Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][NH:24][C:25](=[O:34])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH2:19][CH2:18]1)=[O:16]>CC#N>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]2[C:25](=[O:34])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][C:2]2=[O:4])[CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)Cc2ccccc2N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3NC2=O)CC1
Temperature: 80 °C

Procedure:
Triphosgene (1.3 mmol, 0.39 g) was added portion wise to a solution of trans-4-{[2-(2-amino-phenyl)-acetylamino]-methyl}-cyclohexanecarboxylic acid methyl ester (2.6 mmol, 0.75 g) in dry CH3CN (20 mL) under argon at 0° C. Then the mixture was heated at 80° C. for 1 h with microwave irradiation. The excess of reagent was quenched by careful addition of H2O (2 mL), the solvent was removed under reduced pressure and the crude was purify by flash chromatography on silica (EtOAc-ETP 10:90 to 50:50) to obtain the titled compound (0.24 g, yield 30%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[C:20]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][CH:31]=[C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:27]=3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=1
Reactant: OB(O)c1cncc(-c2ccccc2)c1
Reactant: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3ccccc3)c2)c2cccnc2n1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
150 mg 4-chloronaphthyridine from example 1, 184 mg 5-phenyl-3-pyridyl boronic acid, 326 mg sodium carbonate and 60 mg tetrakistriphenylphosphine palladium(0) were dissolved with 15 ml dioxan, flushed with nitrogen, and heated to 90° C. After addition of 2 ml water, heating continued at 90° C. for 90 minutes to give a dark turbid solution. Work-up as in example 20 yielded after precipitation with ether 141 mg product with correct LC mass: M+H+ 412 and Rt˜2.53 min.
Reaction SMILES: [C:1]([C:4]1[CH2:8][CH2:7][CH2:6][CH:5]=1)(=[O:3])[CH3:2].[OH:9]O.[OH-].[Na+]>CO.O>[C:1]([C:4]12[O:9][CH:5]1[CH2:6][CH2:7][CH2:8]2)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)C1=CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C12CCCC1O2
Reaction time: 1 h

Procedure:
A solution of 11.02 g of 1-acetyl-cyclopent-1-ene in 50 ml of methanol is cooled to -10°C and mixed with 28.8 ml of perhydrol within 5 minutes. In the course of 1 hour, while stirring and cooling, 8.25 ml of 6N-sodium hydroxide solution are added, the whole is stirred for 1/2 hour at room temperature, diluted with 125 ml of water and extracted with pentane. The pentane solution is washed neutral with sodium chloride solution and the pentane is distilled off through a Vigreux column. The residue is distilled under 10 mm Hg pressure, to yield 1-acetyl-1,2-epoxy-cyclopentane passing over at 62° - 63°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(C(=O)N2CCc3cc(OC)ccc3C2Cc2ccc(OCc3ccccc3)cc2)cc1
Yield: 72.6 %

Procedure:
The title compound was prepared as described in Example 24.A, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol) and 4-methoxybenzoyl chloride (0.512 g, 3.0 mmol) to provide the title compound (0.717 g, 73% yield): ES−MS (m/z) 494 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>>[C:11]1(=[O:21])[N:15]([CH2:2][C:3]2[C:4]([CH2:9][Cl:10])=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccccc1CCl
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1CCl
Temperature: 50 °C

