Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:8]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.[CH3:26][O+](C)C>C(Cl)Cl>[CH3:26][O:1][C:2]1[CH:8]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: COC(=O)c1ccccc1CCC1CCCCNC1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1CCC1CCCCN=C1OC

Procedure:
The product of Example 88 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].O=S(Cl)[Cl:16].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-methylsulphonylbenzoic acid (100 mg, 0.48 mmol) in DCM (2 mL) was added SOCl2 (52 μL, 0.73 mmol) and toluene (2 mL) and the resulting reaction was stirred at 60° C. for 20 hours. A further charge of SOCl2 (100 μL, 1.45 mmol) was added and the reaction was heated at 80° C. for a further 24 hours. Volatiles were removed at reduced pressure and the crude product used in subsequent steps without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[C@@H:27]([F:32])[CH2:26]1)[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:31][C@@H:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][C@@H:27]4[F:32])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN1CC[C@@H](N)[C@@H](F)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)[C@@H](F)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (15.35 g, 45.5 mmol), (3S,4R)-1-ethyl-3-fluoro-piperidin-4-ylamine (dihydrochloride salt) (6.30 g, 29.0 mmol), diisopropylethylamine (21.0 ml, 120 mmol) in propan-2-ol (200 ml) was heated at 80° C. for 14 h. The mixture was cooled to 25° C. and was stirred at that temperature for 4 h. The resulting yellow precipitate was collected by vacuum filtration, washed with Et2O (1×30 ml), and air-dried to give (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((3S,4R)-1-ethyl-3-fluoro-piperidin-4-yl)-amine (11.5 g, 90% over 3 steps) as a yellow solid. LCMS (Method G, ESI): RT=0.69 min, m+H=448.3; 1H NMR (400 MHz, CDCl3) δ 9.35 (d, J=8.4 Hz, 1H), 9.12 (s, 1H), 8.29-8.11 (m, 2H), 7.69-7.59 (m, 2H), 7.52 (t, J=7.8 Hz, 2H), 7.26 (s, 1H), 6.65 (d, J=4.2 Hz, 1H), 4.86 (d, J=48.6 Hz, 1H), 4.28-4.05 (m, 1H), 3.27-3.13 (m, 1H), 2.97-2.87 (m, 1H), 2.52 (q, J=7.2 Hz, 2H), 2.49-2.37 (m, 1H), 2.29 (t, J=10.0 Hz, 1H), 2.15-1.98 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH:16]1[CH:21]=[C:20]2[C:22]([O:24][S:25](=[O:27])(=[O:26])[C:19]2=[CH:18][CH:17]=1)=[O:23].O>C(#N)C>[S:25]([C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][C:20]=1[C:22]([O:15][CH2:14][C:2]1([CH3:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13])=[O:23])([OH:27])(=[O:26])=[O:24]
Reactant: CC1(CO)CN(c2ccccc2)NC1=O
Reactant: O=C1OS(=O)(=O)c2ccccc21
Solvent: CC#N
Solvent: O
Product: CC1(COC(=O)c2ccccc2S(=O)(=O)O)CN(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 4-methyl-4-hydroxymethyl-1-phenyl-3-pyrazolidinone (Dimezone-S®) (10 g, 48.5 mmol) in neat acetonitrile (200 ml), there is added 2-sulfobenzoic acid cyclic anhydride (8.9 g, 48.5 mmol) all at the same time, at room temperature, while stirring. The reaction mixture is heated to reflux under nitrogen until complete dissolution is observed. The process is continued for 24 hours and the mixture is cooled in a bath of ice and water for 2 hours. A solid precipitant is obtained that is collected by filtration and washed with acetonitrile cooled by means of ice. After drying under vacuum, 17.9 g (95%) of 4-methyl-3-oxo-l-phenyl-pyrazolidin-4-yl)methyl 2-sulfobenzoate (Compound II) is isolated in the form of a whitish solid.
