: 46.9 %

Procedure:
4.67 g (14 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-(phenylthio)-1,2-dihydropyridine-1-acetate are suspended in 200 ml of a methanol:water (1:1) mixture, 5 ml of a 2 N aqueous hydrochloric acid solution and 5 g (76.4 mmol) of zinc are added successively and the mixture is heated at the reflux temperature for 3 hours. The reaction medium is allowed to cool, filtered and the solvent is evaporated. The medium is neutralized with 200 ml of sodium hydrogen carbonate and extracted with twice 100 ml of dichloromethane. The organic phase is recovered and it is dried and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture. 2 g of product are obtained in the form of a white solid which are recrystallized from ethanol.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH3:17][C:18]1[NH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=1>O>[C:1]1([NH:7][C:8]([N:19]2[C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=[C:18]2[CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ncc([N+](=O)[O-])[nH]1
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ncc([N+](=O)[O-])n1C(=O)Nc1ccccc1
Reaction time: 4 h
Yield: 82.9 %

Procedure:
A solution of 11.9 g. (0.1 mol.) of phenylisocyanate in 75 ml. of toluene is added dropwise to the stirred suspension of 15.2 g. (0.12 mol.) of 2-methyl-5-nitroimidazole in 60 ml. of water at 10° to 12° C. When the addition is complete, the mixture is stirred for further 4 hours. The separated product is filtered off, washed and dried. 20.4 g. (82.9%) of 1-phenylcarbamoyl-2-methyl-5-nitroimidazole are obtained; m.p.: 218°-220° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:32])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][C:14]([NH:32][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:18]([Cl:17])[CH:19]=1)=[O:16]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)CNc1ccc(C(F)(F)F)cc1Br
Product: CCN(CC)CCOc1ccc(NC(=O)CNc2ccc(C(F)(F)F)cc2Br)cc1Cl

Procedure:
The product was obtained according to general working method I starting from (2-bromo-4-trifluoromethyl-phenylamino)-acetic acid (Example 167b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1.O>[OH:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1)([OH:13])[CH2:11][OH:12]
Reactant: Nc1ccc(C(O)(CO)CO)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(O)(CO)CO)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a stirred solution of 2-(4-aminophenyl)propane-1,2,3-triol (900 mg, 4.918 mmol, 1.0 eq) in THF/H2O/sat. NaHCO3 (4 mL: 2 mL: 4 mL) was added phenyl chloroformate (0.68 mL, 5.367 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 0.5 h, then the THF was evaporated, the residue was diluted with EtOAc (20 mL), washed with water (20 mL) followed by brine and the solvent evaporated. The resulting residue was purified by CC using MeOH/CHCl3 (1:19) as eluent to get phenyl 4-(1,2,3-trihydroxypropan-2-yl)phenylcarbamate (900 mg, 60%, white solid; TLC system: MeOH/CHCl3 (1:9), Rf: 0.4).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 4-chloro phenyl isocyanate (0.041 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 49 as a colorless solid (0.052 g, 42%). LCMS m/z (%)=463 (M+H+79Br, 35Cl, 41), 465 M+H+ (81Br35Cl 88), 467 H+ (81 Br 37Cl, 21), 1H NMR (400 MHz, acetone-d6) δ: 8.30 (bs, 1H), 8.24 (bs, 1H), 7.685 (d, J=2.66 Hz, 1H), 7.577 (d, J=1.92 Hz, 2H), 7.74 (d, J=2.65, 1H), 7.292 (d, J=1.9 Hz, 2H), 7.280 (d, J=1.6 Hz, 1H), 7.135 (d, J=9.01 Hz, 1H), 4.256 (m, 1H), 3.811 (s, 3H), 1.447 (d, J=6.61 Hz, 3H), 1.288 (d, J=6.61 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.CC[O-].[Na+].[CH3:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17]>C(O)C>[CH2:8]([O:7][C:5](=[O:6])[C:4]([CH2:15][C:16](=[O:17])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
146 g (1 mol) of oxalic acid diethyl ester are added dropwise to 367.2 g of a 20% strength sodium ethylate solution in ethanol at 5° C. in the course of one hour, whilst stirring. 100 g of technical grade pinacolin are allowed to run in and the mixture is stirred for a further 15 minutes. It is then heated to 80° C. and heated under reflux for 3 hours. The solution is subsequently evaporated to dryness in a rotary evaporator. The residue is suspended in 200 ml of toluene and the suspension is stirred with 253 g of aqueous sulphuric acid (20.9% strength by weight) at 50° C. for 1 hour. The organic phase is separated off and distilled. 177 g of pivaloylpyruvic acid ethyl ester (88.2% of the theoretical yield) are obtained with a purity of 99.6% (by analysis by gas chromatography).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH2:24][N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[NH:27][C:26]1=[O:36]>C(O)C>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH:8]2[CH2:9][CH2:10][N:11]([CH2:22][CH2:23][CH2:24][N:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28](=[O:35])[NH:27][C:26]3=[O:36])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(=O)n(CCCCl)c2ccccc12
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Solvent: CCO
Product: O=c1[nH]c(=O)n(CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)c2ccccc12

