Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[Cl:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:43]=1[S:49](Cl)(=[O:51])=[O:50]>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:49]([C:43]1[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:42]=1[Cl:41])(=[O:50])=[O:51])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: Cc1cccc(Cl)c1S(=O)(=O)NCCc1c(CCN(C)c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
The intermediate from example 146 step 7 was treated with 2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 96% yield.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH2:16])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)C)C=CC=CC=1.C(Cl)(=[O:33])C>>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:33])[CH3:16])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccccc1C(C)c1ccccc1
Reactant: CC(=O)Cl
Agent: CC(c1ccccc1)c1ccccc1
Product: CC(=O)c1ccccc1C(C)c1ccccc1

Procedure:
They can be prepared by a variety of chemical synthetic manners, and for example, phenyl-(vinylpheny)ethane may be prepared by reacting diphenylethane with acetyl chloride in the presence of a Friedel-Crafts catalyst to form phenyl(acetylphenyl)ethane, reducing the latter with sodium boron hydrine or the like, and dehydrating it. Phenyl(isopropenylphenyl)ethane can be prepared by reacting phenyl(formylphenyl)ethane with a Grignard reagent such as methylmagnesium iodide, and carrying out dehydration.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=3)[C:6]=2[CH:22]=1.[Si:27](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.O>ClCCl>[Cl:1][C:2]1[C:3]([C:23]([F:24])([F:26])[F:25])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([OH:12])[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][O:21][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:18]=3)[C:6]=2[CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
A mixture of 1-[6-chloro-1-[4-(2-hydroxyethyl)phenyl]-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethanol (step 3, 461 mg, 1.19 mmol), tert-Butyldiphenylsilyl chloride (0.35 ml, 1.3 mmol), triethylamine (0.2 ml, 1.4 mmol) and N,N-dimethylaminopyridine (6 mg, 0.05 mmol) in dichloromethane (11 ml) was stirred under nitrogen at room temperature for 4 h. was added water (50 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (3:1/1:1) to afford 590 mg (80%) of the title compound as white amorphous.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])[C:3]=1[C:14]#[N:15].[CH3:16][N:17]=[C:18]=[O:19].O>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:16][NH:17][C:18]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])[C:3]=1[C:14]#[N:15])=[O:19]
Reactant: CN=C=O
Reactant: CCCN(CCC)c1nsc(N)c1C#N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)c1nsc(NC(=O)NC)c1C#N
Yield: 70.6 %

Procedure:
A solution of 7.0 g of 5-amino-4-cyano-3-(dipropylamino)isothiazole, 3.6 g of methyl isocyanate and 40 drops of dibutyltin diacetate in 50 ml of tetrahydrofuran was heated under reflux overnight. Thin-layer chromatographic analysis indicated the reaction to be complete. The reaction mixture was poured into rapidly stirred, cold water. The solid precipitate was collected by filtration. The filtrate was extracted with methylene chloride. The solid was combined with the extract and the mixture dried over calcium chloride, then filtered through magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was taken up in a mixture of toluene and benzene to which a little ethanol had been added. Pentane was then added to promote crystallization. The recrystallization yielded 6.2 g of 1-methyl-3-(4-cyano-3-(dipropylamino)-5-isothiazolyl)urea, m.p. 179°-180°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)=[O:47])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: Cc1ccc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(F)c2F)cn1

Procedure:
Starting materials (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3 and N-methoxy-N, 6-dimethylnicotinamide.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[NH:3][CH:2]=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>>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH:13]([N:17]4[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=5)=[O:23])[CH2:18]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: O=C1CC=C(c2ccc3nc[nH]c3c2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc4nc[nH]c4c3)CC2)C1

