Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C(O[N:21]1N=N[C:23]2C=CC=[N:27][C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(=NO)(N)C>CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:27]=[C:22]([CH3:23])[N:21]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(I)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(N)=NO
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(I)ccc1-c1nc(C)no1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
A mixture of 4-iodo-2-methoxy benzoic acid (83 mg, 0.3 mmol), HATU (114 mg, 0.3 mmol), DIEA (26 μL, 0.15 mmol), and HOBt (8 mg, 0.06 mmol) in DMF was stirred at room temperature for 5 minutes. Acetamide oxime (22 mg, 0.3 mmol) was added, and reaction was stirred for 30 minutes at room temperature. The reaction was then heated to 110° C. for 16 hours. Cooled to room temperature. Partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by HPLC to provide 37 mg (39%) of desired product. MS (ESI) m/e 317 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 7.70 (d, J=8.14 Hz, 1H), 7.64 (d, J=1.36 Hz, 1H), 7.53 (dd, J=8.31-1.53 Hz, 1H), 3.94 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Cl[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36].O>CN(C=O)C>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: O=C1CC(C(F)(F)F)=NN1c1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
To a solution of 2,4-dihydro-2-phenyl-5-trifluoromethyl-3H-pyrazol-3-one (Formula III: R1 =Ph; R2 =CF3 ; R3 =H) (1.12 g; 4.91 mmol) in DMF (25 ml) was added 280 mg (4.83 mmol) of KF followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1 g, 3.3 mmol) and the resulting mixture was stirred at room temperature for 24 hours and then was poured into water. The above mixture was extracted with ethyl acetate and the organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.29 g (18%) of 4-isopropyl-6-methoxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a solid
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[C:8](Cl)=[C:7]([CH:14]=O)[C:6]=2[CH:16]=1.[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[C:8]3[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][C:7]=3[C:6]=2[CH:16]=1
Reactant: O=CC1=C(Cl)C2CC(C2)c2cc(F)c(Br)cc21
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(s1)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 60 °C
Yield: 27 %

Procedure:
Into a pressure tube containing a solution of 2-bromo-8-chloro-3-fluoro-6,7-dihydro-5H-5,7-methanobenzo[7]annulene-9-carbaldehyde (125 mg at 79% purity LCMS-UV215) in anhydrous N,N-dimethylformamide (0.5 mL) was introduced ethyl mercaptoacetate (46 mg, 0.38 mmol as a solution in 0.5 mL of anhydrous N,N-dimethylformamide) and finely powdered potassium carbonate (53 mg, 0.38 mmol). After warming to 60° C. for 4 hr, the reaction mixture was concentrated in vacuo, the residue suspended in ethyl acetate (15 mL) and washed with water (2×10 ml) and brine (10 ml). The organic extract was dried over sodium sulfate, filtered and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) furnished the title compound (39 mg, 0.10 mmol, 27% over 2 steps) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.40 (t, J=7.09 Hz, 3H), 1.71 (d, J=8.83 Hz, 2H), 2.86-2.95 (m, 2H), 3.57 (m, 2H), 4.37 (q, J=7.04 Hz, 2H), 6.91 (dd, J=9.14, 2.21 Hz, 1H), 8.06 (dd, J=6.94, 2.21 Hz, 1H), 8.22 (d, J=1.89 Hz, 1H); M+1=381/383.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH3:45])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[NH2:24])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>P([O-])([O-])([O-])=O.[NH4+].[NH4+].[NH4+]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH3:45])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[NH2:24])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(N)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(c3c(N)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 52 %

Procedure:
Diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(2-amino-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (400 mg) was added to a stirred, cooled (ice/H2O bath) solution of trifluoroacetic acid (6 mL) and anisole (0.5 mL). The cooling bath was removed and the solution stirred for 0.33 hr at ambient temperatures. The solution was concentrated and the residue macerated with methylene chloride to afford a yellow solid. The solid was dissolved in 0.05M (pH 6.5) ammonium phosphate. The solution was applied to a Michel-Miller HPLPLC column (22×300 mm) containing Partisil Prep 40 ODS-3. The column was eluted with 0.05M (pH 6.5) ammonium phosphate/acetonitrile (90:10). The appropriate fractions were combined and the pH lowered to 3.7 with the addition of dilute hydrochloric acid. The solution was concentrated to a volume of 50 mL when the title compound crystallized (155 mg, 52% yield).
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:38][CH:39]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 80%).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH2:42][CH2:43][NH2:44])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:35][CH:34]=[C:33]([NH:41][CH2:42][CH2:43][NH:44][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: CCC(=O)c1ccc(NCCN)nc1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C(C)C)CC4)nn23)nc1N
Temperature: 120 °C

