Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([C:13](O)=[O:14])=[CH:6]2.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([CH2:13][OH:14])=[CH:6]2
Reactant: COc1ccc2c(c1)C=C(C(=O)O)CO2
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C=C(CO)CO2
Temperature: -16 °C
Reaction time: 0.17 h

Procedure:
A solution of 2.5 g (12.13 mmol) of the acid obtained in Step A in 30 ml of anhydrous tetrahydrofuran is cooled to −16° C.; 2.5 ml (18.2 mmol) of triethylamine are then added dropwise to the medium. After 10 minutes of stirring, 1.98 g (18.2 mmol) of ethyl chloroformate are slowly added to the reaction mixture. The solution is stirred under argon for 3 hours, the salts are filtered off and then the filtrate is cooled to −16° C. 1.84 g (48.5 mmol) of sodium borohydride are added to the medium all at once; 10 ml of methanol are then added very slowly to the solution. After 2 hours of stirring at −16° C., the reaction mixture is hydrolysed with a saturated solution of ammonium chloride; the aqueous phase is then extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The allyl alcohol of the title is obtained pure in the form of a yellow oil after passage over a silica column (eluant: AcOEt/PE: 30/70 then 50/50).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([F:10])[C:5]=1[NH:11]C(=O)OC(C)(C)C)[CH3:2].[I-].[Na+].C[Si](Cl)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:11][C:5]1[C:6]([F:10])=[N:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1ccnc(F)c1NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CCOc1ccnc(F)c1N

Procedure:
To a solution of 19 g (74 mmol) of t-butyl N-(4-ethoxy-2-fluoro-3-pyridinyl)carbamate and 12.2 g (81.5 mmol) of sodium iodide in 400 mL of dry acetonitrile was added with stirring 8.9 g (81.5 mmol) of trimethylsilyl chloride. The mixture was allowed to react for 4 hr and then a 100 mL solution of aqueous sodium bicarbonate was added with stirring. The resulting mixture was extracted with 1 L of ether and the ether extract was dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography to obtain 6.3 g (55 percent of theory) of the title compound as a colorless solid melting at 76°-77° C.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[OH:39])[O:35][CH2:34][CH2:33][CH:32]2[C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu]Cl>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([O:39][C:38]2[CH:37]=[C:36]3[C:31]([CH:32]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:33][CH2:34][O:35]3)=[CH:30][C:29]=2[Cl:28])=[CH:3][CH:4]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(I)cc1
Reactant: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(Cl)cc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
tert-Butyl 4-iodobenzoate (25.9 g, 85.2 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (7.01 mL, 34.1 mmol) were diluted with NMP (70 mL) and bubbled with Argon for 20 minutes. Copper (I) chloride (16.9 g, 170 mmol), ethyl 6-chloro-7-hydroxychroman-4-carboxylate (24.0 g, 93.7 mmol) and cesium carbonate (55.5 g, 170 mmol) were combined and added to the reaction using a small funnel which was rinsed with NMP (30 mL). The reaction was purged for an additional 10 minutes and then heated to 100° C. and stirred for 5 hours under Argon. The reaction was cooled and loaded directly onto a silica plug (2 kg) and eluted with 10% ethyl acetate/hexanes to yield 10 g of crude product. The crude material was purified by silica gel column chromatography, eluting with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to provide the desired product (14 g, 32.3 mmol, 38.0% yield) as a viscous oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(O)(=O)CC>[CH:5]1[CH:6]=[CH:7][C:2]([C:1]2[C:13]3=[N:9][C:10]([CH:11]=[CH:12]3)=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:10]3=[N:9][C:13]([CH:12]=[CH:11]3)=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]3[NH:9][C:13](=[CH:12][CH:11]=3)[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]3[NH:9][C:13]=2[CH:12]=[CH:11]3)=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: C1=Cc2nc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Reaction time: 24 h
Yield: 20 %

