Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.[C:21](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CC1C=CC(S(C)(=O)=O)=CC=1>C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Agent: Cc1ccc(S(C)(=O)=O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C=C2Oc3cc(OC)ccc3C2=O)c1
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.452 g, potassium carbonate 0.583 g and dimethylformamide 5 ml, methyl p-toluene sulfonate 0.314 g was added. After the mixture was stirred for two hours at a temperature of 60° C., water 100 ml was added, and the mixture was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was washed with a saturated sodium chloride solution 50 ml twice, dehydrated with anhydrous magnesium sulfate, filtered and concentrated at a temperature of 40° C. under reduced pressure to obtain crude powder. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dissolved in ethyl acetate 2 ml and hexane 10 ml, and the solution was allowed to stand at room temperature for two hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 377.2 mg.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH2:3]1.Cl[CH2:34][C:35]1[N:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][N:36]=1>CN(C=O)C.C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH:3]1[CH2:34][C:35]1[N:39]=[C:38]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:37][N:36]=1
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: ClCc1noc(-c2ccccc2)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2noc(-c3ccccc3)n2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.08 h
Yield: 42.1 %

Procedure:
To a stirring solution of 200 mg (0.47 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl acetamide in 4 mL DMF at 0° C. is added dropwise 0.98 mL (0.49 mmol, 1.05 equiv) of a 0.5N solution of KN(TMS)2 in toluene. The resulting solution is stirred 5 min, then 100 mg (0.51 mmol, 1.1 equiv) of 3-chloromethyl-5-phenyl-[1,2,4]oxadiazole is added. The reaction mixture is stirred 30 min at 0° C. then 14 h at RT. The reaction mixture is quenched with 1 mL of H2O and the solvent removed in vacuo. The residue is dissolved in 40 mL EtOAc, washed with 40 mL H2O, and the organic layer is dried (MgSO4) and the solvent removed in vacuo. The resulting oil is purified by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification via reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O with 0.1% TFA as eluent followed by lyophilization to afford 116 mg of 2-[2,4-Dioxo-5-phenyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylmethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.07 (d, 2H, J=6.9), 7.59-7.13 (m, 16H), 7.00 (dd, 1H, J=1.3, 8.1), 5.01 (m, 1H), 4.27 (s, br, 2H), 4.1 (t, 1H, J=6.1), 3.66 (dd, 1H, J=7.8, 17.1), 3.50 (dd, 1H, J=6.1, 17.1) 1.08 (t, 6H, J=6.9); low resolution MS (FAB) m/e 586 (MH+), 451, 277, 227, 195.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:73][C:74]([CH3:87])([CH3:86])[CH2:75][C:76]([C:78]1[CH:85]=[CH:84][C:81]([CH2:82][NH2:83])=[CH:80][CH:79]=1)=[O:77].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:83][CH2:82][C:81]1[CH:84]=[CH:85][C:78]([C:76](=[O:77])[CH2:75][C:74]([CH3:86])([CH3:73])[CH3:87])=[CH:79][CH:80]=1
Reactant: CC(C)(C)CC(=O)c1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Temperature: 100 °C
Yield: 65.4 %

Procedure:
Use a method similar to the General Procedure 5-3 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.588 mmol), palladium(II) acetate (26 mg, 0.118 mmol), tris(dibenzylideneacetone)dipalladium(0) (53 mg, 0.059 mmol), BINAP (0.22 g, 0.353 mmol), 4-(3,3-dimethyl-butyryl)-benzylamine (241 mg, 1.176 mmol) and cesium carbonate (383 mg, 1.176 mmol) in degassed toluene (10 mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C. for 16 h. Cool the mixture to room temperature, dilute with EtOAc and wash with saturated aqueous NaHCO3. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and then hexane/EtOAc (90:10, 85:15) to obtain 7-chloro-6-[4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (185 mg, 65%). MS (ES+) m/z: 481 (M+H)+.
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:30])[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Agent: Cl
Product: Cc1cc(C(C)N2C(=O)c3ccnc(Cl)c3C2C)cnc1OCC(F)(F)F
Yield: 12 %

Procedure:
The title compound is prepared in 12% yield (40 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (262 mg, 0.94 mmol, Step-1 of Intermediate-6, racemate) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.85 mmol, Amine-2, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.Cl(O)(=O)(=O)=O>[Cl:1][C:10]1[S:9][CH:13]=[CH:12][C:11]=1[CH2:14][C:15]#[N:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#CCc1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1ccsc1Cl
Reaction time: 3 h
Yield: 33 %

