Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C2C(=CC=1)NC1C3C=CNC=3CCC2=1.C[O:20][C:21]1[CH:22]=[C:23]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]1[C:28]3[CH:35]=[CH:36][N:37]([CH3:38])[C:27]=3[CH2:26][CH2:25][C:24]2=1>>[CH3:38][N:37]1[C:27]2[CH2:26][CH2:25][C:24]3[C:23]4[C:31]([N:30]([CH3:34])[C:29]=3[C:28]=2[CH:35]=[CH:36]1)=[CH:32][CH:33]=[C:21]([OH:20])[CH:22]=4
Reactant: COc1ccc2c(c1)c1c(n2C)-c2ccn(C)c2CC1
Agent: COc1ccc2[nH]c3c(c2c1)CCc1[nH]ccc1-3
Product: Cn1ccc2c1CCc1c-2n(C)c2ccc(O)cc12

Procedure:
Following the procedure described in Example 125, using 7-methoxy-3,4,5,10-tetrahydro-pyrrolo[3,2-a]carbazole (474 mg, 2.0 mmol) as the starting material, 7-methoxy-3,10-dimethyl-3,4,5,10-tetrahydro-pyrrolo[3,2-a]carbazole as prepared as a crude product. The crude product was then reacted according to the procedure as described in Example 126 to yield the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH2:28][C@H:29]([CH3:32])[CH2:30][OH:31]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:28][C@H:29]([CH3:32])[CH2:30][OH:31])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: C[C@@H](N)CO
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N[C@H](C)CO)cc3)cc12

Procedure:
(2R)-2-(1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethylamino)propan-1-ol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and (R)-2-aminopropan-1-ol (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6): δ: 8.94 (m, 2H), 8.45 (m, 1H), 7.64 (d, 2H), 7.59 (s, 1H), 7.55 (br s, 2H), 7.41 (m, 3H), 4.65 (m, 1H), 3.81 (m, 1H), 3.35 (t, 2H), 3.25 (t, 2H), 2.56 (s, 3H), 1.73 (m, 3H), 1.29 (d, 3H), 1.23 (d, 3H). LRMS [M+H]=415.2
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=2)[N:3]=1.[S:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)CCC>[S:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][N:27]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=3)[N:3]=2)[CH2:26][CH2:25]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Cc1ccc2nc(Cl)nc(NCCNC(=O)OC(C)(C)C)c2c1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of tert-butyl {2-[(2-chloro-6-methylquinazolin-4-yl)amino]ethyl}carbamate (460 mg, 1.366 mmol) in n-butanol (6 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (248 mg, 1.50 mmol) and triethylamine (276 mg, 2.732 mmol). The mixture was heated with stirring at 100° C. in a sealed tube for 4 hours, and then concentrated in vacuo. The residue was purified by flash column chromatography to afford 350 mg of the desired product as a white solid (yield was 55%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1O[Si](C)(C)C(C)(C)C
Yield: 86.6 %

Procedure:
Dissolve 4-bromo-2,6-dimethylphenol (30.16 g, 150 mmol) and imidazole (26.6 g, 390 mmol) in CH2Cl2. Added t-butyldimethylchlorosilane (36.17 g, 240 mmol) and stirred mechanically for 3 h. The solids were vacuum filtered and the filtrate concentrated. Suspended the resulting residue in water and extracted with ethyl acetate (2×150 mL). The combined organic portions were washed with water (150 mL) and brine (150 mL) and then dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. Purify on a Waters Prep 2000 LC (hexanes) to give 40.96 g of the title compound as a clear liquid. 1H NMR(CDCl3): δ6.91 (s, 2H), 2.00 (s, 6H), 0.86 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:24]>O1CCOCC1>[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CC1CCNCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of [1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid (200 mg) in dioxane (1 mL) was added a 4 M hydrogen chloride dioxane solution (1 mL). The reaction liquid was stirred at room temperature for 15 hours, and then concentrated under reduced pressure to obtain piperidin-4-yl acetic acid hydrochloride (140 mg) as a white solid.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:20][C:21]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)=[C:16]([Cl:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.CO>Cl.O>[CH2:27]([N:24]1[CH2:23][CH2:22][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([O:20][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][C:16]=2[Cl:19])[C:9](=[O:8])[NH:10][CH:11]=[CH:12]3)[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1cc2c(OCc3ccccc3)nccc2cc1OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]ccc2cc(OC3(c4ccccc4)CCN(Cc4ccccc4)CC3)c(Cl)cc12
Reaction time: 8 h
Yield: 12.8 %