Procedure:
In a 4-liter flask equipped with a cooling tube, 80 ml (84.8 g) of benzaldehyde, 56 ml (53.6 g) of pyrrol, and 3 liters of propionic acid were placed and reacted for 30 minutes under reflux. Then, the flask was allowed to stand for one day. After filtering the reaction mixture, recrystallization from a mixed solvent of methanol and chloroform (1:1 by weight) was carried out for purification. Thus, α,β,γ,δ-tetraphenylporphine was obtained in 20% yield.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][CH3:30].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:55]>>[NH2:55][C:19]1[C:18]2[N:17]=[C:16]([CH2:28][CH2:29][CH3:30])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:31])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)NC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCCCCC(=O)NC

Procedure:
N-Methyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide (3.8 g, 9.0 mmol) was treated with mCPBA (4.65 g, 26.9 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.31 g, 12.1 mmol) according to the method described in Part D of Example 8. The crude product was purified as described in Part D of Example 8 to provide 1.036 g of 12-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methyldodecanamide as a brown crystalline solid, mp 135-137° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[CH:8]([O-])([O-])[O:9][CH2:10][CH3:11].C(OC(=O)C)(=O)C.CCO>CCOC(C)=O>[CH2:10]([O:9][CH:8]=[C:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])[CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC=C(C(C)=O)C(C)=O
Temperature: 150 °C
Yield: 17 %

Procedure:
A solution of Acetylacetone (40 mL), Ethyl orthoformate (95.4 mL) and Acetic anhydride (54.2 mL) was heated to reflux (150° C.) for 1 hour. The reaction solution was cooled to room temperature and was directly subjected to flash column chromatography (E. Merck Silica Gel (˜120 g); Eluent: 100% EtOAc followed by 5% EtOH in EtOAc). Concentration of the fractions containing the pure product using a rotavap at 40° C. afforded the title compound as a dark red viscous oil (10.4 g, 17.0%).
Reaction SMILES: [CH:1]1([C:11]([O:13]C)=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:10][O:9][C:7]([CH:4]1[CH2:5][CH2:6][CH:1]([C:11]([OH:13])=[O:12])[CH2:2][CH2:3]1)=[O:8]
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)C1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To a stirred solution of dimethyl cyclohexane-1,4-dicarboxylate (10.2 g, 51 mmol) in a mixture of 2:1:1 tetrahydrofuran/methanol/water (52 mL) was added lithium hydroxide (2.13 g, 51 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between diethyl ether and water. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid, and the precipitate collected, and dried under vacuum to afford 4-(methoxycarbonyl)cyclohexanecarboxylic acid (7.4 g): 1H NMR (300 MHz, CDCl3) δ 3.68 (s, 3H), 2.33-2.27 (m, 2H), 2.11-2.06 (m, 4H), 1.50-1.43 (m, 4H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.Cl.[N:33]1([CH:38]2[CH2:42][CH2:41][NH:40][CH2:39]2)[CH:37]=[CH:36][N:35]=[N:34]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:40]4[CH2:41][CH2:42][CH:38]([N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[CH2:39]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1cn(C2CCNC2)nn1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 7580 °C

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (138.5 mg, 0.486 mmol), DBU (190 mg, 1.25 mmol), and 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (216 mg, 1.25 mmol) in pyridine (8 ml) was heated for 20 h at 7580° C. and then pyridine was removed under vacuum. The residue was diluted with acetonitrile. The precipitated solid was washed with acetonitrile, ether and dried at 40° C. Yield: 65 mg (33%), m.p. 244°-246° C. (dec). 1H NMR (TFA) δ: 1.5 (m, 4H), 2.8 (m, 2H), 4.5 (m, 4H), 4.75 (bs, 1H), 5.8 (bs, 1H), 8.15 (d, 1H), 8.6 (s, 1H), 8.7 (s, 1H), 9.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH2:18][CH3:19])[CH2:11]3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1>C(#N)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH2:18][CH3:19])[CH2:11]3)[S:34]([C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)(=[O:36])=[O:35])=[CH:4][CH:3]=1
Reactant: CCN1Cc2cc(NCc3ccc(Cl)cc3)ccc2C1=O
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCN1Cc2cc(N(Cc3ccc(Cl)cc3)S(=O)(=O)c3cn(C)cn3)ccc2C1=O
Temperature: 150 °C