Reaction SMILES: [Li+].CCC[CH2-].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.CCCCCC>CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([B:18]([OH:19])[OH:17])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc(Br)c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-Butyllithium (2.5M; 44 mL; 0.11M) was added dropwise over 15 mins. to a vigorously stirred solution of m-dibromobenzene (25 g; 0.106M) in 500 mL of anhydrous ether at -78° under nitrogen. After stirring 10 mins. more, a solution of triisopropylborate (25.3 mL; 0.11M) in anhydrous ether (200 mL) was added over 20 mins. The cooling bath was then removed, and the stirring solution was allowed to warm to R.T. over ~2 hrs. A small amount of solid separated. After stirring 15 mins. more at R.T., 150 mL of ice cold 8% aqueous hydrochloric acid was cautiously added, and the stirring was continued for 15 mins. The organic phase was separated, washed with 2×100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent removal gave ~30 G of crude product as a semi-solid, which was shaken well with 150 mL of hexane. The solid was filtered and washed with 2×25 mL of hexane. The resulting silky solid (mp 178°-9° C. after softening at ~ 160° C.) (6.5 g) was used as 3-bromophenylboronic acid with a small amount of contamination. The hexane filtrate was concentrated and the residue was stirred well with 150 mL of petroleum ether (30°-60°). The resulting solid was filtered and washed with 2×25 mL of petroleum ether. This resulting solid (4.4 g) melting at 178.3°-179° C. was the desired 3-bromophenylboronic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1>CO.[Pd]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)CCOc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1cccc(N)c1
Yield: 85.1 %

Procedure:
A solution of dimethyl-[2-(3-nitro-phenoxy)-ethyl]-amine (500 mg, 2.38 mmol) in methanol (20 ml) was hydrogenated over 10% Pd—C at 30 psi until no further gas uptake was observed. The reaction mixture was then filtered over celite and concentrated to yield 3-(2-dimethylamino-ethoxy)-phenylamine (365 mg, 85%) as viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[N:7]=[C:6]([CH2:14][OH:15])[CH:5]=[N:4][C:3]1=2.C(N(CC)CC)C.O.C(OCC)(=O)C.CCCCCC>ClCCl>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[N:7]=[C:6]([CH:14]=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2nc(CO)cnc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2nc(C=O)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A solution of 7.7 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxaline-2-methanol in 120 ml of dichloromethane was then added dropwise to the reaction mixture and the resulting mixture-was stirred for 15 minutes. To the reaction mixture were added with 35.1 ml of triethylamine, followed by stirring for 5 minutes. After the reaction mixture was raised to room temperature and stirred for 15 minutes, water was added and the resulting mixture was extracted with dichloromethane. The organic layer was successively washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 10% ethyl acetate/n-hexane), whereby 6.7 g of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20]([CH3:22])=O.C[O-].[Na+]>CO>[CH3:16][O:17][C:18]([C:19]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=2)=[N:2][O:1][C:20]=1[CH3:22])=[O:23]
Reactant: ON=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccc(OC(F)(F)F)cc2)noc1C
Yield: 67 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-4-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylacetoacetate (7.76 g, 66.78 mmol) and sodium methoxide (5.41 g, 100.17 mmol), a white solid required compound (6.74 g, 22.36 mmol, 67%) was obtained.
Reaction SMILES: [C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:6][CH2:7][C@H:8]([CH3:12])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:32]C(OCC)=O>ClCCl>[C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:6][CH2:7][C@H:8]([CH3:12])[C:9]([Cl:32])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)Cl
Reaction time: 1 h

Procedure:
(S)-(+)-3-(tert-Butyl-diphenyl-silanyloxy)-2-methylpropionic acid (0.44 g; 1.20 mmol) (from Example 13a supra) was dissolved in dichloromethane (3 mL, dried over molecular sieves). Triethylamine (0.36 mL; 2.58 mmol) (Aldrich) was added and the solution was cooled in an ice-water bath. Ethyl chloroformate (0.16 mL; 1.63 mmol) (Aldrich) was added dropwise and the mixture was stirred in the cold for 1 hour. The mixture was then diluted with additional dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield (S)-(+)-3-(tert-butyl-diphenyl-silanyloxy)-2-methylpropionic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[O:20]1[CH2:22][CH:21]1[C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1.Cl([O-])(=O)(=O)=O.[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:27]1[C:26]2[CH:31]=[CH:32][C:23]([CH:21]([OH:20])[CH2:22][N:17]3[CH2:18][CH2:19][CH:14]([C:12]([C:10]4[S:11][C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=5[N:9]=4)=[O:13])[CH2:15][CH2:16]3)=[CH:24][C:25]=2[O:30][CH2:29][CH2:28]1
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Reactant: c1cc2c(cc1C1CO1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cccc2sc(C(=O)C3CCN(CC(O)c4ccc5c(c4)OCCO5)CC3)nc12
Temperature: 80 °C
Yield: 73.3 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (83 mg, 0.3 mmol), 6-oxiranyl-2,3-dihydro-benzo[1,4]dioxine (53.5 mg, 0.3 mmol), lithium perchlorate (32 mg, 0.3 mmol) and potassium carbonate (42 mg, 0.3 mmol) in DMF (2 ml) was heated at 80° C. overnight. The mixture was poured on water and extracted with EtOAc. Organic extracts were washed with water and brine, dried over MgSO4 and concentrated. Chromatography on SiO2 (EtOAc/MeOH 9:1) gave the title compound as a beige solid (100 mg, 73%, 4:1 mixture of regioisomers).
