Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H:10]([NH:15][C@H:16]1[C@H:24]2[C@H:19]([C@@H:20]3C[C@H:23]2[CH:22]=[CH:21]3)C(=O)O1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[ClH:28]>O>[ClH:28].[CH2:16]([NH:15][C@@H:10]([C:9]([OH:27])=[O:8])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:24]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C[C@@H](N[C@@H]1OC(=O)[C@@H]2[C@H]1[C@@H]1C=C[C@H]2C1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)C[C@@H](NCc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 2 g of the product of Example 1, 15 ml of demineralized water and 1.5 ml of hydrochloric acid was stirred at 20° C. for one hour and was then heated at 60° C. for one hour and then cooled to 20° C. 15 ml of water were added to the mixture and the mixture was extracted with methylene chloride. The organic phase was washed with aqueous N sodium hydroxide solution and then with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure. The residue was taken up in 10 ml of ether and a current of hydrogen chloride was slowly bubbled through the solution. The mixture was vacuum filtered to obtain 800 mg of benzyl D-leucine hydrochloride melting at 137° C. and having a specific rotation of [α]D20 =+3.5° (c=1% in 0.1 N hydrochloric acid).
Reaction SMILES: Cl[O-].[Na+].[CH:4]1([CH2:7][CH:8]([O:12][CH2:13]/[CH:14]=[N:15]/[OH:16])[CH2:9][CH:10]=[CH2:11])[CH2:6][CH2:5]1.C(N(CC)CC)C>ClCCl.O>[CH:4]1([CH2:7][C@@H:8]2[O:12][CH2:13][C:14]3=[N:15][O:16][CH2:11][C@@H:10]3[CH2:9]2)[CH2:5][CH2:6]1
Reactant: C=CCC(CC1CC1)OC/C=N/O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C1O[C@@H](CC2CC2)C[C@H]2CON=C12

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 100 mL, 78.6 mmol) was added drop-wise to a solution of (1E)-2-[(1-cyclopropylpent-4-en-2-yl)oxy]-N-hydroxyethanimine (C68) (10 g, 55 mmol) and triethylamine (0.47 mL, 3.4 mmol) in dichloromethane (200 mL) that was immersed in a room temperature water bath. The rate of addition was adjusted to maintain the internal temperature of the reaction between 19.5° C. and 22.8° C. After completion of the addition, the reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided the product as a yellow oil. Yield: 3.8 g, 21 mmol, 39%. The indicated relative stereochemistry of compound C69 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. LCMS m/z 182 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 4.69 (d, J=13.6 Hz, 1H), 4.62 (dd, J=10.0, 8.0 Hz, 1H), 4.19 (d, J=12.8 Hz, 1H), 3.73-3.80 (m, 1H), 3.54-3.58 (m, 1H), 3.47-3.40 (m, 1H), 2.30 (dd, J=12.8, 6.4 Hz, 1H), 1.64 (quintet, J=6.8 Hz, 1H), 1.49 (q, J=11.7 Hz, 1H), 1.20-1.29 (m, 1H), 0.75-0.79 (m, 1H), 0.44-0.51 (m, 2H), 0.03-0.11 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C.C(O)(=O)C>[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:1][C:2]1[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][C:3]=12
Reactant: NNc1ccccc1
Reactant: O=C1Cc2ccccc2C1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Temperature: 85 °C

Procedure:
A modified version of the method reported by Okamoto, et al. was employed. Okamoto, T. A.; Kobayashi, S. M.; Yamamoto, H. N., DE1952019, 1970. To a solution of 2-indanone (16.3 g, 123 mmol) in ethanol (80 mL) was added phenyl hydrazine (12.1 mL, 123 mmol) followed by acetic acid (12 drops) at room temperature. While stirring, the solution was warmed to reflux (oil bath at 85° C.) for 15 minutes at which point it was removed from the oil bath and allowed to cool to room temperature. Light yellow needle-like crystals precipitated from the solution. Upon cooling to room temperature, the solution was cooled to 0° C. for 30 minutes. The crystals were filtered via vacuum filtration and used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH3:14][C:15]([NH2:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:22][C:15]([CH3:21])([CH3:14])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)CC(C)(C)C
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g, 0.20 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added 1,1,3,3-tetramethylbutylamine (0.066 g, 0.406 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the titled compound. MS (DCI) m/z 290 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2.02 (10H, m), 2.07-2.21 (2H, m), 2.45-2.50 (2H, m), 3.03-3.5 (6 Hs), 3.76 (1H, d), 3.78-4.53 (2H, m), 4.53-4.55 (1H, t), 5.06 (1H, m), 5.1 (1H, m).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][C:41]([CH2:60][OH:61])([CH3:59])[CH2:40]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][C:41]([CH2:60][OH:61])([CH3:59])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(CO)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(CO)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 37.7 %

