Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:12]1[S:11][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(F)c(-c2cccs2)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
Ex-20A: A solution of 3-bromo-4-flouro-benzaldehyde (5.0 g, 24.6 mmol) and thiophene-2-boronic acid (4.7 g, 37.0 mmol) in ethylene glycol dimethyl ether (100 mL) was stirred at room temperature under nitrogen for 15 min. Then tetrakis(triphenylphosphine)-palladium(0) (2.8 g, 2.42 mmol) and a sodium carbonate solution (2 M, 33 mL) were added, and the resulting mixture was refluxed under nitrogen overnight. Upon cooling to room temperature the reaction was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 1:1) gave 4.8 g (95%) of the desired 4-fluoro-3-(thiophen-2-yl)-benzaldehyde product as a yellow oil. 1H-NMR (300 MHz, CDCl3) δ 10.0 (s, 1H), 8.18 (dd, 1H, J=7.3 and 2.4 Hz), 7.80 (m, 1H), 7.56 (dd, 1H, J=3.7 and 1.7 Hz), 7.44 (d, 1H, J=5.1 Hz), 7.36 (m, 1H), 7.16 (dd, 1H, J=5.1 and 3.7 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH:8]=[CH:7]2.[CH:11]([Mg]Br)([CH3:13])[CH3:12].[Cl-].[NH4+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[CH:11]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH:8]=[CH:7]2)([CH3:13])[CH3:12]
Reactant: Brc1cccc2c1CC=C2
Reactant: CC(C)[Mg]Br
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1cccc2c1CC=C2
Yield: 88 %

Procedure:
Using a 300 ml three-necked flask as the reactor, under a nitrogen stream, 1.36 g (2.57 millimoles) of [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) was dissolved in 20 ml of tetrahydrofuran. To this suspension there was added a solution of 10 g (51.30 millimoles) of 7-bromoindene in 100 ml of tetrahydrofuran, prepared based on the method described in J. Org. Chem. 49, 4226–4237(1984). After dropwise addition of 51 ml (102.60 millimoles) of isopropylmagnesium bromide (2N) to the mixed solution while cooling on ice, the mixture was heated to reflux for 20 hours. After reflux, hydrolysis was performed with a saturated aqueous solution of ammonium chloride, distilled water was added, extraction was performed several times with diethyl ether, and then the extract was washed once with saturated saline and dried over anhydrous magnesium sulfate. After drying, the magnesium sulfate was filtered off and the solvent was purified with a silica gel column to obtain 7.14 g of 7-isopropylindene as a yellow oil (88% yield).
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Reactant: OCCCCCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCCCCO)cc2)cc1