Procedure:
A mixture of α,α'-dichloroxylene (8.75 g, 50 mmol) and potassium phthalimide (5.6 g, 30 mmol) was heated to 50° C. for 24 h. Then the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate and, after usual work-up, the desired compound was obtained by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (6 g, 65%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:18]([OH:21])(=[S:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([S:20][CH2:3][CH2:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][O:15]2)=[CH:8][CH:9]=1)(=[O:21])[CH3:19]
Reactant: C=CCc1ccc(C2OCC(C)(C)CO2)cc1
Reactant: CC(O)=S
Solvent: Cc1ccccc1
Product: CC(=O)SCCCc1ccc(C2OCC(C)(C)CO2)cc1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
Following a general procedure (Lub et al. (1997) Liebigs Ann. Recueil, 2281-2288), 13 (845 mg, 3.60 mmol) and thioacetic acid (910 μL, 12.7 mmol) were dissolved in toluene (20 mL) and the solution was purged with argon for 15 min. Then AIBN (200 mg) was added and the mixture was heated to 90° C. Over a period of 23 h more AIBN (1.10 g) was added in several portions. Then aq NaHCO3 (10%, 50 mL) was added and the phases were separated. The aqueous phase was washed with ether and the combined organic phases were dried (Na2SO4). Purification by column chromatography (silica, ether/hexanes, 1:4) gave an orange oil, which solidified upon standing at −20° C. and was recrystallized from pentane to give 708 mg (63%) of colorless needles. mp 44° C. IR (neat): {tilde over (v)} 2951, 2850, 1692, 1620, 1518; 1H NMR δ 0.79 (s, 3H), 1.29 (s, 3H), 1.78-1.94 (m, 2H), 2.33 (s, 3H), 2.68 (t, 3J=7.3 Hz, 2H), 2.86 (t, 3J=7.3 Hz, 2H), 3.64 (d, 2J=11.0 Hz, 2H), 3.76 (d, 2J=11.0 Hz, 2H), 5.37 (s, 1H), 7.18, 7.42 (AA′BB′, 2×2H); 13C NMR (APT) δ 21.6 (−), 22.8 (−), 28.1 (+), 29.9 (+), 30.4 (−), 30.8 (+), 34.3 (+), 77.3 (+), 101.4 (−), 126.0 (−), 128.1 (−), 136.1 (+), 141.5 (+), 195.3 (+); GC-MS (EI) obsd 308, 307, 265, 232, 221, 204, 199, 180, 146, 133, 115, 91, 69, 43; Anal. Calcd for C17H24O3S: C, 66.20; H, 7.84; S, 10.40. Found: C, 66.19; H, 7.89; S, 10.54.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]([CH3:18])=O>CC(C)=O>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([C:11]2[CH:12]=[CH:13][C:8]([OH:14])=[CH:9][CH:10]=2)([CH3:18])[CH3:15])=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: Oc1ccccc1
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Phenol and acetone were passed through a column type reactor in which an ion exchange resin having a sulfonic group packed, in a molar ratio of phenol/acetone of 13, and a reaction solution of bisphenol A was obtained with 95% of conversion of acetone by a reaction at an inlet temperature of 55° C. and an outlet temperature of 75° C. Then, the above reaction solution was subjected to distillation to remove low boiling point substances such as unreacted acetone and water as a by-product, followed by crystallization at 50° C. by means of external intercooling to obtain a slurry containing an adduct crystal (adduct) comprising bisphenol A and phenol. The crystal adduct slurry was subjected to filtration under reduced pressure by means of a filter having a filter cloth with an aperture of 106 μm set thereto, while keeping the slurry temperature at 50° C., and the obtained crystal adduct cake was washed with refined phenol. The finally obtained adduct was a mixture with a composition of bisphenol A/phenol=7/3 (weight ratio). Impurities in the adduct at this stage were 2,4-bisphenol A=84 ppm, chroman-1=5 ppm and trisphenol=30 ppm, and no 4-isopropenyl phenol was detected. In order to hold the adduct in a molten state in a stock tank (made of SUS316) under conditions of the temperature and time as identified in Table 1, phenol was added to obtain a composition adjusted to have the composition as identified in Table 1. Then, the composition was held in a molten state under normal pressure under nitrogen sealing under conditions as identified in Table 1, and then the content of 4-isopropenyl phenol (IPP) contained in the composition was measured. The results are shown in Table 1.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([C@@H:24]5[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]5[OH:30])[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].[CH3:31][N:32]([CH3:37])[C:33](=[O:36])[CH2:34]Cl>>[OH:30][C@H:25]1[C@H:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7][N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:29][CH2:28][N:27]([CH2:34][C:33]([N:32]([CH3:37])[CH3:31])=[O:36])[CH2:26]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@@H]3CCNC[C@H]3O)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@@H]3CCN(CC(=O)N(C)C)C[C@H]3O)cc1OCC2
Yield: 80.4 %