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH:20](O)[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].P(Br)(Br)[Br:24].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[Br:24][CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][N:11]2[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:21]
Reactant: BrP(Br)Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)O)cccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 282 (400 mg, 1.27 mmol) in dry DCM (2 mL) and dry Et2O (2 mL) at 0° C. under Argon was added PBr3 (515 mg, 1.91 mmol) and the mixture was stirred at RT overnight. The mixture was poured into cold NaHCO3 (aq.) and extracted with EtOAc. The combined extracts were washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 450 mg (92%) of 4-(1-bromoethyl)-1-tosyl-1H-indole (284) give as a yellow oil, which was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.65 (d, J=2.8 Hz, 1H), 7.35-7.23 (m, 4H), 6.89 (d, J=2.8 Hz, 1H), 5.53-5.50 (m, 1H), 2.36 (s, 3H), 2.13 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(C)cc1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.77 (t, J=7.0 Hz, 3 H), 1.1-1.3 (m, 15 H), 2.27 (m, 2 H), 2.42 (s, 3 H), 3.4 (m, 2 H), 4.34 (d, J=6.0 Hz, 2 H), 5.30-5.40 (m, 1 H), 5.90 (d, J=16.0 Hz, 1 H), 7.0 (d, J=8.0 Hz, 2 H), 7.18 (d, J=8.0 Hz, 2 H). FAB-MS: calculated for C24H33NO 352; found 352 (M+H, 100%). Rf=0.38 (10% ethyl acetate/n-hexane). mp 72-75° C.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:17]2[C:12](=[N:13][C:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:16]=2)[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:10](=[O:36])[C:9]=1[Cl:37])C(=O)C)(=[O:3])[CH3:2].CO.C1COCC1>C(N(CC)CC)C>[Cl:37][C:9]1[C:10](=[O:36])[N:11]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:12]2[C:17]([C:8]=1[NH:4][C:1](=[O:3])[CH3:2])=[CH:16][C:15]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[C:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:13]=2
Reactant: CC(=O)N(C(C)=O)c1c(Cl)c(=O)n(CC(C)C)c2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1c(Cl)c(=O)n(CC(C)C)c2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
The product of EXAMPLE 69 (85 mg) was combined with methanol (7 mL), THF (4 mL) water (2 mL) and triethylamine (2 mL) at room temperature. After 1.5 hours the reaction was concentrated and the residue dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4). The concentrated residue was purified by flash chromatography on silica gel eluted with 0-50% EtOAc in hexane affording the title compound. HPLC/MS: 513.9 (M+I), 515.9 (M+3); Rt=4.05 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1N)=[O:5])[CH3:2].N(OC(C)(C)C)=O.[Cl-].[NH4+]>C(O)C.[Cu](Br)Br>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CC)sc1N
Agent: Br[Cu]Br
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)c1csc(CC)c1
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
2-Amino-5-ethyl-thiophene-3-carboxylic acid ethyl ester (2.5 g, 12.5 mmol) was added to a suspension of t-butyl nitrite (18.8 mmol) and copper (II) bromide (15.1 mmol) in ethanol (120 mL). The reaction mixture was stirred for 15 minutes then saturated aqueous ammonium chloride (7 mL) was added and the mixture stirred for a further 15 minutes. The solvent was removed under vacuum and product partitioned between diethyl ether and water. The organic layer was dried over magnesium sulphate, filtered and the solvent removed. The product was purified by column chromatography on silica, eluting with 0%-10% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (1.2 g). 1H NMR (400 MHz, CHCl3-d): δ 7.9 (s, 1H), 7.2 (s, 1H), 3.4 (q, 2H), 2.8 (q, 2H), 1.4 (m, 6H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:17][N:18]=[CH:19][C:11]=4[C:10]=3[C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24]N1C(=O)CCC1=O.O>ClCCl>[Br:24][C:19]1[C:11]2[C:10]3[C:9]4[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=4[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:17][N:18]=1