Procedure:
30 mg (0.07 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 21 mg (0.09 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}propan-1-one hydrochloride (Example 25A) and 75 μl (0.4 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 120° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 21 mg (50% of theory) of the product as a solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1>CN(C=O)C>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: Nc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(-n2ncc3ccc(I)cc32)ncn1
Temperature: 60 °C
Reaction time: 17 h
Yield: 35.9 %

Procedure:
To a solution of 6-iodoindazole (500 mg, 2.05 mmol) in DMF (8 mL) was added NaH (60% oil dispersion, 131.12 mg, 3.28 mmol) at 0° C. The mixture was stirred at 0° C. to RT for 10 minutes before addition of 6-chloropyrimidin-4-amine (477.78 mg, 3.69 mmol) and stirring at 60° C. for 17 hr and then transferred to a pressure tube and heated at 70° C. for a further 6 hr. The reaction mixture was cooled and quenched by the addition of water (10 ml) and EtOAc (a few drops) was added. The resultant precipitate was collected by suction filtration and then thoroughly dried under high vacuum to give the title intermediate (248 mg): LC-MS: m/z=+338.20 (M+H)+.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH:17]4[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]4)[N:13]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:5][C:4]=2[CH:3]=1.[CH3:27][C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30](C(OC(C)(C)C)=O)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:27][C:28]1[NH:29][N:30]=[CH:31][C:32]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH:17]4[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]4)[N:13]3[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1C2CCC(CC2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3C4CCC(CC4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
tert-Butyl (3S)-3-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate (190 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (266 mg), sodium carbonate (78 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (35 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (146 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:8]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A mixture of 4-chloro-2-nitrobenzenamine (5.1 g, 30 mmol) and N-bromosuccinimide (6.2 g, 36 mmol) in acetonitrile (50 mL) was heated at reflux for overnight. It was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed with saturated aqueous K2CO3 solution (100 mL×2). The organic phase was separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 109a as a yellow solid (8.1 g, 100%). LCMS: [M+H]+ 253. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=2.5 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 6.64 (s, 2H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([OH:24])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CC1(C)[O:41][CH:40]([CH2:42][CH2:43]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:39][O:38]1.O>CN(C=O)C>[CH:1]([O:4][C:5](=[O:29])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:43][CH2:42][CH:40]([OH:41])[CH2:39][OH:38])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC1(C)OCC(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCC(O)CO)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of [4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (100 mg, 0.26 mmol) in DMF (3 mL) is added K2CO3 (43.2 mg, 0.312 mmole) and 4-nitrobenzenesulfonic acid 2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (129 mg, 0.39 mmole) and the reaction is stirred for 18 h at ambient temperature. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with EtOAc/hexane and dried in vacuo to afford 96 mg, 84% of the desired product, (4-{3-cyano-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-1H-indol-2-yl}carbamic acid isopropyl ester, compound 1428.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:27]=[CH:26][C:25](I)=[C:24]([CH3:29])[CH:23]=2)[CH:18]=[CH:19][C:20]=1[I:21].C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[CH3:29][C:24]1[CH:23]=[C:22]([C:17]2[CH:18]=[CH:19][C:20]([I:21])=[C:15]([CH3:14])[CH:16]=2)[CH:27]=[CH:26][C:25]=1[N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Cc1cc(-c2ccc(I)c(C)c2)ccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc(-c2ccc(N(c3ccccc3)c3ccccc3)c(C)c2)ccc1I
Yield: 57.1 %

Procedure:
20.3 g (0.12 mol) of diphenylamine, 65.1 g (0.15 mol) of 3,3'-dimethyl-4,4'-diiodobiphenyl, 19.3 g (0.14 mol) of anhydrous potassium carbonate, 1.52 g (0.024 mol) of copper powder, and 20 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 190° C. to 205° C. for 21 hours. The reaction product was then extracted with 200 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 2/7 mixture of toluene and n-hexane) to obtain 32.6 g (yield: 57.2%) of N-(3,3'-dimethyl-4'-iodo-4-biphenylyl)-N,N-diphenylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[C:6]=1[O:16][CH3:17])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[NH:27][C:13]=2[CH3:14])[C:6]=1[O:16][CH3:17])[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1OC
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1OC