Procedure:
Following the procedure for Example 330, trans-racemic-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-ol hydrochloride (0.15 g, 0.35 mmol) was reacted with N,N-dimethyl-2-chloroacetamide (46 mg, 0.38 mmol) to give 304 (135 mg, 80%). LCMS: RT=2.50 min, [M+H]+=480. 1H NMR 400 MHz (CDCl3) δ: 8.40 (1 H, d, J=8.26 Hz), 7.86 (1 H, s), 7.43 (1 H, s), 7.08-7.03 (1 H, m), 6.82 (1 H, d, J=1.72 Hz), 6.02 (1 H, m), 4.38 (4 H, m), 4.10 (1H, br, m), 3.38 (2H, m), 3.31 (2 H, m), 3.09 (3 H, s), 3.00 (1H, m), 2.98 (3 H, s), 2.47 (2H, m), 1.86 (2 H, m), 1.60 (6 H, dd, J=6.59, 2.76 Hz)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Si:58]([O:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]([CH2:73]O)=[N:71][CH:72]=1)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]>O1CCCC1>[Si:58]([O:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]([CH2:73][N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[N:71][CH:72]=1)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:59])[CH3:60]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CO)nc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCc1nc(C)n(Cc2ccc(CO[Si](C)(C)C(C)(C)C)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.6 g), 1,1′-(azodicarbonyl)dipiperidine (0.48 g), tributylphosphine (0.95 g), [5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]methanol (0.48 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 49%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl>[Br:33][C:3]1[N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)cn1
Solvent: ClCCl
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Imidazo[1,2-a]pyridin-6-ylmethyl-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 10, 10 mg, 0.030 mmol) was dissolved in DCM (0.3 mL) with NBS (5.9 mg, 0.033 mmol). The RM was stirred at rt for 2 h. The solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and the acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and it was extracted with EtOAc/MeOH (9:1) twice. Combined organic layers was washed with brine and dried over Na2SO4, filtered and concentrated. The solid obtained was triturated with Et2O. The precipitate was filtered off to afford the title compound as a white solid (tR 0.7 min (conditions 2), MH+=408).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl>C(O)(C)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[NH:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Clc1ccncc1Cl
Reactant: Cc1cn(N)c2ccccc12
Agent: Cl
Solvent: CC(C)O
Product: Cc1cn(Nc2ccncc2Cl)c2ccccc12

Procedure:
The title compound was prepared from 3-methyl-1H-indol-1-amine and 3,4-dichloropyridine hydrochloride in isopropanol at 80° C. for 5 hours in substantially the same manner as in Example 17. Recrystallized from ethanol, m.p. 278°-280° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Cl)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)CCCCl)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(N2CCCC2=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
The ester compound in dry THF (15 mL) was added to a suspension of NaH (352 mgs, 8.81 mmol) in dry THF (3 mL) and stirred at room temperature for 16 hours. The reaction mixture was then quenched with water (4 mL), diluted with ethyl acetate (60 mL), dried over MgSO4, filtered, and purified by flash chromatography on silica gel with stepwise elution using 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes gave 4-(2-oxo-pyrrolidin-1-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.28 g, 58.0% yield).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]2[C:11]3[NH:12][C:13]([C:15]([O:17]CC)=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+].CO>C1COCC1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:11]3[NH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(c1ccc(-c3ccccc3)cc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C(c1ccc(-c3ccccc3)cc1)CC2
Yield: 30.1 %

Procedure:
The title compound was synthesized from ethyl 6-(biphenyl-4-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.1776 g, 0.54 mmol, 1 equiv) and sodium hydroxide (1.36 mL, 13.6 mmol, 10 M, 25 equiv), according to General Procedure 7. A 4-5:1 mixture of methanol (MeOH) and THF (5-6 mL) was used. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 60% methanol and increasing to 100% over 7 minutes) afforded the title compound (49.3 mg, 30%) with purity by HPLC of 96.6% (UV). LCMS m/e 302.2 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.24-2.37 (m, 1H) 2.66 (ddd, J=8.74, 5.64, 5.53 Hz, 1H) 2.72-2.82 (m, 1H) 2.97 (dd, J=12.96, 4.98 Hz, 1H) 4.31 (dd, J=8.44, 5.37 Hz, 1H) 6.68 (s, 1H) 7.20 (d, J=8.20 Hz, 2H) 7.27-7.34 (m, 1H) 7.40 (t, J=7.63 Hz, 2H) 7.56 (dd, J=15.79, 7.71 Hz, 4H).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].Cl.[NH2:11][C@@H:12]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]([O:15][CH3:16])=[O:14]>O1CCCC1>[CH2:8]([O:7][C:5]([CH2:4][NH:1][C:2]([NH:11][C@@H:12]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]([O:15][CH3:16])=[O:14])=[O:3])=[O:6])[CH3:9]
Reactant: CCOC(=O)CN=C=O
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
5.13 ml (45.8 mmol) of ethyl isocyanatoacetate are added dropwise to a suspension of 10 g (45.8 mmol) of the compound (3.3) in 100 ml of tetrahydrofuran and the mixture is left to stir at room temperature for 3 h; the solvent is removed in vacuo and the residue is chromatographed through silica gel using ethyl acetate/methanol=20/1. 13.44 g (85%) of (3.4) are obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]=1[CH2:17]O.S(Cl)([Cl:21])=O>>[Cl:21][CH2:17][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(-c2ccc(C(F)(F)F)cc2)c1CO
Reactant: O=S(Cl)Cl
Product: Cc1onc(-c2ccc(C(F)(F)F)cc2)c1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 5-methyl-3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (1.75 g) and thionyl chloride (5.0 ml) was stirred at 0° C. for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated to give 4-chloromethyl-5-methyl-3-(4-trifluoromethylphenyl)isoxazole (1.50 g, yield 80%). The crystals were recrystallized from diisopropyl ether. melting point: 91–92° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:14][O:15][CH:16]([O:20][CH3:21])N(C)C>>[CH3:14][O:15][CH:16]([O:20][CH3:21])[N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:9][CH2:10]1
Reactant: c1cn(CCC2CCNCC2)cn1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(CCn2ccnc2)CC1
Yield: 87 %