Procedure:
Perchloric acid (0.070 mL, 0.81 mmol) was added to a rapidly stirring suspension of N-chlorosuccinimide (10.8 g, 81.2 mmol) and 2-(thiophen-3-yl)acetonitrile (10.0 g, 81.2 mmol) in carbon tetrachloride (40 mL). After 3 h at room temperature, the reaction mixture was treated with solid NaHCO3 (300 mg, 3.6 mmol), then filtered and concentrated. The residue was purified by chromatography, eluting with a gradient of 5-15% EtOAc/hexanes to afford pure 2-(2-chlorothiophen-3-yl)acetonitrile as a pale yellow oil (4.23 g, 26.8 mmol, 33% yield). MS (M+H)+ 158/160.
Reaction SMILES: [F:1][C:2]([F:19])([C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][OH:8].ClC1C=CC=C(C(OO)=O)C=1.[OH2:31].[OH2:32].O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O>C(Cl)Cl>[F:19][C:2]([F:1])([C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[CH2:3][CH2:4][S:5]([CH2:6][CH2:7][OH:8])(=[O:32])=[O:31]
Reactant: O
Reactant: OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCO)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 65.3 %

Procedure:
2-(3,3,4,4,5,5,6,6,6-nonafluorohexylthio)ethanol (50.0 g, 154 mmol) prepared in Synthetic Example 3 was dissolved in methylene chloride (850 ml), and m-chloroperbenzoic acid (m-CPBA) (58.6 g, 340 mmol) was added at 0° C. for 15 minutes with stirring in nitrogen atmosphere. The mixture was stirred at room temperature for one night and then methylene chloride (300 ml) was added to the reaction mixture. The reaction mixture was injected into a mixture of an aqueous saturated sodium thiosulfate pentahydrate solution (100 g) and water (100 ml). An organic layer was removed and an aqueous layer was extracted with methylene chloride (50 ml). Organic layers were joined, washed with a saturated sodium hydrogen carbonate solution (200 ml) and with a saturated saline solution (150 ml), and then dried over magnesium sulfate. A filtrate after filtration was concentrated at reduced pressure. A residue was subjected to a silica gel column chromatography (hexane/ethyl acetate (1/1→1/2)), and fractions having Rf value of 0.41 [Rf value (Thin Layer Chromatography (TLC))=(Migration distance of sample)/(Migration distance of eluting solvent)] were gathered and concentrated at reduced pressure and dried at vacuum to give crystalline 2-(3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)ethanol (35.8 g). Yield: 65.2%.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23].[CH3:28][N:29]1[C:34](=[O:35])[CH:33]=[C:32]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:31]=[C:30]1[CH2:42][C:43]([O-])=[O:44].[Na+]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:43](=[O:44])[CH2:42][C:30]2[N:29]([CH3:28])[C:34](=[O:35])[CH:33]=[C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:31]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(Cl)c2)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
120 ml of pyridine, 182 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 210 mg of 3-chloro-4-fluoroaniline are added to a solution of 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 2.5 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature overnight and is then concentrated under reduced pressure. Water is added, followed by extraction with ethyl acetate, further washing with water, and concentration under reduced pressure. The residue obtained is washed with ethyl acetate and then rinsed with ethyl ether. 76 mg of N-(3-chloro-4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a violet solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[CH:8]2)=[O:4].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:10][C:9]=2[CH3:14])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2[nH]c(C)c(Cc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A methylene chloride (15 ml) solution of 5-(methoxycarbonyl)-2-methylindole (0.567 g) and 4-benzyloxybenzaldehyde (0.700 g) is dropwise added to a methylene chloride (15 ml) solution of trifluoroacetic acid (0.513 g) and triethylsilane (1.047 g) in an ice-water bath, over a period of 15 minutes. This is stirred for 30 minutes in the ice-water bath, and an aqueous solution of 2 M sodium hydroxide is added thereto to stop the reaction. The organic layer is washed with a saturated saline solution, dried and concentrated. The resulting residue is purified through silica gel column chromatography (eluent: ethyl acetate/hexane=3/7) to obtain 3-(4-benzyloxybenzyl)-5-(methoxycarbonyl)-2-methylindole (62) (0.510 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: BrCc1cncnc1
Reactant: COC(=O)c1c(C)[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)n(Cc2cncnc2)c2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of methyl 2-methyl-1H-indole-3-carboxylate (0.5 g, 2.6 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (1.7 g, 5.2 mmol) and 5-(bromomethyl)pyrimidine (0.3 g, 1.7 mmol). The mixture was stirred at 100° C. for 1 hour and then concentrated to give a residue. The residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give methyl 2-methyl-1-(pyrimidin-5-ylmethyl)-1H-indole-3-carboxylate (110 mg, 14%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].[CH2:18](I)[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[N:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH2:18][CH3:19]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
3-Bromo-N-tert-butoxycarbonylaniline (0.82 g, 3.0 mmol) was dissolved in anhydrous DMF (15 ml) and cooled to 0° C. Sodium hydride (0.145 g, 3.6 mmol, 1.2 eq.) was added to the solution. The reaction stirred at 0° C. for 10 minutes then was warmed to room temperature. After 30 minutes at room temperature the reaction was cooled to 0° C. and Ethyl iodide (0.27 ml, 3.3 mmol, 1.1 eq.) was added over ˜1 minute. The reaction was stirred at 0° C. for 5 minutes then was warmed to room temperature. The reaction stirred at room temperature for 22 hours and was then cooled to 0° C. and quenched with a saturated bicarbonate solution and extracted with EtOAc (2 times). The combined organic layers were washed with H2O (5 times) then brine. The organic phase was dried with MgSO4/Na2SO4, filtered and the solvent was removed in vacuo to give 0.93 g of crude product which was used as is. HPLC ret time 11.83 min. (100%).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC>[Cl:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1Cl
Yield: 80.2 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (60 mg, 0.147 mmol) in DME (3 ml)/2M Na2CO3 (256 uL, 0.513 mmol) was treated with 3-chlorophenylboronic acid (34 mg, 0.219 mmol) and Pd[PPh3]4 (34 mg, 0.029 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (52 mg, 80%). LC-MS m/e 441.24 (M+H+)
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1cccc(C2(N)CCC(=O)CC2)c1
Product: COc1cccc(C2(N)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-amino-4-(3-methoxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: C([N:4]1[C:16]2[C:11](=[CH:12][C:13](Br)=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]1=2)(=O)C.S1C2C=CC=CC=2N=C1C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]1[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[C:8]2[CH:25]=[CH:24][CH:23]=1)[NH:4][C:16]1[C:11]3=[CH:12][CH:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]2=1
Reactant: CC(=O)n1c2ccc3ccccc3c2c2cc(Br)c3ccccc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccc(-c2nc3ccccc3s2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)ccc1c2[nH]c2ccc3ccccc3c21