Procedure:
To a solution of 51 (13 mg, 15.5 μmol) in a mixture of MeOH (1.2 mL) and THF (0.4 mL) was added Pd(OH)2/C (15 mg) and 1,2-dichlorobenzene (20 μL). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified via preparatory TLC (5% MeOH in DCM) to give 52 (2.8 mg, 38%). 1H NMR (300 MHz, CD3OD) δ 7.34 (s, 1H), 7.07 (s, 4H), 6.81 (s, 1H), 3.97 (s, 2H), 3.85 (dd, J=2.1, 11.1 Hz, 1H), 3.67-3.74 (m, 3H), 3.44-3.56 (m, 3H), 3.23 (t, J=9.3 Hz, 1H), 2.58 (q, J=7.5 Hz, 2H), 2.45 (d, J=15.3 Hz, 1H), 2.16 (d, J=15.6 Hz, 1H), 1.42 (s, 3H), 1.19 (t, J=7.5 Hz, 3H). LCMS m/z 479 (M+H), 501 (M+Na).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[CH3:24][C:25]([OH:34])([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:24][C:25]([CH3:33])([O:34][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(O)c1ccc(F)cc1
Product: CC(C)(Oc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1)c1ccc(F)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with α,α-dimethyl-4-fluorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(α,α-dimethyl-4-fluorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): 1H-NMR 500 MHz (CDCl3): δ 1.91 (s, 6H), 6.90-7.00 (m, 5H), 7.20-7.25 (m, 3H), 7.30 (s, 1H), 7.41-7.45 (m, 2H), 8.40 (s, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.[Si:12]([O:19][CH2:20][C@H:21]1[O:27][C@H:25]([CH3:26])[CH:24]=[CH:23][C@@H:22]1[OH:28])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>ClCCl>[Si:12]([O:19][CH2:20][C@H:21]1[O:27][C@H:25]([CH3:26])[CH:24]=[CH:23][C@@H:22]1[O:28][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: C[C@@H]1C=C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: N#CC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1C=C[C@H](OC(=N)C(Cl)(Cl)Cl)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.00 ml, 6.83 mmol) was added to a dichloromethane (22 ml) solution of the compound (6.83 mmol) obtained in Step 2 above combined with trichloroacetonitrile (0.82 ml, 8.20 mmol) under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure and the residue was dissolved in chloroform and added dropwise into n-hexane:ethyl acetate [4:1 (v/v)] mixed solvent. The resulting insoluble matter was removed by filtration through celite and the solvent in the filtrate was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=99:1→10:1 (v/v)] to give 2.1 g (77%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:5]2[C:23](=[O:36])[CH:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:4]2[C:3]1=[O:37].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[OH:37][CH:3]1[C@@H:4]2[CH:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23](=[O:36])[N:5]2[CH:6]([C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH:2]1[CH3:1]
Reactant: CC1C(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Product: CC1C(O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
According to the procedures detailed in Example 3, benzhydryl 2-methyl-1-oxo-6-(2-phenoxyacetamido)carbapenam-3-carboxylate (138 mg., 0.28 mmole) in 15 ml. of methylene chloride was reduced with tetrabutylammonium borohydride (18 mg., 0.07 mmole) at -78° C., monitored and isolated as a washed, dried methylene chloride solution of benzhydryl 1-hydroxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate [Rf 0.24 (4:1 chloroform:ethyl acetate)]. If desired, the product is further isolated by evaporation to dryness in vacuo.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.O(Cl)[Cl:24].O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([Cl:24])=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: ClOCl
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Di-cyclopropylmethyl-8-nitro xanthine (6 g, 0.023 mol) was dissolved in dimethylformamide (20 ml) and reacted with phosporous oxychloride (14 g) for 1 hour at 120° C. The mixture was then treated with water and stirred for 1 hour at room temperature. The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yield 2.5 g (40%), m.pt. 220° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[CH:12]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:6][C:7]1[S:8][C:9]([C:23]2([OH:25])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:24]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:10][CH:11]=1
Reactant: Cc1cccs1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)c3ccccc3-c3ccccc32)s1
Temperature: 0 °C

