Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)=[CH:11][CH2:10]3)[OH:2].C1(N=C=NC2CCCCC2)CCCCC1.[O:38]([CH2:45][C:46](O)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[O:38]([CH2:45][C:46]([O:22][C@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C:3]2=[N:1][OH:2])[CH2:13]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)COc1ccccc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)COc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.6 %

Procedure:
To the stirred solution of 17-Oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.342 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml), phenoxyacetic acid (0.24 g, 1.6 mmol) was added. The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered and the solvent removed under vacuum. The resulting residue was crystallized from ethyl acetate:petroleum ether (60:80) to give 17-oximino-5-androsten-3β-yl phenoxyacetate (16) (0.27 g, 54.0%) mp 118-122° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[Br:23]N1C(=O)CCC1=O>C(OCC)(=O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([Br:23])[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCC(=O)C(Br)C(=O)OCC
Reaction time: 0.08 h

Procedure:
3-Oxo-hexanoic acid ethyl ester (4.0 mL, 25 mmol) and magnesium perchlorate (1.7 g, 7.6 mmol) were placed in 500 mL of ethyl acetate and allowed to stir for 5 minutes. N-Bromosuccinimide (4.7 g, 26 mmol) was added and the reaction mixture was allowed to stir for 15 minutes, at which time thin-layer chromatography (10% ethyl acetate in hexanes, silica gel, 254 nm irradiation) indicated the reaction was complete. The reaction mixture was diluted with 500 mL of ethyl ether and washed three times with an equal volume of saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26]O)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(OP(OC2C=CC=CC=2)([N:76]=[N+:77]=[N-:78])=O)=CC=1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>O1CCCC1>[N:76]([CH2:26][C@@H:18]1[C@H:19]2[O:23][C:22]([CH3:24])([CH3:25])[O:21][C@H:20]2[C@H:16]([N:13]2[C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]4[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:3]=4[O:2][CH3:1])[C:8]=3[CH:15]=[CH:14]2)[O:17]1)=[N+:77]=[N-:78]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of ((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2.83 g, 6.20 mmol) and triphenylphosphine (2.28 g, 8.68 mmol) in dry tetrahydrofuran (32 mL) was cooled at 0° C. in an ice/water bath. Diisopropyl azodicarboxylate (1.71 mL, 8.68 mmol) was added dropwise, followed by a solution of diphenylphosphonic azide (1.87 mL, 8.68 mmol) in tetrahydrofuran (5.3 mL, 66 mmol). Upon addition of the DPPA solution, a white milky precipitate formed. After about 30 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. After 24 h, HPLC indicated that all the starting material had been consumed. The reaction mixture was concentrated to about ½ the original volume and purified by flash chromatography (175 g silica gel, 10-55% EA/hept) to yield the title compound (2.49 g, 83%) as a slightly yellow stiff foam: MS (ESI+) for C23H27N7O5 m/z 482.2 (M+H)+; (ESI−) for C23H27N7O5 m/z 480.1 (M+H)−, m/z 526.1 (M+CO2H)−; HPLC purity 97%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:26]#[N:27].[Cl:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1)[NH2:32].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:28][C:29]1[CH:30]=[C:31]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([N:15]4[CH2:20][CH2:19][CH:18]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:17][CH2:16]4)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:26]#[N:27])[CH:33]=[CH:34][C:35]=1[S:36][C:37]1[N:38]([CH3:42])[CH:39]=[CH:40][N:41]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: N#Cc1cnc2cc(N3CCC(N4CCCC4)CC3)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c([N+](=O)[O-])cc23)cc1Cl
Temperature: 105 °C
Yield: 60.9 %