Procedure:
To 500 ml of toluene in a one liter round bottom flask, fitted with a condenser and magnetic stirrer, is added 14 g (0.05M) of 4-hydroxy-4'-nitrostilbene potassium salt, 14 g of 6-iodo-1-hexanol, and 0.5 g of 18-crown-6 ether. The mixture is refluxed for about 20 hours, and then the reaction medium is filtered hot, and the product crystallizes from the toluene on cooling, m.p. 154°-157° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11](Br)[CH:12]=[CH2:13]>CN(C)C=O>[CH2:13]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Sodium hydride (4.8 g, 0.2 mol, 50% dispersion in mineral oil) was added under nitrogen at room temperature to benzyl alcohol (21.6 g., 0.2 mol) in 150 ml. of dry dimethylformamide. The suspension was stirred at room temperature for 30 minutes and then heated at 60° C. for 30 minutes. Allyl bromide (24.2 g., 0.2 mol) was added to the suspension dropwise at 50° C. with stirring. The reaction mixture was heated at 90° C. for five and a half hours under nitrogen, cooled and stirred at room temperature overnight. The dimethylformamide was removed on a rotary evaporator and the resulting oil was extracted with ether, dried over sodium sulfate and the ether evaporated off. The resulting oil was purified on a silica gel column using hexane (500 ml) to remove the mineral oil, followed by methylene chloride (750 ml) to elute the desired product. Evaporation of the solvent yielded the title compound as a pale yellow liquid, 16 g., 54% yield.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][C:14](OCC)=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][OH:15])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1nc(-c2ccccc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCCCc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of ethyl 3-(4-phenylthiazol-2-yl)propanoate (0.5 g, 1.91 mmol) in MeOH—H2O (10 mL, 9:1 v/v) was cooled to 0° C. and sodium borohydride (0.29 g, 7.65 mmol) was added. The reaction mixture was warmed to room temperature and further stirred for 8 h. The mixture was quenched with ice water and the organic product was extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 3-(4-phenylthiazol-2-yl)propan-1-ol (0.4 g, yield 95%) as colorless liquid, which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 7.87-7.85 (m, 2H), 7.44-7.40 (m, 2H), 7.35-7.32 (m, 2H), 3.83-3.81 (t, J=5.8 Hz, 2H), 3.24-3.21 (m, 3H), 2.14-2.08 (m, 2H). MS (ESI) m/z: Calculated for C12H13NOS: 219.07. found: 220.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:12][OH:13])[CH2:9][C:10]#[N:11])=[C:4]([O:14][CH3:15])[CH:3]=1.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.[BH4-].[Na+].C(NCC)C>CO>[C:20]([O:19][C:17](=[O:16])[NH:11][CH2:10][CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:14][CH3:15])[CH2:12][OH:13])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1cc(Br)ccc1[C@@H](CO)CC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCNCC
Product: COc1cc(Br)ccc1[C@@H](CO)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
To a solution of (S)-3-(4-bromo-2-methoxy-phenyl)-4-hydroxy-butyronitrile (459 mg, 1.699 mmol) in MeOH (12.1 mL) at 0° C. was added (BOC)2O (736.3 mg, 3.398 mmol), NiCl2.6H2O (40.75 mg, 0.17 mmol), and (in portions) sodium borohydride (450.3 mg, 11.9 mmol). The mixture was stirred at room temperature for 18 hours. Diethylamine (0.183 mL, 1.699 mmol) was then added and the mixture was stirred for 30 minutes. Solvent was evaporated under reduced pressure and a solution of aqueous NaHCO3 (10%) was added. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 7/3) to give 405 mg (64% yield) of [(S)-3-(4-bromo-2-methoxy-phenyl)-4-hydroxy-butyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[C:38]([CH3:46])=[C:37]([OH:47])[C:36]3=[O:48])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[C:38]([CH3:46])=[C:37]([O:47][CH3:3])[C:36]3=[O:48])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: OCCO
Product: COC1=C(C)C(C2CCCCC2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-cyclohexyl-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (1.00 g, 3.22 mmol, 1 eq) and MeOH (10 ml); yield: 0.250 g (25%); MS m/z: 326.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.05 (d, 3H), 1.40 (d, 2H), 1.65-1.60 (m, 4H), 2.05 (s, 3H), 4.03 (s, 3H), 4.40 (s, 1H), 7.05 (s, 1H), 7.62 (s, 1H), 7.63 (s, 1H), 7.82 (s, 1H); HPLC (METHOD [A]): rt 11.25 min (98.78%)
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:21][O:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)=[O:24].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:7]([NH:6][C:4]([C:3]1[CH:10]=[C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][C:2]=1[NH:1][C:29]([C:28]1[CH:32]=[CH:33][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][CH:27]=1)=[O:30])=[O:5])([CH3:8])[CH3:9]
Reactant: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1N
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Oc3ccccc3)cc2C(=O)NC(C)C)cc1
Temperature: 65 °C
Yield: 84.8 %