Procedure:
A 2.5M solution of butyllithium in hexanes (9.6 mL, 24 mmol), (Aldrich) was added dropwise to a solution of 2-methylthiophene (1.96 g, 20 mmol) in anhydrous tetrahydrofuran (10 mL) with stirring under argon at 0° C. The mixture was stirred at room temperature for 0.5 h and then cooled to 0° C. A solution of 9-fluorenone (3.6 g, 20 mmol), (Aldrich) in anhydrous tetrahydrofuran (5 mL) was added dropwise to the mixture with stirring and cooling at 0° C. The reaction mixture was stirred at room temperature for 1 h, poured into a saturated solution of ammonium chloride (5 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were washed with brine (10 mL), dried (MgSO4), the solvent evaporated and the residue chromatographed on silica gel column with 10% ethyl acetate in hexanes to give the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=2)=[O:10])=[C:4]([CH3:29])[CH:3]=1.[Cl:30][C:31](OCCl)=O>ClCCl.CN(C)C=O.C(OCC)(=O)C>[Cl:30][CH2:31][N:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[CH:22][C:7]=2[O:6][C:5]2[CH:27]=[CH:28][C:2]([F:1])=[CH:3][C:4]=2[CH3:29])=[CH:13][C:14]1=[O:18]
Reactant: O=C(Cl)OCCl
Reactant: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(F)ccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1ccn(CCl)c(=O)c1

Procedure:
A solution of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) (406.3 mg, 1.0 mmol) and chloromethyl chloroformate (106.7 μL, 1.2 mmol) in dichloromethane (3.5 mL) and N,N-dimethylformamide (0.3 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried with Na2SO4, filtered and evaporated to dryness to give N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide that was used in the next step without further purification. ESI-MS m/z calc. 454.07, found 455 (M+1)+; Retention time: 0.73 minutes (1 minute run).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][C:12]([C:14]1[C:15]([CH3:23])=[C:16]([C:19]([F:22])=[CH:20][CH:21]=1)[C:17]#[N:18])=[O:13].[C:24]([N:31]1[CH2:36][CH2:35][NH:34][C@H:33]([CH2:37][OH:38])[CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.CCOC(C)=O>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][N:34]2[C@H:33]([CH2:37][O:38][C@@:12]([C:14]3[CH:21]=[CH:20][C:19]([F:22])=[C:16]([C:17]#[N:18])[C:15]=3[CH3:23])([OH:13])[CH2:11]2)[CH2:32]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: Cc1c(C(=O)CBr)ccc(F)c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c([C@]2(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropylethylamine (44.0 mL, 252 mmol) was added to a stirred, room temperature mixture of 72 wt % 3-(2-Bromo-acetyl)-6-fluoro-2-methyl-benzonitrile (69 g, 194 mmol) and (S)-4-N-Boc-2-hydroxymethyl-piperazine (42.0 g, 194 mmol) in THF (1000 mL) and the mixture was stirred at room temperature for 18 h. The reaction was diluted with 1 L EtOAc, washed 2× with 500 mL 10% w/w NaHCO3 aqueous solution, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (40-80% EtOAc/Hexanes, linear gradient), to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[CH:5]=[C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:7]2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][C:2]1[CH:11]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[CH:5]=[C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:7]2
Reactant: C1COCCN1
Reactant: O=c1cc(-c2ccccc2)oc2cc(OS(=O)(=O)C(F)(F)F)cc(O)c12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2)oc2cc(N3CCOCC3)cc(O)c12
Temperature: 25 °C
Yield: 22.1 %