Procedure:
920 mg of 1-Benzyloxy-6-(1-benzyl-4-phenyl-piperidin-4-yloxy)-7-chloro-isoquinoline (68) were suspended in 1M HCl and dissolved by addition of methanol. After stirring overnight, the solution was diluted with water, extracted with methyl tert. butyl ether and the aqueous layer was lyophilized. The product was purified by crystallization to give 98 mg of the desired product as a white solid as the hydrochloride. Rt=1.46 min (Method A). Detected mass: 445.3 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+]>CN(C)C=O>[C:9]1([S:15][C:2]2[N:3]=[C:4]([Cl:8])[CH:5]=[N:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cncc(Sc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2,6-dichloropyrazine (0.100 mol) and freshly distilled thiophenol (0.100 mol) in 200 ml. N,N-dimethylformamide is treated with five grams of sodium hydride (50% dispersion in Nujol) gradually with vigorous stirring under nitrogen at room temperature. After 3 hr. the mixture is concentrated in vacuo, and the residue partitioned between water and benzene. The benzene extract is washed with water, dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil which is the crude title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:33][CH3:34])=[C:20]([CH2:24][N:25]4[CH2:28][CH:27]([C:29]([O:31]C)=[O:30])[CH2:26]4)[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[C:19]([CH2:33][CH3:34])=[C:20]([CH2:24][N:25]4[CH2:26][CH:27]([C:29]([OH:31])=[O:30])[CH2:28]4)[CH:21]=[CH:22][CH:23]=3)=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of methyl 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D87) (126 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (21.2 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (E38) (60 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.05 (3H, t), 1.36 (6H, d), 2.78 (2H, d), 3.64 (1H, m), 4.27 (4H, m), 4.54 (2H, m), 4.91 (1H, m), 7.42 (4H, m), 7.87 (1H, s), 8.22 (1H, dd), 8.28 (1H, d), 10.21 (1H, br s), 13.19 (1H, br s). δF (DMSO-d6, 376 MHz): −73.6. MS (ES): C26H27N3O3S requires 461. found 462.3 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[NH2:16].Cl.[CH:19](N)=[NH:20]>C(O)C>[Cl:15][CH2:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[N:20][CH:19]=[N:16]2)=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: N=CN
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1N
Agent: Cl
Solvent: CCO
Product: COc1cc2c(O)ncnc2cc1OCCCl
Temperature: 130 °C
Yield: 95.6 %

Procedure:
To a solution of 2-amino-4-(2-chloro-ethoxy)-5-methoxy-benzoic acid methyl ester (2.4 g, 9.24 mmol) in ethanol was added formamidine hydrochloride (2.97 g, 36.96 mmol). The mixture was heated at 130° C. in sealed tube for 8 h. The precipitate formed was filterd and washed with ethanol and dried to afford the pure compound 7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ol (2.25 g, 96%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.45 (s, 2H), 7.15 (s, 1H), 4.40 (t, 2H), 4.00 (t, 2H), 3.88 (s, 3H), LC-MS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17](=[O:18])[CH2:16][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(F)cc1F
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1ccc(F)cc1F
Reaction time: 16 h

Procedure:
A suspension of 2,4-difluoroaniline (15.0 g) and sodium bicarbonate (19.5 g) in methyl chloroacetate (15.2 ml) was stirred at 90°-100° under nitrogen for 16 h. Work up according to the method of Intermediate 11 gave an oil (14.1 g) which was purified by FCC on triethylamine deactivated silica eluting with chloroform:petroleum ether (1:8) to give the title compound (8.75 g) as an oil, t.l.c. on triethylamine deactivated silica (chloroform:petroleum ether, 1:8) Rf 0.21.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]([CH:24]([CH3:26])[CH3:25])[C:16]3=[O:27])[N:10]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:5]1[C:13]2[N:12]=[C:11]([CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]([CH:24]([CH3:25])[CH3:26])[C:16]3=[O:27])[N:10]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1cccc2c1nc(Cn1c(=O)n(C(C)C)c3ccccc31)n2CCC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CO)cccc21
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
To a cooled (0° C.) solution of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-4-carboxylic acid methyl ester (2.36 g, 5.44 mmol) in THF (33 mL) was slowly added 1M LiAlH4 in THF (5.46 mL, 5.46 mmol) under nitrogen. The mixture turned bright yellow and was stirred for 10 min at the same temperature. The mixture was quenched with satd. Na/K tartrate (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine and dried with MgSO4. The residue after concentration was purified by flash chromatography (eluent dichloromethane: acetone 4:1, 3:1, 5:2, 2:1) to give 1-[4-Hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (1.21 g, 55%) as a white foam:
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35](CC3C=CC(OC)=CC=3)[N:36]=[C:4]2[N:3]=1.C(O)(C(F)(F)F)=[O:47]>>[OH:47][C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:24])=[O:25])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][NH:35][N:36]=[C:4]2[N:3]=1
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc(=O)c2c(Cl)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Reactant: O=C(O)C(F)(F)F
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc(=O)c2c(O)nc3n[nH]cc3c2[nH]1
Temperature: 25 °C

