Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-:4])C.[K+].[N+]([CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:14][C:13](=[O:22])[CH2:12][CH2:11]1)([O-])=O>ClCCl.CO>[O:4]=[C:10]1[CH2:11][CH2:12][C:13](=[O:22])[NH:14][CH:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC([N+](=O)[O-])C(c2ccccc2)N1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C1CCC(=O)C(c2ccccc2)N1
Temperature: -78 °C

Procedure:
Potassium t-butoxide (1.68 g, 15 mmol) was added to a solution of 5-nitro-2-oxo-6-phenylpiperidine (3 g, 13.6 mmol; Example 2a) in a mixture of dichloromethane (50 ml) and methanol (50 ml) and the mixture was cooled to -78° C. under nitrogen. Ozone was bubbled through the solution for 3 h. A yellow-green solution resulted, and TLC indicated no starting material remained. The reaction mixture was purged with oxygen for 5 min to remove excess ozone, then dimethylsulfide (7 ml) was added and the reaction mixture was allowed to warm to 23° C. The solvent was removed in-vacuo and the residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, then dried (K2CO3) and concentrated to leave 3,6-diketo-2-phenylpiperidine as a white solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2([C:26]([F:29])([F:28])[F:27])[O:17][N:16]=[C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2([C:26]([F:27])([F:28])[F:29])[O:17][N:16]=[C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: OCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.14 g of 4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzyl alcohol in 20 mL of dichloromethane, 2.00 g of silica gel was added, and 0.80 g of pyridinium chlorochromate (PCC) was added to the resultant mixture while stirring the mixture at room temperature, followed by stirring the resultant mixture at the same temperature for 17 hours. After the completion of the reaction, the reaction mixture was passed through silica gel column chromatography eluting with ethyl acetate to obtain 0.97 g of a crude objective substance as a white solid. This substance was used in the next process as it was without being further purified.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:17]=1.C=O.[BH3-][C:34]#N.[Na+]>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:34])[CH2:27][CH2:28]2)[CH:17]=1
Reactant: [BH3-]C#N
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(CN2CCNCC2)c1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Temperature: 27 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
The solution of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3-(piperazin-1-ylmethyl)benzamide (78 mg, 0.19 mmol) and HCHO solution (0.5 mL) in MeOH (10 mL) was stirred at 27° C. for 1 h. Then NaBH3CN (14.5 mg, 0.23 mmol) was added to the solution and stirred at 27° C. for 4 h. The solution was concentrated and the residue was purified by column chromatography to give the title product (14.1 mg, Yield 17.5%). 1H NMR (CD3OD, 400 MHz): δ 7.79 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.39-7.32 (m, 1H), 7.20-7.07 (m, 3H), 7.06-6.98 (m, 1H), 4.13 (quin, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.63-3.44 (m, 4H), 2.95-2.83 (m, 4H), 2.78-2.62 (m, 3H), 2.62-2.30 (m, 7H), 2.28 (s, 3H). LCMS (m/z): 423.2 (M+1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]([F:28])([F:27])[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([Cl:22])[CH:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[N:12]=1.[C:29](=[O:31])=[O:30].Cl>COCCOC.O>[F:28][C:10]([F:9])([F:27])[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([Cl:22])[C:14]([C:29]([OH:31])=[O:30])=[C:13]([C:23]([F:24])([F:25])[F:26])[N:12]=1
Reactant: O=C=O
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)O)c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
To a -78° C. solution of LDA (0.128 mol) in 85 ml of DME was added a solution of 18.28 g (0.057 mol) of product of Example 9 in 20 ml of DME. The reaction mixture was stirred at -78° C. for 1 hour. To the above solution was added excess of dry ice. After stirring at -78° C. the reaction mixture was warmed to room temperature in 1 hour and poured into 250 ml of water containing 50 ml of concentrated HCl. The oil precipitate was extracted into ether. The ether extract was extracted with saturated NaHCO3. The basic extract was made acidic with concentrated HCl. The oil precipitate was extracted into ether. The ether solution was dried (MgSO4) and concentrated in vacuo to give 7.81 g (37.6%) of product as a solid; mp 113°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.C(=O)([O-])O.[Na+].[C:16]([C:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([CH3:20])[CH3:19])#[N:17]>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:18]([C:16]#[N:17])([CH3:19])[CH3:20])[CH:22]=2)=[CH:3][C:4]=1[OH:10])#[N:7]
Reactant: N#Cc1ccc(N)cc1O
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(O)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a two-layer solution of 4-amino-2-hydroxybenzonitrile (3.16 g, 23.5 mmol) in tetrahydrofuran (80 mL)/1N aqueous sodium hydrogen carbonate solution (80 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 18 hr. The aqueous layer was separated, and extracted with ethyl acetate (100 mL). The combined organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (300 mL), anhydrous potassium carbonate (3.5 g) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (300 mL) was added to the obtained residue, and the mixture was washed with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate (50 mL)/hexane (50 mL) to give the title compound (3.10 g, 44%) as a pale-brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[NH:12][C:13]([CH:15]1[NH:19][CH:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]2([C:32]3[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:34])[CH:16]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[F:42])=[O:14].[NH4+].[Cl-]>CO.[Zn]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([NH:12][C:13]([CH:15]2[NH:19][CH:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[CH:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide (35 mg, 0.057 mmol) in methanol (3 mL) was added an aqueous solution (1.5 mL) of NH4Cl (30 mg, 0.57 mmol), followed by activated Zinc (Aldrich, 37 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was filtered through a short pad of celite. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-50% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-amino-2-methoxy-phenyl)-amide as a off white solid (24 mg, 72%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1F)[C:11]([OH:13])=[O:12]>>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: C1COCCN1
Product: O=C(O)c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C