Procedure:
Following the above procedure, Suzuki coupling of 3.8 g of 7-acetyl-12-bromo-7H-dibenzo [a,g]carbazole and 2.7 g of (4-benzo[d]thiazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.02 g of tetrakis(triphenylphosphine)palladium, 2.1 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 4.1 g of 7-acetyl-12-[4-benzo[d]thiazol-2-yl) phenyl]-7H-dibenzo[a,g]carbazole as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[C:9]1=[O:27])(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:18]=2)[C:9]1=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 45 °C
Yield: 82 %

Procedure:
A solution of 137 mg (0.36 mmol) of (S)-[1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester in 2 ml of dioxane is treated with 0.3 ml of hydrochloric acid (37%). The solution is warmed to 45° C. for 1 h forming a white suspension. For the working-up, the reaction mixture is evaporated under reduced pressure and the solid residue is triturated with a small volume of methanol. After filtration and drying, 94 mg of (S)-3-amino-1-(4-benzyloxy-phenyl)-pyrrolidin-2-one hydrochloride (82% of theory) are obtained as a white solid. MS: m/e=283 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].Cl.[CH3:16][C@@H:17]([NH2:22])[C:18]([F:21])([F:20])[F:19].C(O)(=O)C>CO>[CH3:16][C@@H:17]([NH:22][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C[C@@H](N)C(F)(F)F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](NCc1ccc(C#N)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
Add sodium cyanoborohydride (3.36 g, 53.5 mmol) to a solution of 4-cyanobenzaldehyde (1.75 g, 13.35 mmol) and (R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (2 g, 13.37 mmol) in methanol (17 mL) containing acetic acid (1.53 mL, 26.75 mmol). Stir the mixture at room temperature overnight. Partition the mixture between 1N aqueous NaOH/DCM (1:1, 500 mL) and extract the aqueous layer twice with DCM. Dry the combined organic extracts over MgSO4, concentrate in vacuo and purify by chromatography on silica gel (120 g) eluting with hexane/EtOAc (19:1, 9:1, 85:15 and 4:1) to obtain the desired intermediate (0.83 g, 27%). MS (ES+) m/z: 229 (M+H)+.
Reaction SMILES: O1CCC[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C([O:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=1)C.CI.Cl.[OH-].[Na+]>O1CCCC1.C(O)C.O>[CH3:2][CH:22]1[CH2:21][CH2:20][C:19](=[O:23])[CH2:18][C:17]1=[O:16]
Reactant: CCOC1=CC(=O)CCC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: CI
Product: CC1CCC(=O)CC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
To a stirred solution of lithium diisopropylamide mono (tetrahydrofuran) (100 ml, 150 mM, 1.5M solution) in dry tetrahydrofuran (100 ml) under an atmosphere of nitrogen and at -78° C. was added dropwise 3-ethoxy-2-cyclohexen-1-one (21.0 g, 150 mM) dissolved in tetrahydrofuran (70 ml) over a period of 15 min. After an additional 45 min, methyl iodide (21.29 g, 150 mM) dissolved in dry tetrahydrofuran (10 ml) was added dropwise over a period of 5 min. After a further 15 min the cooling bath was removed and the whole stirred at room temperature for 1 h. Water was then added and the enol ether intermediate recovered into ether, washed (brine), dried (Na2SO4) and evaporated to dryness. The oil thus obtained was dissolved in ethanol (100 ml) and 5N hydrochloric acid (228 ml) added. The whole was stirred at room temperature for 45 min. Water (800 ml) was added, the aqueous phase made basic to pH 8-9 (NaOH) and extracted with ethyl acetate. The aqueous phase was re-acidified (HCl) and the product extracted into ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and evaporated to give the title compound (D11) (17.6 g) (92%) as an oil. Product could be used directly in the preparation of intermediate D13 without further purification.