Procedure:
A solution of trifluoromethanesulfonic acid 5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl ester (200 mg, 0.518 mmol), morpholine (0.05 mL, 0.622 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.4 mg, 0.010 mmol), racemic-2,2′bis(diphenylphosphino)-1,1′-binapthyl (19 mg, 0.030 mmol), and cesium carbonate (236 mg, 0.725 mmol) in toluene (5 mL) was heated to reflux for 24 h. The mixture was allowed to cool to room temperature, filtered through a ¾″ silica gel (60 Å) plug, then the plug was washed with EtOAc (40 mL). The resulting solution was concentrated under vacuum and purified via Biotage chromatography with gradient elution from 15% EtOAc/hexanes to 50% EtOAc/hexanes to yield 37 mg (22%) of 5-hydroxy-7-morpholin-4-yl-2-phenyl-chromen-4-one. See, A. Echavarren et al., J. Am. Chem. Soc., 109, pp. 5478-5486 (1987). Rf=0.12 (25% EtOAc/hexanes).
Reaction SMILES: BrC1C=CC2NC3C(C=2C=1)=CC=CC=3.ClCCOS(C1C(C)=CC=CC=1)(=O)=O.[OH-].[Na+].[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH2:45][CH2:46]Cl)[C:37]3[C:42]([C:43]=2[CH:44]=1)=[CH:41][CH:40]=[CH:39][CH:38]=3.[OH-].[K+]>CC(C)=O.O.C(OCC)C.O1CCCC1.C(O)C>[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:45]=[CH2:46])[C:37]3[C:42]([C:43]=2[CH:44]=1)=[CH:41][CH:40]=[CH:39][CH:38]=3
Reactant: ClCCn1c2ccccc2c2cc(Br)ccc21
Agent: Brc1ccc2[nH]c3ccccc3c2c1
Agent: Cc1ccccc1S(=O)(=O)OCCCl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: C=Cn1c2ccccc2c2cc(Br)ccc21
Reaction time: 24 h
Yield: 95 %

Procedure:
3-Bromocarbazole (24.6 g, 0.1 mole) was dissolved in acetone. To it was added β-chloroethyltoluenesulfonate (31.68 g, 0.135 moles) and sodium hydroxide (13 g, 0.325 mole) dissolved in 10 ml of distilled water. The mixture was brought to reflux. After 24 hours, equal amounts of β-chloroethyltoluenesulfonate, sodium hydroxide, and water were added. Refluxing was continued until 3-bromo-9-(2-chloroethyl)-carbazole was formed in >95 percent yield as judged by GLPC analysis. The product was dissolved in a mixture of 250 ml diethyl ether and tetrahydrofuran (50:50 v/v) and washed successively with two 150 ml portions of distilled water and 100 ml saturated sodium chloride solution. The organic phase was separated and dried over sodium sulfate and filtered. Solvents were removed on a rotary evaporator at reduced pressure. The crude 3-bromo-9-(2-chloroethyl)carbazole was dissolved in 230 ml isopropanol. 8.4 g (0.15 mole) potassium hydroxide dissolved in 15 ml ethanol was added. The resulting solution was refluxed for 11/2 hours. 4.2 g of solid potassium hydroxide was then added, and refluxing was continued for an additional 11/2 hours. The solution was cooled in a freezer during which time a solid residue formed. After filtration, the solid was washed with water. Recrystallization from methanol gave 13.94 g 3-bromo-9-vinylcarbazole as pale yellow-white needles (mp 74-74.5 degrees Celsius).
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:14]1([C:20]2[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:20]2[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=2[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([N:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]4[CH2:1][CH2:2][CH2:3][C@@H:4]4[CH2:13]3)=[O:30])=[CH:32][CH:33]=2)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(c1)NC[C@H]1CCCN21
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Product: O=C(Nc1ccc(C(=O)N2C[C@H]3CCCN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 57.8 %

Procedure:
The same procedures used in Example 1 were repeated using (3aR)-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline prepared in Reference Example 15 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give the title compound after recrystallization from dioxane-hexane. Yield 57.8%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]OS(C)(=O)=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)[CH2:29][CH2:28]1.CO>O>[CH3:1][O:2][C:3](=[O:20])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:27]2[CH2:28][CH2:29][CH:30]([C:33]3[NH:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:31][CH2:32]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(C)c1ccc(CCN2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Yield: 83.9 %

Procedure:
In a reaction vessel, 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (3.0 g) prepared in the Example 5, sodium carbonate (1.1 g), 2-(4-piperadinyl)-1H-benzoimidazole (3.0 g) and methylalcohol (30 mL) were introduced, and the mixture was reacted for 14 hours under reflux condition. Distilled water (50 mL) was added to crystallize. The crystals were filtered under reduced pressure, washed with distilled water, and dried to obtain 2-(4-{2-[4-(1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid methylester (3.4 g, yield 85%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)cc3ccccc23)CC1
Yield: 89 %

Procedure:
A mixture of 1-chloro-3-(4-methoxyphenyl)isoquinoline (0.89 g), N-ethylpiperazine (0.86 g) and potassium carbonate (1.10 g) was heated in dimethylformamide (20 ml) at 90° C. for 12 hr. The reaction mixture was evaporated, water was added to the resulting residue, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried over magnesium sulfate, and then the solvent was removed. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a pale brown oil (1.02 g, yield; 88%).