Procedure:
A 2 L 3-neck round bottom flask fitted with mechanical stirrer and reflux condenser was charged with morpholine (700 g, 700 ml, 8 mol) and to the stirring solution was added 3,4-difluorobenzoic acid (158 g, 1 mol) (AmplaChem, Inc). The clear solution was heated at reflux and after 29 hours a ca. 0.5 ml aliquot was removed from the light yellow reaction solution, acidified with 6 N HCl and the precipitate was analyzed by 1H NMR (DMSO-d6) showing that the reaction was complete by the absence of the aromatic peaks at δ7.78-7.92 present in the starting material. The reaction was allowed to cool to below 100° C. and was carefully acidified (pH 1 to 2) with 6 N hydrochloric acid with rapid stirring (initial addition of 6N HCl was dropwise but then as a slow stream with cooling). The product starts to precipitate as the pH falls below 6. The precipitate was collected by filtration and washed thoroughly with hot (80° C.) water (2 L) to ensure the removal of morpholine hydrochloride (that appears as two triplets just above the morpholine peaks for (14) in the NMR) The white precipitate was dried at 110° C. under house vacuum and recrystallized by dissolving in ethanol (4.5 L) and concentration to 1.5 L with stirring. Crystals started to form in the refluxing solution when the volume had been reduced to ca. 3.5 L. The crystals were cooled to room temp with stirring, cooled in an ice bath for 1 hour with stirring, collected by filtration and dried in vacuo at 80° C. (172.5 g, 77%). 1H NMR spectrum identical with that for the product described in the previous paragraph.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[CH2:9]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>N1C=CC=CC=1>[CH2:9]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CC)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
2-Amino-5-ethyl-1,3,4-thiadiazole (169 mg, 1.3 mmol) was suspended in pyridine (0.5 mL). p-Dodecylbenzenesulfonyl chloride (300 mg, 0.87 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (5 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (225 mg, 0.51 mmol, 59%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 93-94° C.; 1H NMR (500 MHz, CDCl3) δ 0.88 (3, t, J=6.5 Hz), 1.20-1.36 (18, m), 1.33 (3, t, J=7.5 Hz), 1.54-1.63 (2, m), 2.63 (2, t, J=7.5 Hz), 2.84 (2, q, J=7.5 Hz), 7.25 (2, d, J=8.5 Hz), 7.83 (2, d, J=8.5 Hz), 12.30 (1, br s); 13C NMR (125 MHz, CDCl3) δ 12.6, 14.1, 22.7, 24.4, 29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.5, 128.8, 138.4, 148.2, 160.1 168.2; MS (ESI+, m/z) Calcd for C22H36N3O2S2 438.2249, found 438.30 (M+H)+; HRMS (ESI+, m/z) Calcd for C22H36N3O2S2 438.2249, found 438.2247 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ncccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCc1ncccn1
Reaction time: 0.33 h