Procedure:
A solution of 34C (72 mg, 0.27 mmol) in DMF (4 mL) was treated with 4-(methoxycarbonyl)benzoic acid (78 mg, 0.43 mmol), HOBt (66 mg, 0.43 mmol) and triethylamine (100 mg, 1.0 mmol). The solution was treated with EDCI (96 mg, 0.5 mmol) at room temperature for 15 minutes, and then warmed to 65° C. for 16 hours. The reaction mixture was partitioned between EtOAc (20 mL) and 1 M HCl (20 mL). The organic layer was washed with 1 N HCl (20 mL), 1 N NaOH (20 mL) and brine (20 mL). The reaction was dried (Na2SO4), filtered, and concentrated to a solid. The crude material was purified by chromatography (SiO2, 1:2 EtOAc in heptane) to afford 34D (99 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CSc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(CSc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 90 °C
Yield: 107.9 %

Procedure:
To a solution of ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (5 mg, 0.008 mmol) in 1:1 tetrahydrofuran:methanol (0.5 mL) was added 1 N sodium hydroxide (0.04 mL, 0.04 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes and 1 N hydrochloric acid (0.04 mL, 0.04 mmol) was added. The mixture was concentrated and the residue was taken up with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (5 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ 8.44 (d, J=9 Hz, 1H), 8.29 (d, J=9 Hz, 1H), 8.21 (d, J=9 Hz, 1H), 8.10-8.07 (m, 2H), 7.70 (d, J=9 Hz, 2H), 7.34-7.14 (m, 3H), 7.10 (d, J=9 Hz, 2H), 5.08 (s, 2H), 4.16 (s, 2H), 3.20 (septet, J=7 Hz, 1H), 1.32 (d, J=7 Hz, 6H). HRMS (ESI) C30H24Cl2N2O4S calculated: 579.0912 (M+H)+, found: 579.0925 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1CCNC1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and pyrrolidine. LCMS (Method C): 524 (M+H)+, Retention time 11.6 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([F:40])[CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[C:5]([F:40])[CH:4]=1)(=[O:41])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-fluoro-phenyl)-amide (50 mg, 0.086 mmol) in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.15 g, 1.3 mmol), then aqueous solution (1N) of NaOH (0.4 mL, 0.4 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-fluoro-phenyl)-amide as a off white solid (Yield 25 mg, 49%)
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCC(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:7](=[O:8])[S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Sc1ccccc1
Solvent: CCCC(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Sc1ccccc1)C1CCCCC1
Yield: 92.2 %

Procedure:
Cyclohexanecarbonyl chloride (669 μL, 5.0 mmol) in 15 mL toluene was added to a solution of triethylamine (0.70 mL, 5.0 mmol) and thiophenol (0.51 mL, 5.0 mmol) in 10 mL toluene. Reaction monitoring was accomplished by TLC: iso-hexane/ethyl acetate 25:1, Rf=0.45. Workup yielded 1016 mg (92%) S-phenyl cyclohexanecarbothioate 8 as crystalline colourless solid.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH:20]N(C)C)[CH:18]=O)=[CH:13][CH:12]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CO.O>[C:4]([C:6]1[C:7](=[O:8])[NH:9][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:20]=1)#[N:5]
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O
Temperature: 25 °C