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Methoxy-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].CCN(CC)CC>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: NO
Reactant: Cc1cc(C=O)ccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C=NO)ccc1Br
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a mixture of 4-bromo-3-methyl-benzaldehyde (372 mg, 1.87 mmol) and hydroxylamine hydrochloride (306.5 mg, 4.41 mmol) in ethanol (5 mL) at rt was added Et3N (0.15 mL). The reaction mixture was heated under reflux for 2 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA (10 mL), washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 4-bromo-3-methylbenzaldehyde oxime (384 mg; yield 96%) as a white solid.
Reaction SMILES: B1C2CCCC1CCC2.[C:10]([O:14][C:15](=[O:46])[NH:16][C:17]1([CH2:43][CH:44]=[CH2:45])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][C:33]=2[Cl:34])[C:30]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:29][CH:28]=[CH:27]3)[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[OH-:47].[Na+].OO>C1COCC1>[C:10]([O:14][C:15](=[O:46])[NH:16][C:17]1([CH2:43][CH2:44][CH2:45][OH:47])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][C:33]=2[Cl:34])[C:30]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:29][CH:28]=[CH:27]3)[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CCCO)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.87 mL (1.43 mmol) of a 0.5M solution of 9-BBN in THF were added to a solution of 250 mg (0.48 mmol) of [1-allyl-4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (52) in 5 mL THF at 0° C. The reaction mixture was allowed to warm to room temperature over night, before being cooled to 0° C. Then, 5 mL of 3M aqueous sodium hydroxide and 5 mL of 30% aqueous hydrogen peroxide were added slowly, and the mixture was stirred for 5 h. The mixture was extracted twice with ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 196 mg of the title compound 53 could be isolated as mixture of diastereoisomers in a purity sufficient for further conversion. Rt=2.05 min (Method C). Detected mass: 541.3 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1.O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)[C:10]=3[F:50])[CH2:2][CH2:3]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(-n2nc3cc(OCC4CC4)ccc3c2F)cc1)(C(C)C)C(C)C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (218 mg) in THF (2.5 mL) was added dropwise a THF solution (1.11 M, 0.59 mL) of lithiumdiisopropylamide at −78° C. under an argon atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added N-fluorobenzenesulfonimide (236 mg) at −78° C., and the mixture was stirred at 0° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (110 mg).
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)C)=O)C=C(F)C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.[F:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46]([NH:48][C@H:49]([C:51]([NH:53][C@H:54]2[C:60](=[O:61])[NH:59][C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[S:56][C@H:55]2[C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:67]=2[F:73])=[O:52])[CH3:50])=[O:47])[CH:41]=[C:42]([F:44])[CH:43]=1>ClCCl>[F:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46]([NH:48][C@H:49]([C:51]([NH:53][C@@H:54]2[C:60](=[O:61])[NH:59][C:58]3[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=3[S:56][C@@H:55]2[C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:67]=2[F:73])=[O:52])[CH3:50])=[O:47])[CH:41]=[C:42]([F:44])[CH:43]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of racemic 2,3-cis-3-amino-2-(2,5-difluorophenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (1d) (300 mg) in dichloromethane (40 mL) at 0° C. under nitrogen was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (238 mg), HOBt-hydrate (330 mg), EDAC-HCl (282 mg) and NMM (165 mg). The reaction mixture was stirred 1 h at 0° C., concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, saturated aqueous sodium bicarbonate, and brine, dried, filtered and evaporated to yield a mixture of the title compound and N2-[(3,5-difluorophenyl)acetyl]-N1-[(2S,3S)-2-(2,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-L-alaninamide. The crude product (500 mg) was purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound (180 mg, 69%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ1.22 (d, 3H), 3.48 (s, 2H), 4.29 (m, 1H), 4.93 (t, 1H), 5.68 (d, 1H), 6.01 (d, 1H), 6.50 (d, 1H), 6.73-6.80 (m, 3H), 6.93-7.02 (m, 2H), 7.15 (d, 1H), 7.30 (t, 1H), 7.43 (t, 1H),7.5-7.6 (m, 1H), 7.73 (d, 1H), 7.74 (s, 1H). MS APCI, m/z=532 (M+1). LC/MS: 2.53 min.