Procedure:
A mixture of 0.5 g (1.45 mmol) of 4-chloro-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile, 0.38 g (1.6 mmol) of 3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]aniline and 0.17 g of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at 105° C. for 1 hour. After cooling to room temperature, the mixture is stirred with 15 mL of saturated solution of sodium bicarbonate. The resulting solid is collected by filtration and washed with water. Some of the product dissolves in water, which is recovered by extracting the aqueous layer with solution of 95:5 methylene chloride/methanol. The organic layer is evaporated to provide crude product. The combined solids are purified by silica gel chromatography (gradient 95:5methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 0.52 g of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile as an orange solid, mp 220-230° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[C:33]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:42]3[CH2:43][CH2:44][N:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:40][CH2:41]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCN(c4ccccc4)CC3)cc2F)CC1
Yield: 11.8 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.48 g, 3.3 mmol) by using 1-phenylpiperazine (5.0 g) as an amine to yield the titled compound (237 mg, 12%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[NH:15][C:16](=[O:32])[C@@H:17]([NH:25][CH2:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:3]([NH:15][C:16](=[O:32])[C@@H:17]([NH:25][CH2:26][C:27]3[N:28]=[CH:29][S:30][CH:31]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:4]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1cc(-c2ccc(O)c(NC(=O)[C@H](Cc3ccccc3)NCc3cscn3)c2)ccn1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccnc(C)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
Phenol 64.D (248 mg, 0.56 mmol), methyl 2-bromoacetate (85 mg, 0.56 mmol), and Cs2CO3 (182 mg, 0.56 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 1 h. The reaction mixture was partitioned with EtOAc/H2O and the aqueous layer was exctracted with EtOAc (3×). The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The crude product was first purified on a silica gel column (12 g, 0-10% MeOH:DCM) and then by prepHPLC(C18, ACN:H2O:0.1% TFA, gradient). The desired fractions were combined, partially concentrated on a rotavap, neutralized with NaHCO3 (sat), and extracted with DCM (2×). The organic layers were combined, dried with sodium sulfate, filtered, and concentrated to yield 64 (190 mg, 66%). LC-MS (+esi, M+H+=517.2). 1H NMR (400 MHz, MeOH) δ ppm 8.86 (d, J=1.96 Hz, 1H) 8.59 (d, J=2.35 Hz, 1H) 8.42 (d, J=5.09 Hz, 1H) 7.56 (s, 1H) 7.46-7.51 (m, 2H) 7.34 (d, J=1.96 Hz, 1H) 7.19-7.30 (m, 5H) 7.09 (d, J=8.61 Hz, 1H) 4.84 (s, 2H) 3.85-4.02 (m, 2H) 3.78 (s, 3H) 3.59 (dd, J=8.41, 4.89 Hz, 1H) 3.19 (dd, J=13.69, 5.09 Hz, 1H) 2.92 (dd, J=13.69, 8.61 Hz, 1H) 2.60 (s, 3H).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].CCOCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:30][CH2:29][C:28]([O:27][CH3:26])=[O:31])=[O:24]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CNC(=O)c1cc2ccccc2n1C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
DMAP (1.222 g, 0.01 mol) and EDAC (2.680 g, 0.014 mol) were added as solids to a solution of 1-methylindole-2-carboxylic acid (1.752 g, 0.01 mol) and glycine methyl ester hydrochloride (1.256 g, 0.01 mol) in methylene chloride (30 mL) and DMP (5 mL) under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and then for 3 hours at room temperature. The reaction mixture was partitioned with ethyl acetate and 5% KHSO4 solution and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) solution and brine, dried over sodium sulfate, and concentrated to give a purple powder as crude product. Trituration of the powder with ether afforded the title product (1.734 mg, 70%). TLC: (methanol/methylene chloride 1:9): Rf=0.61; 1H NMR (CDCl3): δ7.65 (dt, J=8.0, 1.1, 1H), 7.41-7.31 (m, 2H), 7.16 (dd, J=6.6, 1.4, 1H) 6.96 (d, J=0.5, 1H), 6.67 (bs, 1H), 4.25 (d, J=5.2, 2H), 4.05 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH2:10]Br.[CH3:12][Si:13]([CH3:29])([CH3:28])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C:19]1=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Br:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][C:20]1([C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:28])([CH3:12])[CH3:29])[C:19]1=[O:27])[CH2:10]2
Reactant: BrCc1ccc(Br)cc1CBr
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(Br)cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-bis(bromomethyl)-4-bromobenzene (40.9 g, 132 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (31.5 g, 119 mmol, described in Intermediate 4) in MeOH (2 L) was added cesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h, the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H2O (1 L). The organic layer was washed with H2O (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=445 (M+1).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35]>CCOCC>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([O:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1)=[O:35]
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Reactant: OCc1cccc(Oc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)n1)c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of (6-phenoxy-2-pyridyl)methanol (0.2 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20% ether/hexane, gives (6-phenoxy-2-pyridyl)methyl 2-(2-napthyl)-3-methyl-butanoate, MS m/e 411(M+).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]1[O:16][CH:15]2[N:12]([C:13](=[O:17])[CH2:14]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([S:8]([CH2:9][CH:10]1[O:16][CH:15]2[N:12]([C:13](=[O:17])[CH2:14]2)[CH2:11]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CC2OC(CSCc3ccccc3)CN12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CC2OC(CS(=O)Cc3ccccc3)CN12
Reaction time: 1 h