Procedure:
Methanesulfonyl chloride (4.40 mL, 57.1 mmol) was added to a stirred solution of 2-hydroxymethylpyrimidine (6.28 g, 57.1 mmol) and triethylamine (9.50 mL, 68.5 mmol) in DCM (250 mL) at 0° C. After approximately 20 min, the reaction mixture was poured into water, the organic layer was separated and the aqueous phase was re-extracted twice with DCM. The combined organic extracts were washed with water, brine, dried (sodium sulfate), and concentrated in vacuo to afford the title compound i-2a. 1HNMR (500 MHz, CDCl3): δ 8.81 (d, 2H, J=4.8 Hz), 7.32 (t, 1H, J=4.9 Hz), 5.46 (s, 2H), 3.24 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:22][O:23][CH2:24][C@H:25]([CH3:45])[O:26][C:27]1[CH:28]=[C:29]([OH:44])[CH:30]=[C:31]([C:33]2[NH:34][C:35]([C:38]3[O:39][C@@H:40]([CH3:43])[CH2:41][N:42]=3)=[CH:36][CH:37]=2)[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:11]([CH3:12])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:44][C:29]3[CH:30]=[C:31]([C:33]4[NH:34][C:35]([C:38]5[O:39][C@@H:40]([CH3:43])[CH2:41][N:42]=5)=[CH:36][CH:37]=4)[CH:32]=[C:27]([O:26][C@@H:25]([CH3:45])[CH2:24][O:23][CH3:22])[CH:28]=3)=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:15][CH:16]=1
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (228 mg, 0.70 mmol) synthesized in Example (121b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (434 mg, 1.33 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (293 mg, yield 71%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([S:32](Cl)(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1.Cl>ClCCl>[CH3:2][O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:32]([C:28]1[C:29]([CH3:31])=[CH:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=1[CH3:36])(=[O:34])=[O:33]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)C(C)CCC1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(piperidin-2-yl)butanoic acid methyl ester hydrochloride (1.26 g, 5.683 mmol) was dissolved in dichloromethane (25 ml) and triethylamine (4 ml, 28.417 mmol) and a solution of 4-methoxy-2,6-dimethylbenzenesulfonic acid chloride (2.67 g, 11.37 mmol) in dichloromethane (10 ml) was added. The mixture was stirred overnight at room temperature. 1 mol/l HCl solution (10 ml) was added to the reaction mixture, followed by phase separation and extraction of the aqueous phase with dichloromethane (2×20 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with hexane/dichloromethane/diethyl ether (400:100:50). Yield: 1.65 g (75%)
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[C:34]1[O:38][C:37]([CH3:39])=[N:36][CH:35]=1.[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50](Cl)[N:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([C:34]3[O:38][C:37]([CH3:39])=[N:36][CH:35]=3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1cnc(C)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnc(C)o1
Yield: 26.7 %