Procedure:
To solution of sodium methoxide (7.52 g) in methanol (130 ml) was added cyanoacetamide (5.84 g) followed by 2-(4-chlorophenyl)-3-dimethylaminopropenal and the resulting suspension was refluxed overnight. During this time a yellow solid was formed. The mixture was cooled to room temperature and glacial acetic add (50 ml) was added followed by water (100 ml). The resulting yellow orange solid was filtered off, washed several times with water and dried to yield 8.1 g of 3-cyano-5-(4-chlorophenyl)-2-pyridinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:39])[CH2:18][C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)[CH2:12]3)[N:8]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:7]=2[CH:45]=1>C(Cl)Cl>[NH2:31][C@H:19]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH2:18][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([C:9]2[N:8]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:7]3[CH:45]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N:10]=2)[CH2:12]1)=[O:39]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)cc21
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
tert-Butyl (R)-4-((R)-3-(6-methoxy-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (42F) (0.63 mmol, 387 mg) in DCM (15 mL) was added TEA (3 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (20-50% CH3CN in H2O) to afford (R)-3-amino-1((R)-3-(6-methoxy-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-(naphthalen-2-yl)butan-1-one (110) (0.05 mmol, 27 mg, yield: 7.9%). ESI-MS: m/z 515.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.56 (m, 1H) 1.72-1.99 (m, 4H) 2.01-2.21 (m, 2H) 2.58-2.77 (m, 3H) 2.87-2.98 (m, 1H) 3.01-3.25 (m, 7H) 3.37 (t, J=5.75 Hz, 2H) 3.82 (d, 0.1=10.23 Hz, 2H) 3.88 (d, J=7.07 Hz, 3H) 4.05-4.69 (m, 3H) 7.04-7.12 (m, 1H) 7.35 (d, J=13.07 Hz, 1H) 7.45 (dd, J=8.46, 2.72 Hz, 1H) 7.48-7.55 (m, 2H) 7.64 (t, J=9.69 Hz, 1H) 7.80 (d, J=6.06 Hz, 1H) 7.83-8.03 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][CH2:14][N:5]3[CH:4]=[C:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[CH:9][CH:10]=2.[Br:20]Br.O>C(O)(=O)C>[Br:20][C:9]1[CH:10]=[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][CH2:14][N:5]3[CH:4]=[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]2=[O:1])[CH:8]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)CCC2
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(Br)cc3c1=O)CCC2

Procedure:
Ethyl 1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (290 mg, 1.13 mmol) was dissolved in acetic acid (3 mL) and bromine (197 mg, 1.23 mmol) was added dropwise. The reaction was followed by LC/MS, additional bromine (2×197 mg) was added. After 24 hours water was added and the precipitate was filtered off, washed with diethyl ether then dried in a dessicator in the presence of phosphorus pentoxide to provide an orange solid which was purified by chromatography on silica gel eluting with 0-1.5% (9:1 MeOH/20 M NH3) in dichloromethane to yield the title compound as a white solid. ESMS m/z 336/338 (MH+). 1H NMR (CDCl3) δ 8.34(d, 1H), 8.31 (s, 1H), 7.48 (d, 1H), 4.37 (q, 2H), 4.17 (t, 2H), 3.03 (t, 2H), 2.23 (tt, 2H), 1.40 (t, 3H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([N:20]1[CH2:26][C@@H:25]([CH2:27][C:28]([OH:30])=O)[C@H:24]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[O:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:39]([O:41][C:42](=[O:47])[CH2:43]C([O-])=O)[CH3:40].[K+].[Cl-].[Mg+2].[Cl-].Cl>C1COCC1>[Cl:38][C:33]1[CH:32]=[C:31]([C@@H:24]2[O:23][CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:26][C@H:25]2[CH2:27][C:28](=[O:30])[CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:47])[CH:36]=[CH:35][C:34]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(=O)O)C1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
CDI (0.991 g, 6.11 mmol) was added to a solution of [(6R,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]acetic acid (1.9 g, 4.70 mmol) in THF (20 ml), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added potassium 3-ethoxy-3-oxopropanoate (0.880 g, 5.17 mmol) and magnesium chloride (0.492 g, 5.17 mmol). The reaction mixture was stirred at 60° C. for 5 hr. To the reaction mixture was added 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.959 g).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([Cl:17])[CH:3]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(C)(C)C)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (77 mg, 84%), MS (ISP) m/z=367.5 [(M+H)+], mp 252° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:23]I>O1CCCC1>[CH3:23][N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2C
Reaction time: 0.33 h

Procedure:
A solution of hexyl-carbamic acid-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.276 g., 1 mmol) in dry tetrahydrofuran (5 ml) was added to a stirred suspension of sodium hydride (0.024 g., 1 mmol) in dry tetrahydrofuran (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then methyl iodide (0.224 ml, 3.6 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 1.25 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (30:70) as eluant to give 2m; yield: 0.15 g. (51.7%).