Procedure:
To the solution of (3RS, 5SR)-3-Benzylthiomethyl-4-oxa-1-azabicyclo[3,2,0] heptan-7-one (926 mg) in Dichloromethane (10 ml), the solution of m-Chloroperbenzoic acid (72%, 755 mg) in Dichloromethane (30 ml) was added dropwise under ice-cooling and stirred at same condition for 1 hr. The reaction mixture was poured into aqueous Sodium hydrogen carbonate, extracted with Chloroform, and dried over Sodium sulfate. The reaction mixture was purified by column (Ethyl acetate+Acetone 5:1). Yield: 570 mg (58%). m.p. 80.5°~94.5° C. NMR (CDCl3): 2.63-3.39 (5H, m), 4.03-4.15 (3H, m), 4.59-4.77 (1H, m), 7.26-7.40 (5H, m). IR (Nujol), cm-1 : 2940, 1706, 1494.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:28][C@H:29]1[C@H:32]([CH3:33])[N:31]([S:34]([O-:37])(=[O:36])=[O:35])[C:30]1=[O:38])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:28][C@H:29]1[C@H:32]([CH3:33])[N:31]([S:34]([OH:37])(=[O:35])=[O:36])[C:30]1=[O:38]
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCO
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reaction time: 1 h

Procedure:
A mixture consisting of 5.52 g of potassium carbonate in 20 ml of water and 160 ml of 1,2-dichloroethane is brought to reflux and 15.5 mmole of N-sulfonyl benzyloxycarbonylthreonine amide, O-mesylate, tetrabutylammonium salt is added in 20 ml of 1,2-dichloroethane (20 ml used as a rinse). After refluxing for 30 minutes, the mixture is poured into a separatory funnel, diluted with 50 ml of water and 100 ml of methylene chloride and the phases split. The resulting organic phase is dried over sodium sulfate and concentrated to yield crude (3S-trans)-3-benzyloxycarbonylamino-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt. The crude azetidinone is treated in 250 ml of ethanol with 0.8 g of 5% palladium on charcoal catalyst and hydrogen is bubbled through the solution. After 90 minutes the mixture is filtered through Celite with 50 ml of ethanol used as a rinse. The addition of 1.2 ml of formic acid to this solution causes an immediate precipitation of the title zwitterion which is filtered after stirring for 1 hour to yield, after drying at 10-1 torr for 1 hour, 1.1 g of product. A second crop of product is obtained upon concentration of the filtrate and addition of more formic acid to give 1.3 g of the title zwitterion.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24][CH2:23][C:22]=12>>[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([C:2]4[CH:1]5[CH2:8][CH:5]([CH2:4][CH:3]=4)[CH2:6][CH2:7]5)=[CH:10][CH:11]=3)=[O:14])[CH2:23][C:22]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(O)c1ccc(C2=CCC3CCC2C3)cc1
Product: O=C(c1ccc(C2=CCC3CCC2C3)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 86.1 %