Procedure:
Palladium(II) acetate (5.4 mg, 0.024 mmol) and 2-(dicyclohexylphosphino)biphenyl (17 mg, 0.048 mmol) were stirred in dioxane (3 mL) for 20 minutes under an atmosphere of nitrogen. Sodium tert.-butylate (44 mg, 0.45 mmol), 3-methoxy-4-(2-methyl-oxazol-5-yl)-phenylamine (61 mg, 0.30 mmol, CAS 568556-28-5; E. J. Iwanowicz et. al. Bioorganic & Medicinal Chemistry Letters, 13(12), 2059-2063; 2003) and 4-benzyl-2-chloro-6-methyl-pyrimidine (72 mg, 0.33 mmol) were added. The reaction was heated for 30 minutes to 130° C. in a microwave oven. Water was added and the reaction was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane and then methylenechloride/methanol (19:1 v/v) as eluent to yield the title compound as a yellow solid (31 mg, 27%). MS ISP (m/e): 387.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.86 (s, 1H), 7.61 (d, 2H), 7.26-7.33 (m, 5H), 7.15 (br s, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 3.97 (s, 2H), 3.90 (s, 3H), 2.51 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]([CH3:17])[C:8]2[NH:12][C:11]([CH2:13][CH2:14][CH3:15])=[N:10][C:9]=2[CH:16]=1)=[O:4].[OH-].[Na+].[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH:24][C:3]([C:5]1[CH:6]=[C:7]([CH3:17])[C:8]2[NH:12][C:11]([CH2:13][CH2:14][CH3:15])=[N:10][C:9]=2[CH:16]=1)=[O:4]
Reactant: COC(CN)OC
Reactant: CCCc1nc2cc(C(=O)OC)cc(C)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCc1nc2cc(C(=O)NCC(OC)OC)cc(C)c2[nH]1

Procedure:
[step 1] 6-Methoxycarbonyl-4-methyl-2-propylbenzimidazole (EP502314; 500 mg, 2.29 mmol) was suspended in ethanol (15 mL), 4 mol/L aqueous sodium hydroxide solution (3.1 mL) was added, and the mixture was stirred under reflux for 7 hr. The mixture was concentrated under reduced pressure, and water (20 mL) was added. Under ice-cooling, the mixture was adjusted to pH 1 with 2 mol/L hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, aminoacetaldehyde dimethylacetal (0.50 mL, 4.58 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (527 mg, 2.75 mmol) and 1-hydroxybenzotriazole (421 mg, 2.75 mmol) were added, and the mixture was stirred at room temperature for 6 hr. To the mixture were added saturated aqueous sodium hydrogen carbonate solution (100 mL) and chloroform (100 mL), and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 6-(2,2-dimethoxyethylcarbamoyl)-4-methyl-2-propylbenzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C-:11]#[N:12].[Na+]>[Cu]C#N>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([C:11]#[N:12])=[O:6]
Reactant: [C-]#N
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: N#C[Cu]
Agent: [Na+]
Product: N#CC(=O)c1cccc(Cl)c1
Temperature: 220 °C
Yield: 96.5 %

Procedure:
175 g (1 mol) of 3-chlorobenzoyl chloride, 48.5 g (0.97 mol) of sodium cyanide and 2.7 g of copper(I) cyanide were mixed in a three-necked flask and the mixture was warmed to 220° C. in the course of 90 minutes, whilst stirring. the reaction product was removed from the sodium chloride by applying a vacuum. Fractional distillation gave 155 g (94% of theory) of 3-chlorobenzoyl cyanide; boiling point: 112°-115° C. at 12 mm Hg.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH2:36])=[O:35])[C:23]=6[CH:37]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1>CC(N(C)C)=O.CC(N(C)C)=O>[CH3:7][N:6]([CH3:11])/[C:5](=[N:36]\[C:34]([C:24]1[C:23]2[CH:37]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]4[O:12][CH2:11][N:6]5[C:7]6[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=6[CH:4]=[C:5]5[C:14]=4[N:15]=3)[C:20]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:21][C:22]=2[O:26][C:25]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)=[O:35])/[CH3:4]
Reactant: CN(c1cc2oc(-c3ccc(F)cc3)c(C(N)=O)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Solvent: CC(=O)N(C)C
Product: C/C(=N/C(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12)N(C)C

Procedure:
To a solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.17 mmol) in DMA-DMA (2 mL) was stirred at 120° C. for 2 hour. The reaction mixture was concentrated in vacuo and the resulting residue was used to the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:7]1[CH:6]=[C:3]([C:4]#[N:5])[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:9][CH:8]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1cc(F)ccc1Br
Product: N#Cc1cc(F)ccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-5-fluorobenzonitrile was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 2 to give 4,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.38-7.56 (4H, m), 8.33-8.40 (2H, m).