Procedure:
A solution of 1-[[3-[5-Chloro-4,8-dihydro-8-[(4-methoxyphenyl)methyl]-4-oxo-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-yl]-4-propoxyphenyl]sulfonyl]-4-ethylpiperazine (20 mg) in TFA (8 mL) was heated at 70° C. under nitrogen for 2 h. After cooling to rt, the mixture was subjected to preparative HPLC to give the titled compound (15 mg). LC:2.65′ (Gradient 1); MH+: 514.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][C:20]1([CH2:24][OH:25])[CH2:23][O:22][CH2:21]1>>[CH3:19][C:20]1([CH2:24][O:25][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][O:22][CH2:21]1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: CC1(CO)COC1
Product: CC1(COc2ncc(C#Cc3ccccc3)cn2)COC1

Procedure:
The title compound, yellow solid, MS: m/e=281.1 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and (3-methyl-oxetan-3-yl)-methanol by using Cs2CO3 as base and dioxane as solvent for 16 hours at 100° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>C1(C)C=CC=CC=1.CN1C(=O)CCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(Oc2ccc(C#N)cc2)c(C)c1
Temperature: 140 °C
Yield: 97 %

Procedure:
Into a 250 mL three-necked, round-bottomed flask equipped with a magnetic stir-bar, nitrogen inlet, and a condenser, 2,4,6-trimethylphenol (6.00 g, 44.1 mmol), 4-fluorobenzonitrile (5.34 g, 44.1 mmol), potassium carbonate (7.30 g, 52.8 mmol), and a mixture of NMP (100 mL) and toluene (60 mL) were placed. The reaction mixture was then heated and maintained around 140° C. for 8 h with vigorous nitrogen flow. The dark solution was filtered while it was warm and the filtrate was poured into distilled water containing 5% hydrochloric acid. The solution was separated into organic layer and aqueous layer. The organic layer was diluted with dichloromethane and separated. The solvent was removed to dryness. Light brown oily residue was freeze-dried to afford 10.1 g (97% yield): Anal. Calcd. for C16H15NO: C, 80.98%; H, 6.37%; N, 5.90%; O, 6.74%. Found: C, 80.31%; H, 6.37%; N, 5.75%; O, 6.46%. FT-IR (KBr, cm−1): 2226 (C≡N stretch). Mass spectrum (m/e): 237 (M+, 100% relative abundance), 222, 204, 194. 1H NMR (CDCl3, ppm) δ 2.05 (s, 6H, CH3), 2.30 (s, 3H, CH3), 6.81-6.84 (d, 2H, Ar), 6.91 (s, 2H, Ar), 7.53-7.56 (d, 2H, Ar). 13C NMR (CDCl3, ppm) δ 16.10, 20.79, 115.48, 129.07, 129.15, 129.88, 130.48, 134.25, 147.84, 150.03, 161.44.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>C(O)C.O>[CH:1]1([CH2:7][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
A solution comprised of diethyl 2-cyclohexylmethylmalonate (12.817 g, 50 mmol) in ethanol (100 mL) was treated with a solution of comprised of lithium hydroxide (1.198 g, 50 mmol) in water (50 mL) and the mixture was stirred for approximately 12 hours at ambient temperature. Solvent was removed by evaporation and the residue was diluted with water (50 mL). The dilution was extracted with diethyl ether (2×). The aqueous layer was cooled to 0° C., acidified to pH 1.5 with 1N hydrochloric acid (50 mL), saturated with solid sodium chloride and then extracted with ethyl acetate (2×). The combined ethyl acetate extracts were dried (MgSO4) and concentrated. The residue was dried to provide 3-cyclohexyl-2-ethoxycarbonylpropionic acid (8.52 g, 37 mmol) as an oil.
Reaction SMILES: C1(SC)C=CC=CC=1.[OH:9][C:10]1[CH:11]=[C:12]([NH:17][S:18]([NH:21][C:22]([N:24]2[CH2:27][C@H:26]([NH:28]C(=O)OCC3C=CC=CC=3)[C:25]2=[O:39])=[O:23])(=[O:20])=[O:19])[CH:13]=[CH:14][C:15]=1[OH:16].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:28][C@H:26]1[CH2:27][N:24]([C:22]([NH:21][S:18]([NH:17][C:12]2[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([OH:9])[CH:11]=2)(=[O:20])=[O:19])=[O:23])[C:25]1=[O:39]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Nc2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)Nc2ccc(O)c(O)c2)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 10 ml of thioanisole and 40 ml of trifluoroacetic acid was cooled to 0° C., and 8.36 g (20 mmol) of (S)-[1-[[[[(3,4-dihydroxyphenyl)amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added. The reaction mixture was stirred overnight at room temperature and the trifluoroacetic acid evaporated in vacuo. The oily residue was triturated with ether and the precipitate filtered off by suction. The crude product was washed with ether, dichloromethane and isopropanol and dried in vacuo; yield: 6.86 g.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:25])[C:9]([O:23]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>ClCCl>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]([F:21])([F:22])[F:20])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:25])[C:9]([OH:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C(F)(F)F)=C1c1ccc(OC)c(Cl)c1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(C(F)(F)F)=C1c1ccc(O)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 1.58 h