Procedure:
2.7 g (0.01 mole) of 4-(diphenylhydroxymethyl) piperidine, 1.2 g (0.005 mole) of 1-(3-chloropropyl)-2,4(1H,3H)-quinazolinedione in 75 ml of ethanol are heated at reflux temperature for 7 h.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][CH2:17][CH2:18][Cl:19])/[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4].[Cl:20]N1C(=O)CCC1=O>>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([Cl:20])=[C:9](/[C:11](=[N:15]/[O:16][CH2:17][CH2:18][Cl:19])/[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4]
Reactant: O=C(CCl)Nc1nc(/C(=N/OCCCl)C(=O)O)cs1
Reactant: O=C1CCC(=O)N1Cl
Product: O=C(CCl)Nc1nc(/C(=N/OCCCl)C(=O)O)c(Cl)s1

Procedure:
2-(2-Chloroacetamidothiazol-4-yl)-2-(Z)-(2-chloroethoxyimino)acetic acid and N-chlorosuccinimide are reacted in the procedure of Reference Example 37 to give 2-(2-chloroacetamido-5-chlorothiazol-4-yl)-2(Z)-(2-chloroethoxyimino)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)c(I)c1
Reactant: Sc1ccc(Cl)cc1
Product: Fc1ccc(Br)c(Sc2ccc(Cl)cc2)c1

Procedure:
Prepared from 4-chloro-benzenethiol and 1-bromo-4-fluoro-2-iodo-benzene.
Reaction SMILES: C([O:4][C:5]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:26][C:27](=[O:29])[CH3:28])[CH2:13][CH2:12]4)[CH2:9][C:8](=O)[C:7]=2[CH:6]=1)(=O)C.Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[C:27]([O:26][C@H:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C:20]1[CH:21]=[C:22]([O:23][CH2:24][CH3:25])[C:5]([OH:4])=[CH:6][C:7]=1[C:8](=[N:32][OH:33])[CH2:9]3)(=[O:29])[CH3:28]
Reactant: NO
Reactant: CCOc1cc2c(cc1OC(C)=O)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc2c(cc1O)C(=NO)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Temperature: 100 °C
Yield: 102 %

Procedure:
A solution of 3,17,β-diacetoxy-2-ethoxy-estra-1,3,5(10)-triene-6-one (5, 800 mg, 1.93 mmol) in pyridine (12 ml) was treated with hydroxylamine hydrochloride (1.07 g, 15.4 mmol). The resulting mixture was stirred and heated at 100° C. for 30 min. The mixture was cooled to room temperature and then poured into ice/water mixture (150 ml). The compound was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with sodium bicarbonate (100 ml), water (2×100 ml) and brine (2×100 ml), dried over sodium sulfate, and evaporated to dryness. Chromatography of the residue on silica gel using 30% ethyl acetate in hexane gave the title compound (763 mg, 89%), which was crystallized from ethyl acetate/hexane to afford title compound 27 as yellowish crystals: mp 226-227° C. 1H NMR (CDCl3) δ7.55 (s, 1 H). 6.78 (s, 1 H), 4.75 (t, J=8.5 Hz, 1 H), 4.19 (q, J=6.9 Hz, 2 H), 3.15 (dd, J=4.3 and 12 Hz, 1 H), 1.2-2.40 (m, 18 H), 0.85 (s, 3 H); CIMS (isobutane) m/z (rel intensity) 388 (MH+, 100), 372 (MH—H2O, 10), 328 (75); Anal. Calcd for C22H29O5N: C, 68.20; H, 7.54; N, 3.61. Found: C, 68.04; H, 7.62; N, 3.54.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:26]([S:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[CH2:34]2)(=[O:30])=[O:29])[CH3:27]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2/[CH:24]=[C:34]2\[C:35](=[O:40])[NH:36][C:37]3[C:33]\2=[CH:32][C:31]([S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:39][CH:38]=3)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCOC(=O)N1CCN(CCCc2c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)CC)cc43)[nH]c3c2CCCC3)CC1