Reactant: c1ccc(C2Cc3cnc4[nH]ncc4c3-c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: Brc1n[nH]c2ncc3c(c12)-c1ccccc1C(c1ccccc1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of 7-phenyl-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c]isoquinoline (0.018 g, 0.060 mmol) in dichloromethane (2 mL) was added N-bromosuccinimide (0.011 g, 0.063 mmol). The reaction was stirred at room temperature for 16 hours followed by addition of water (2 mL) and dichloromethane (3 mL). The organic layer was separated, dried using Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, 10% EtOAc in hexane) to give the pure desired product, 1-bromo-7-phenyl-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c]isoquinoline as a yellow solid (0.010 g, 44%). M.p.=176-178° C.; 1H NMR (DMSO-d6, 400 MHz) δ 9.36 (m, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 7.56 (m, 2H), 7.30-7.15 (m, 6H), 4.73 (t, J=7.2 Hz, 1H), 3.42 (m, 2H); LCMS [M+H]: 377; Elemental analysis (%): C, 63.59; H, 4.10; N, 10.98. Calcd for C20H14BrN3: C, 63.85; H, 3.75; N, 11.17.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Reactant: OCc1ccccn1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2ccccn2)n1

Procedure:
Prepared by the method of Example 20 using pyridine-2-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.07 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]3[CH2:18][CH2:19][N:20](C([O-])=O)[CH:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[ClH:24]>[Pd].C(O)C.CO>[ClH:1].[ClH:24].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][NH:20][C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])N1CCC2C(c3ccc(Cl)cc3)Nc3ccccc3C21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Clc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of benzyl(3aR*,4R*,9bR*)-4-(4-chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (730 mg, 1.75 mmol) and 10% palladium on carbon (50% aqueous, 0.3 g) in ethanol (10 ml) was added a hydrogen chloride in methanol solution (1 ml) and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hrs. The reaction mixture was filtered, washed with aqueous methanol, and the filtrate was concentrated. The residue was dried under reduced pressure to give the crude title compound as an oil. (350 mg, ca. 100%)
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[N:30]=[C:31]=[O:32]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:31]([NH:30][C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:32])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1cccs1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccs1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-thienyl isocyanate (0.153 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 257 mg (85.1%) of the desired product as a solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:22](=[O:23])[C:21]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[C:37]6[NH:41][C:40](=[O:42])[O:39][N:38]=6)=[CH:27][CH:26]=5)=[C:20]([CH2:43][CH2:44][CH3:45])[N:19]=[C:18]4[CH2:46][CH3:47])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1>O1CCCC1.C(OCC)(=O)C>[CH2:46]([C:18]1[N:17]([C:14]2[CH:13]=[CH:12][C:11]([N:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)[C:22](=[O:23])[C:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:20]([CH2:43][CH2:44][CH3:45])[N:19]=1)[CH3:47]
Reactant: CCCc1nc(CC)n(-c2ccc(N3CCC4(CC3)OCCO4)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(CC)n(-c2ccc(N3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Yield: 107.5 %

Procedure:
A solution of 3-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.45 g) in tetrahydrofuran (10 mL)-1 M hydrochloric acid (10 mL) was stirred at 60° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated 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 as a colorless solid (0.45 g, 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][N:46]([CH3:55])[C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50][NH2:51]>CN(C=O)C>[CH3:45][N:46]([CH3:55])[C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[CH2:50][NH:51][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:22]
Reactant: CN(C)c1cccc(CN)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(N(C)C)c4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 3-dimethylaminobenzylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(3-dimethylaminobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.11 min, MH+ 427.