Procedure:
The free base 4[2-(imidazol-1-yl)ethyl]piperidine (5.1 g, 28.7 mM) and dimethylformamide dimethyl acetal (23 ml) was heated at 100° C. for 6 hours. Removal of the excess of dimethylformamide dimethyl acetal gave 4-[2-(imidazol-1-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal (6.32 g, 87%) which was dissolved in CH2Cl2 (27 ml) and added to the mixture of 6-aminopenicillanic acid (5.6 g, 258 mM) and diisopropylethylamine (3.41 ml) in CH2Cl2 (100 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr. and room temperature for 3 hrs. The solvent was then removed and water (100 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6-beta)]-6-[[[4 -[2-(1H-imidazol-1-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrate hydrochloride (1.8 g, 16% yield).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH:12](OC)([O:15][CH3:16])[O:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COC(OC)OC
Reactant: CCCCCCCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCCCCCCC(OC)OC

Procedure:
Decanal dimethyl acetal was prepared by reacting 796 g decanal with 763.5 g trimethyl orthoformate in the presence of 1.97 g p-toluene sulfonic acid dissolved in 6.07 g methanol at a temperature of 45° C. for a period of time of 0.33 hours. The resulting product was washed with an aqueous 2.5% sodium bicarbonate solution, and then with water; dried over anhydrous sodium sulfate; filtered through CELITE®/sodium sulfate and distilled at 92–98° C. at 4.36–4.97 mm Hg. Then, into a 2 liter reaction flask equipped with stirrer, thermometer, heating mantle, addition funnel, vacuum apparatus, and reflux condenser the following ingredients were added at 17° C.:
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[O:23][CH2:24][CH3:25])=[CH:4][CH:3]=1.N[C:27]1C(O)=C(S(N(CC)OC)(=O)=O)C=CC=1>>[CH2:24]([O:23][C:18]1[C:19](=[O:22])[C:20](=[O:21])[C:17]=1[NH:16][C:5]1[C:6]([OH:15])=[C:7]([S:8]([N:11]([CH2:12][CH3:27])[O:13][CH3:14])(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=1)[CH3:25]
Reactant: CCN(OC)S(=O)(=O)c1cccc(N)c1O
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Product: CCOc1c(Nc2cccc(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O

Procedure:
This compound was prepared analogously to 6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A step 3) by replacing 3-amino-6-chloro-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide with 3-amino-N-ethyl-2-hydroxy-N-methoxybenzenesulfonamide (step 1). [M+H]+ 371
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].O=P(Cl)(Cl)[Cl:17]>C(#N)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:17])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)ccnc2cc1Br
Solvent: CC#N
Product: COc1cc2c(Cl)ccnc2cc1Br
Temperature: 90 °C

Procedure:
To a flask charged with 7-bromo-6-methoxyquinolin-4-ol (0.595 g, 2.342 mmol) was added Acetonitrile (11.71 ml) and POCl3 (0.229 ml, 2.459 mmol) and the resulting suspension heated to 90° C. for 2.5 hr affording a brown solution and near complete conversion to desired product. The mixture was added to a cooled solution of sat. aq. NaHCO3 and extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The organic phase was dried under reduced pressure and purified with an 40 g HP silicycle column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording isomer separation, both obtained as white solids. NMR indicated that the first eluting peak was the desired isomer, obtained as an off-white solid 7-bromo-4-chloro-6-methoxyquinoline (0.240 g, 0.881 mmol, 37.6% yield). The second peak (looked like about 60:40 ratio of product 1 to 2 by MPLC trace) was not isolated. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.66 (d, J=4.7 Hz, 1H), 8.38 (s, 1H), 7.49 (d, J=4.7 Hz, 1H), 7.47 (s, 1H), 4.08 (s, 3H). m/z (ESI) 272.1 (M+H)+.