Procedure:
4-Bicyclo[3.2.1]oct-2-en-2-yl-benzoic acid of Step B (0.270 g, 1.18 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.240 g, 1.30 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.401 g) as white crystals, m.p. 157° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24].N1C=CC=CC=1>C(Cl)Cl>[C:23]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)=O)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and acetyl chloride with pyridine in methylene chloride there is obtained 2-chloro-4-fluoro-5-[2-methoxy -6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-phenyl acetate, m.p. 110°-112° C.;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH2:20][C:21]([O:23]CC)=[O:22])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1)#[N:2].O1CCCC1.[OH-].[K+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH2:20][C:21]([OH:23])=[O:22])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)Cc1nn2c(CC)ccc2c(-c2ccc(C#N)cc2)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CC(=O)O)nn2c(CC)ccc2c1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a solution of ethyl 4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate (77.9 mg) in ethanol (0.5 mL)-tetrahydrofuran (0.5 mL) was added 1N potassium hydroxide. The resulting solution was stirred for 2.5 hours at room temperature. The mixture was stirred for further 1 hour after adding 1N potassium hydroxide (0.04 mL). The reaction was quenched by adding 1N hydrochloric acid (0.23 mL). The volatile was evaporated off, and the resulting residue was partitioned between ethyl acetate (10 mL) and 1N hydrochloric acid (6 mL). The organic layer was washed with brine, dried, and evaporated to give [4-(4-cyanophenyl)-3-(ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]acetic acid as an yellow solid (67.7 mg, 93.4%).
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:17][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 61.9 %

Procedure:
A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid methyl ester (113 mg, 0.42 mmol) and 2-aminothiazole (84 mg, 0.84 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.4 mL, 1.69 mmol) was heated under reflux at 100° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (87 mg, 53%) as a white solid: mp 138.8–141.2° C.; EI-HRMS m/e calcd for C17H19ClN2OS (M+) 334.0906, found 334.0907.
Reaction SMILES: [C:1](Cl)(=O)C.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1>CO>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:1])=[O:14])=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccc(Cl)nc1
Solvent: CO
Product: COC(=O)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of MeOH (25 mL) was added slowly acetyl chloride (3.5 mL). After 30 min, 2-(6-chloropyridin-3-yl)acetic acid (2.5 g) was added and the resulting reaction mixture stirred at room temperature for 2 hr. Solvents were then removed. The residue was dissolved in EtOAc and washed with 10% NaHCO3. The organic phase was dried and concentrated to afford the product (2.5 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[N:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=2)[CH:5]=1.O.[OH-].[Li+]>O1CCCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:13]2[N:12]=[N:11][C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])=[N:14]2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccc(-c2nnn(Cc3ccc(OC)cc3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(-c3cccc(C(=O)O)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
The ester prepared in Step (b) (10.4 g, 0.032 mol) was suspended in aqueous tetrahydrofuran (20 mL, 1:1) followed by the addition of lithium hydroxide monohydrate (4 g, 0.096 mol) in one portion. Dissolution occurred after stirring at room temperature for 30 minute. The solution was stirred for an additional 16 hours. The THF was concentrated in vacuo and the aqueous solution was acidified to pH=1 using concentrated HCl. The resulting precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (10 g, 100%) as a white solid. 1H NMR (DMSO-d6) δ 8.6 (s, 1H), 8.3 (d, 1H), 8.1 (d, 1H), 7.7 (t, 1H), 7.4 (d, 2H), 6.9 (d, 2H), 6.9 (s, 2H), 3.7 (s, 3H) ppm.