Procedure:
The title compound was prepared as a white solid by hydrogenation of 4-(3H-benzoimidazol-5-yl)-cyclohex-3-enone (as prepared in the previous step) using the procedure described in Step C of Example 5 followed by reductive amination of the ketone with 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: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([CH:17]=[O:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:16][C:5]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:3][C:4]=1[CH:17]=[O:18]
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C=O)cc(-c2cccnc2)n1S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Under an argon atmosphere, a suspension of 5-bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (497 mg), 3-pyridineboronic acid (376 mg), sodium carbonate (481 mg) and tetrakis(triphenylphosphine)palladium (89.2 mg) in 1,2-dimethoxyethane (12 mL) and water (6 mL) was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:4) to give the title compound as a white solid (yield 353 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CCCCCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCCCCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 654 mg (7.5 mmol) of pentylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 788 mg (yield: 91.4%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=[O:13].Cl[Si](C)(C)C.N1C=CC=CC=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.CC(N(C)C)=O>[C:26]1([S:32]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[C:12]([OH:14])=[O:13])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2ccccc2c1C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of Example 42B (0.033 g, 0.200 mmol) in dichloromethane (1 mL) was treated with 1M chlorotrimethylsilane in dichloromethane (440 μL, 0.044 mmol) and pyridine (56.6 μL, 0.70 mmol), shaken for 4 hours at ambient temperature, treated with a solution of benzenesulfonyl chloride (0.042 g, 0.24 mmol) in dimethylacetamide (1 mL), shaken for 16 hours at ambient temperature, and concentrated. The concentrate was acidified to pH 1.0 with 5% aqueous HCl and extracted with dichloromethane. The extracts were washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (ESI(+)) m/e 328 (M+H)+, 345 (M+NH4)+, 350 (M+Na)+; (ESI(−)) m/e 326 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.30 (br s, 1H), 8.10 (d, 1H), 7.95 (d, 1H), 7.89 (d, 1H), 7.78 (dd, 2H), 7.63-7.50 (m, 5H), 7.31 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[CH:28]=[CH:27][C:26]=1[CH3:34]>C(#N)C>[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:32](=[O:33])[NH:31][C:29]1[CH:28]=[CH:27][C:26]([CH3:34])=[C:25]([Cl:24])[CH:30]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: O[C@@H](CN1CCOC(c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Solvent: CC#N
Product: Cc1ccc(NC(=O)O[C@@H](CN2CCOC(c3ccc(C(F)(F)F)cc3)C2)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1,1,1-Trifluoro-3-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-propan-2-ol (50 mg, 146 μmol) and 2-chloro-4-isocyanato-1-methylbenzene (prepared by a similar procedure as for intermediate A, 24.4 mg, 146 μmol) were combined in acetonitrile (1 mL). A mixture was stirred at room temperature overnight and evaporated. The residue was purified by flash chromatography (20% EtOAc/hexanes) to provide (3-chloro-4-methylphenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[2-(4-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester, which was converted to the HCl salt to afford (3-chloro-4-methylphenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[2-(4-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride as a white solid (15 mg). (M+H)+=511 m/e.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([C:9]1([OH:32])[C:29]2[CH:28]=[C:27]3[N:15]([CH2:16][C:17]4[C:18]3=[N:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH:26]=4)[C:14](=[O:30])[C:13]=2[CH2:12][O:11][CH:10]1[OH:31])[CH3:8]>O.C(O)(=O)C>[CH:10]([O:11][CH2:12][C:13]1[C:14](=[O:30])[N:15]2[C:27](=[CH:28][C:29]=1[C:9](=[O:32])[CH2:7][CH3:8])[C:18]1=[N:19][C:20]3[C:25]([CH:26]=[C:17]1[CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:31]
Reactant: CCC1(O)c2cc3n(c(=O)c2COC1O)Cc1cc2ccccc2nc1-3
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)c1cc2n(c(=O)c1COC=O)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of sodium Metaperiodate (14 g, 65 mmol) in water (140 ml) is added drop-wise to a suspension of 4-ethyl-3,4-dihydroxy-1H-pyrano [3',4': 6,7] indolizino [1,2-b] quinoline-14(4H,12H)-one (13.4 g, 38 mmol) in glacial acetic acid (720 ml) and the resulting solution is agitated for one hour at ambient temperature. The reaction mixture is then poured into a mixture of ice/water (650 ml) and the resulting suspension is agitated for one half-hour then filtered and washed successively with water, isopropyl alcohol, and etherdiethyl alcohol, which, after drying under reduced pressure, the sought compound (11.5 g) in the form of a pale yellow solid, m.p. >200° C. (d).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[C:16]([O:20][C:21]([N:23]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:24]1[C:25]([C:31]2[O:35][N:34]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([C@@H:42]4[CH2:47][O:46][CH2:45][CH2:44][N:43]4[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:38][CH:37]=3)[CH:32]=2)=[N:26][C:27](Br)=[CH:28][N:29]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+].O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CC#N>[C:58]([O:57][C:55]([N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:24]1[C:25]([C:31]2[O:35][N:34]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([C@@H:42]4[CH2:47][O:46][CH2:45][CH2:44][N:43]4[C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[CH:38][CH:37]=3)[CH:32]=2)=[N:26][C:27]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=2)=[CH:28][N:29]=1)=[O:56])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc([C@@H]3COCCN3C(=O)OC(C)(C)C)cc2)no1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc([C@@H]5COCCN5C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Temperature: 50 °C
Yield: 87.9 %

Procedure:
A mixture of (4-isopropylsulfonylphenyl)boronic acid (892.7 mg, 3.914 mmol), tert-butyl (3R)-3-[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]isoxazol-3-yl]phenyl]morpholine-4-carboxylate (2.5 g, 3.558 mmol), Na2CO3 (3.558 mL of 2 M, 7.116 mmol), water (17.60 mL) and MeCN (25.00 mL) were degassed by vacuum/nitrogen cycles (3×) then Pd[P(tBu)3]2 (90.92 mg, 0.1779 mmol) was added and vessel flushed with nitrogen via vacuum/nitrogen cycles (2×). Mixture then heated at 50° C. (drysyn block temp) for 3 h. The reaction was cooled to rt, and then diluted with EtOAc (10 mL) and water (10 mL) and the organic layer separated and then washed with water (2×10 mL) and brine (1×10 mL), dried MgSO4, filtered and concentrated in vacuo. The crude product purified by ISCO (120 g SiO2, 0 to 50% EtOAc/petroleum ether) to leave product as a white foam (2.52 g, 88% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH2:13].[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[ClH:44]>C(O)C.C(O)(=O)C.ClCCCl.O1CCCC1>[ClH:44].[ClH:44].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][CH:19]1[CH2:18][CH2:17][C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([N:15]([CH3:29])[CH3:14])[CH2:21][CH2:20]1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3ccc(F)cc23)CC1
Reaction time: 0.25 h