Procedure:
4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazine-1-carboxylic acid ethyl ester (65 mg, 0.1 87 mmol), prepared as described in Example 8, was condensed with 5-ethylsulfonyloxindole (61 mg, 1.01 eq.) give the desired product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][OH:17].CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][OH:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCNCCO
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCNCCO)cc1
Temperature: 60 °C
Yield: 92.7 %

Procedure:
6 g of 4-fluoronitrobenzene and 10 g of 2-(2-aminoethylamino)ethanol were added to a solution of 100 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 4 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 8.88 g of 2-[2-(4-nitrophenylamino)ethylamino]ethanol (1) were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[C:31]([Cl:32])[N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:41]1([CH3:50])[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[C:31]([Cl:32])[N:17]2[N:16]=1)[CH2:13][CH3:14])[C:47](=[O:48])[C:44]1[CH:45]=[CH:46][C:41]([CH3:50])=[CH:42][CH:43]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To a solution of (±)-N-{3-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (0.51 g, 1.08 mmol) and Et3N (0.25 mL, 1.79 mmol) in CH2Cl2 (10 mL) at rt was added p-toluoyl chloride (0.21 mL, 1.58 mmol) under N2 and stirred at rt for 3 hr. The reaction mixture was diluted with CH2Cl2 to 100 mL, washed with aq. NaHCO3 solution (30 mL), dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1.5:8.5 to 1:3) gave the title compound as pale oil (0.43 g, 67%): 1H NMR (CDCl3) δ 7.30 (m, 2H), 7.24 (m, 1H), 7.15 (m, 2H), 7.10 (d, 1H, J=4.4 Hz), 6.53 (d, 1H, J=4.4 Hz), 5.91 (m, 1H), 4.95 (m, 1H), 3.35 (m, 2H), 2.70 (m, 1H), 2.36 (s, 3H), 2.05 (m, 1H), 1.95 (m, 1H), 1.43 (m, 3H), 1.35 (s, 9H), 0.67 (m, 3H); MS (ESI+) 592.15 (M++H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:10]=1.[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:63]/[O:64][CH3:65])/[C:37]([NH:39][CH:40]2[C:61](=[O:62])[N:42]3[C:43]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)=[O:50])=[C:44]([CH2:47]Cl)[CH2:45][S:46][C@H:41]23)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:63]/[O:64][CH3:65])/[C:37]([NH:39][CH:40]2[C:61](=[O:62])[N:42]3[C:43]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)=[O:50])=[C:44]([CH2:47][S:1][C:2]4[S:3][C:4]5[CH:5]=[N:6][CH:7]=[CH:8][C:9]=5[N:10]=4)[CH2:45][S:46][C@H:41]23)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Sc1nc2ccncc2s1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CSc3nc4ccncc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 67 %

Procedure:
Using 60 mg of 2-mercaptothiazolo[5,4-c]pyridine in place of 2-mercaptothiazolo[4,5-c]pyridine and 238 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 186 mg of the title compound in a yield of 67%.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[C:7]([CH3:14])[CH:6]=1)C.Cl>[OH-].[Na+]>[CH3:14][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[C:8]=1[O:12][CH3:13])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)c1cc(C)c(OC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)cc(C(=O)O)cc1C

Procedure:
A mixture of 3,5-dimethyl-4-methoxybenzoic acid ethyl ester (PREPARATION 2, 10.5 g) and aqueous sodium hydroxide (20%, 100 ml) is refluxed for 18 hours. The solution is cooled and acidified with hydrochloric acid (12N, pH 2). The acidified solution is extracted with chloroform (3×). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure to give a solid which is recrystallized from ether/pet ether mixture to give the title compound, mp 189°-191°.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1
Reactant: OCCO
Reactant: CSCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CSCCC1OCCO1