Procedure:
A solution of 9a-butyl-8-chloro-7-methoxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (32 mg, 0.086 mmol) in anhydrous dichloromethane (0.86 mL) was cooled in a dry ice-acetone bath (−78° C.) and the solution was treated with 1M boron tribromide in dichloromethane (0.258 mL, 0.258 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 95 minutes. Additional 1M BBr3 in CH2Cl2 (0.5 mL, 0.5 mmol) was added and the mixture was stirred at room temperature for an additional 100 minutes. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (3 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The oily residue was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 5% EtOAc in CH2Cl2. The product band was eluted with EtOAc, the eluent evaporated under vacuum, and the residue lyophilized from benzene to afford 9a-butyl-8-chloro-7-hydroxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:38])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30]CC4C=CC=CC=4)=[CH:26][CH:25]=3)[CH3:18])=[CH:15][C:9]=2[O:8][CH2:7]1)=[O:5])C>C(O)C.[C].[Pd]>[OH:38][C@H:21]([CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[CH2:20][NH:19][C@H:17]([CH3:18])[CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[O:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7][O:8][C:9]=2[CH:15]=1
Reactant: CCOC(=O)[C@H]1COc2cc(C[C@@H](C)NC[C@H](O)COc3ccc(OCc4ccccc4)cc3)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](Cc1ccc2c(c1)OC[C@H](C(=O)O)O2)NC[C@H](O)COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 6-[2-(R)-[3-(4-benzyloxyphenoxy)-2-(S)-hydroxypropylamino]propyl-2,3-dihydro-1,4-benzodioxine-2-(R)-carboxylic acid ethyl ester obtained in Example 11 (270 mg) in ethanol (20 mL) was added 10% palladium-carbon (50 mg). This solution was stirred under hydrogen atmosphere at room temperature for 16 hours. After filtration through Celite, the filtrate was concentrated under reduced pressure. A solution of the residue in 1N—HCl (8 mL) was stirred at 100° C. for 5 hours. After allowing to cool to room temperature, it was concentrated to dryness under reduced pressure. The residue was dissolved in water/acetonitrile=1/1 (v/v) (10 mL), and the pH was adjusted to 6.3 by addition of saturated aqueous sodium bicarbonate. It was concentrated under reduced pressure, the residue was purified by HP column chromatography and the title compound (209 mg) was obtained from the effluent with water/methanol=40/60 (v/v). Yield: 85%
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[C:19](=[O:20])[N:11]2[CH:12]([C:17]#[N:18])[C:13]([CH3:16])([CH3:15])[S:14][C@H:10]12.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41])([NH:8][CH:9]1[C:19](=[O:20])[N:11]2[CH:12]([C:17]#[N:18])[C:13]([CH3:15])([CH3:16])[S:14][C@H:10]12)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C#N
Reactant: Cc1ccccc1C(Cl)(c1ccccc1)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(NC1C(=O)N2C(C#N)C(C)(C)S[C@H]12)(c1ccccc1)c1ccccc1C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Triethylamine (444 mg., 4.4 mmole) is added to a suspension of 6-amino-2,2-dimethyl-3-cyanopenam (468 mg., 2 mmole) in methylene chloride (20 ml.) and the resulting mixture cooled to -10° C. A solution of α,α-di(2-methylphenyl)benzyl chloride (614 mg., 2 mmole) in methylene chloride (12 ml.) is added over a ten minute period and the resulting yellow solution stirred for one hour at -10° C. The cooling bath is removed and the mixture stirred and allowed to warm to room temperature. It is stirred for two hours at room temperature and is then concentrated under reduced pressure to a brown sludge. The sludge is chromatographed on a silica gel column (70-23- mesh., 380 × 20 mm. column) using chloroform as eluent. Fractions (15 ml. each) are collected. Fractions 13-19 are combined and concentrated in vacuo to dryness to give 155 mg. of product as a foam.