Procedure:
To a mixture of tetrahydrofuran (12 ml) and 1,2-dichloroethane (4 ml) there were added, under argon, first 2-(5-fluoro-1H-indol-3-yl)ethylamine (282 mg) and 4-dimethylamino-4-phenylcyclohexanone (343 mg), and acetic acid (0.09 ml) was added thereto. After 15 minutes, NaBH(OAc)3 (474 mg) was added, and stirring was carried out for 40 hours at RT. The reaction mixture was concentrated, and the residue was taken up in 1M hydrochloric acid (20 ml) and extracted with ether (2×30 ml). A white precipitate (191 mg) separated out here and was separated off. The aqueous solution was then rendered alkaline with 1M NaOH (28 ml) and extracted with ether (2×30 ml) and ethyl acetate (2×30 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue (468 mg) consisted of two products, just like the solid separated off previously. They were together (459 mg) purified by column chromatography with methanol/ammonia (500:1). The nonpolar diastereomer was obtained as a white solid (218 mg; m.p. 191-192° C.), was dissolved in ethanol (15 ml), with heating, and 3.3N ethanolic hydrochloric acid (0.47 ml, 1.56 mmol.) was added thereto. Because no solid had yet precipitated after 90 minutes, 2-butanone (5 ml) was added. Crystallisation of the hydrochloride then began after a short time (184 mg; m.p. 230-237° C.).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[C:32]([OH:34])=[O:33].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[C:32]([OH:34])=[O:33])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H]2CCCC[C@H]2C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (30 mg, 0.09 mmol), cis-2-amino-cyclohexanecarboxylic acid (67 mg, 0.47 mmol, Acros) and sodium methoxide (20 mg, 0.37 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes with 0.5% formic acid) to give the title compound in 34 mg. MS: (−) m/z 429.99 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@H:9](OS(C)(=O)=O)[C@H:8]([O:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:7]=1)=[O:5])C.C(N)CN>C(O)C>[CH2:20]([CH:19]([O:18][C@H:8]1[C@@H:9]2[C@H:10]([NH:12]2)[CH2:11][C:6]([C:4]([OH:3])=[O:5])=[CH:7]1)[CH2:22][CH3:23])[CH3:21]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](OS(C)(=O)=O)[C@H](N)C1
Solvent: CCO
Solvent: NCCN
Product: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H]2N[C@@H]21
Yield: 92.3 %

Procedure:
A yellowish solution of 0.87 g (2.5 mmol) (3R,4S,5R)-5-amino-3-(1-ethyl-propoxy)-4-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester and 0.17 ml (2.5 mmol) of ethylenediamine in 4.4 ml ethanol was heated to reflux for 1 hour. The resulting suspension was evaporated in a rotary evaporator to dryness and the residue was suspended in 5 ml ethyl acetate, extracted with 2 ml aqueous 1M NaHCO3 solution, dried over Na2SO4, filtered and evaporated in a rotary evaporator at reduced pressure to dryness to yield 0.52 g (82%) of (1R,5R,6S) 5-(1-ethyl-propoxy)-7-aza-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethy as a yellow oil. IR (film): 3312, 2966, 2936, 2877, 1715, 1660, 1464, 1254, 1083, 1057, 799 cm−1; MS (EI, 7o eV)): 253 (M+), 224, 208, 182, 166, 110 m/z.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][Mg]Br.[Cl-].[NH4+]>CCOCC>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C@H:10]([OH:11])[CH3:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[Mg]Br
Reactant: O=C[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C[C@@H](O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 66.1 %

Procedure:
Ether (100 mL) was added to a 500 mL round-bottom flask containing (S)-2-(dibenzylamino)-3-(4-(trifluoromethyl)phenyl)propanal (4.51 g, 11.3 mmol). The mixture was cooled to −78° C., and methylmagnesium bromide (3.16 M ether, 35.9 mL, 113 mmol) was added dropwise over 15 minutes. After 5 hours, ammonium chloride (50 mL) was added dropwise, and the mixture was warmed to room temperature. The mixture was extracted with EtOAc (2×500 mL), washed with brine (250 mL), dried over sodium sulfate, and purified by chromatography through a 300 g column eluting with a gradient of 0% to 70% EtOAc in hexane, to provide (2R,3S)-3-(dibenzylamino)-4-(4-(trifluoromethyl)phenyl)butan-2-ol (3.09 g, 65.9% yield) as a yellow oil. LCMS (ES+) m/z=414.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.28 (m, 3H) 2.84-2.94 (m, 2H) 3.08 (dd, J=12.81, 6.36 Hz, 1H) 3.66-3.76 (m, 4H) 4.03 (dt, J=10.66, 6.41 Hz, 1H) 7.15-7.28 (m, 12H) 7.51 (d, J=8.02 Hz, 2H).