Procedure:
A solution of 3-(methylthio)propanal (5.2 g, 0.05 mol) and ethyleneglycol (3.4 g. 0.055 mol) in 100 mL of benzene was treated with 300 mg p-toluenesulfonic acid and heated at reflux for 4 hrs. The solution was cooled and decanted. Concentration and drying in vacuo provided the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm: 4.93 (1H, t, J=4.76 Hz) 3.74–4.03 (4H, m) 2.46–2.68 (2H, m) 2.08 (3H, s) 1.83–2.00 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37](B(O)O)=[CH:36]3)[C:10]=1[CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:61]=[CH:60][C:59](I)=[CH:58][CH:57]=1)#[N:55].C([O-])([O-])=O.[Na+].[Na+].COCCOC>O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:37]([C:59]2[CH:60]=[CH:61][C:56]([C:54]#[N:55])=[CH:57][CH:58]=2)=[CH:36]3)[C:10]=1[CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(-c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Reactant: N#Cc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(-c2ccc3c(c2)cc(-c2ccc(C#N)cc2)n3C(=O)OC(C)(C)C)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A mixture of the boronic acid obtained in Step 1 (75 mg, 0.10 mmol), 4-cyanoiodobenzene (24 mg, 0.10 mmol) Pd(PPh3)4 (12 mg, 0.01 mmol), Na2CO3 (33 mg, 0.30 mmol), DME (0.9 mL) and H2O (0.1 mL) was stirred under argon at 85° C. for 2 hr. The mixture was then concentrated to dryness and chromatographed (silica gel, ethyl acetate in hexanes 0-15% gradient) to provide tert-butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-ethylpyridin-2-yl)-2-(4-cyanophenyl)-1H-indole-1-carboxylate (42 mg, yield: 55%). LC-MS 770.6 [M+H]+, RT 1.16 min. (1 min. Method). This was dissolved in diphenyl ether (1 mL) and heated to 210° C. for 0.5 hr. After cooling the mixture was chromatographed (silica gel, ethyl acetate in hexanes 0-50% gradient) to furnish 6-(2-(4-cyanophenyl)-1H-indol-5-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid (29 mg, yield: 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:32][CH:29]1[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)CC1
Yield: 87.4 %

Procedure:
The title compound (0.32 g, 88%) was prepared as a white solid from 3-fluoro-4′-(methylsulfonyl)-4-biphenylol (0.21 g, 0.79 mmol), N-Boc-4-piperidinemethanol (0.18 g, 0.79 mmol) and Ph3P (0.21 g, 0.79 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.17 g, 94%, 0.79 mmol) in THF (1.5 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.6 Hz), 7.70 (d, 2H, J=8.6 Hz), 7.40-7.30 (m, 2H), 7.06 (t, 1H, J=8.5 Hz), 4.25-4.15 (m, 2H), 3.92 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 2.80-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 464 (M+H).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1.O=S(Cl)[Cl:22]>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:22])(=[O:15])=[O:14])=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Temperature: 90 °C

Procedure:
DMF (0.06 ml, cat) was added to a solution of 4-chloro-2-nitro-benzenesulfonic acid (600 mg, 2.5 mmol) in SOCl2 (3.1 ml) and the mixture was heated at 90° C. for 3 h. After cooling, the solvent was removed in vacuo. The mixture was diluted with water and extracted repeatedly with chloroform. The combined organic layers were washed with saturated NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo to give the title compound (560 mg) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: C([N:14]1[CH2:17][C:16]2([CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][O:18]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:15]1[C:16]2([CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][O:18]2)[CH2:17][NH:14]1
Reactant: CC(C)(C)OC(=O)N1CCOC2(C1)CN(C(c1ccccc1)c1ccccc1)C2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC2(CNC2)C1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate (0.85 g) (example 176 step b), ammonium formate (0.883 g) and palladium on carbon JM type 87 L (0.459 g) in ethanol (50 mL) was refluxed for 30 minutes. The mixture was cooled to RT and filtered through celite, the solvent was evaporated under reduced pressure. The celite pad was washed with 10 mL of DMF) and then with 50 mL of acetonitrile. These washings were used to dissolve the residue obtained from evaporation of the initial mixture. This solution was passed through a 10 g SCX cartridge, followed by washing with acetonitrile. The cartridge was the eluted with a 10% solution of 880 ammonia in acetonitrile (80 mL) to bring off product. The solvents were evaporated under reduced pressure and the residue diluted with acetonitrile and evaporated under reduced pressure to afford the subtitled compound. Yield 0.490 g.