Procedure:
To a stirred solution of 5-(4-Chloro-benzylamino)-2-ethyl-2,3-dihydro-isoindol-1-one (40 mg, 0.133 mmol) and pyridine (23 μM, 0.29 mmol) in dry acetonitrile (1 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (52 mg, 0.29 mmol) and the reaction heated to 150° C. in a microwave for 0.5 hrs. The reaction was filtered and purified by preparative HPLC (Method B) to afford the title compound as an off white solid (17 mg, 25%). HPLC retention time 4.00 min. Mass spectrum (ES+) m/z 445 (M+H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:5]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.ClCCl.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>C(N(CC)CC)C>[CH3:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:5]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:40]([C:36]2[O:35][CH:39]=[CH:38][CH:37]=2)=[O:41])[CH2:28][CH2:27]1
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN1CCNCC1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN1CCN(C(=O)c2ccco2)CC1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a mixture of 6-methyl-5-(1-piperazinylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine dihydrochloride (1 g), dichloromethane (10 ml) and triethylamine (0.48 g), was added 2-furoyl chloride (0.31 g) at 5° C. under ice cooling. After stirring for 1 hour at the same temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water and adjusted to pH=9 with aqueous saturated sodium hydrogen carbonate. The precipitate was collected by filtration, washed with water and dried in vacuo to give 6-methyl-5-[4-(2-furoyl)piperazin-1-ylmethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine (1.02 g).
Reaction SMILES: C[O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:9]3[CH2:22][CH2:23][N:24]=[C:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1>CN1C(=O)CCC1>[OH:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:9]3[CH2:22][CH2:23][N:24]=[C:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: CN1CCCC1=O
Product: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
N-(7-Methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Step 5, 8.7 g, 27 mmol) in NMP (90 mL) was heated to 150° C. and Na2S (10.6 g, 135 mmol) was added portionwise. The reaction color briefly became blue-green, then changed back to yellow-brown. After stirring at this temperature for 1.5 h, the reaction was cooled to rt whereupon a yellow solid precipitated. The mixture was diluted with EtOAc (200 mL) and the solid collected by vacuum filtration. The solid was suspended in water (200 mL), the pH adjusted to ˜7 by the slow addition of aqueous 2N HCl and the mixture was stirred 2 h. The solid was collected via vacuum filtration and washed with water (50 mL) and finally with acetone (50 mL). High vacuum drying overnight gave the title compound (7.8 g, 93%): HPLC MS RT=0.34 min, MH+=308.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 4.25-4.31 (2H, m), 4.57-4.64 (2H, m), 7.45-7.49 (2H, m), 7.69-7.72 (1H, m), 7.92 (1H, dd), 8.78 (1H, dt), 8.97 (1H, dd), 9.49 (1H, d).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[S:18][C:19]([CH3:22])=[N:20][N:21]=3)[N:5]=2)[CH2:3][CH2:2]1.CCO.O.[Cl-].[NH4+]>ClCCl.[Fe]>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[S:18][C:19]([CH3:22])=[N:20][N:21]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc(Cn2nc(C3CC3)c3c(N)cccc32)s1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
To a suspension of 2-((3-cyclopropyl-4-nitro-1H-indazol-1-yl)methyl)-5-methyl-1,3,4-thiadiazole (61.7 mg, 0.196 mmol) in 4:1 EtOH/H2O (2 mL) was added iron powder (0.219 g, 3.91 mmol) and ammonium chloride (10.5 mg, 0.196 mmol). The reaction mixture was heated to reflux for three hours. The reaction mixture was cooled to ambient temperature, diluted with excess dichloromethane, and the resulting suspension was dried over anhydrous sodium sulfate. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in dichloromethane, passed through a silica plug, eluting with 10% MeOH/DCM, and concentrated under reduced pressure to afford the product (27 mg) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH3:14].[C:15]([NH:18][C:19]1[CH:20]=[C:21]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])(=[O:17])[CH3:16]>O1CCCC1>[C:15]([NH:18][C:19]1[CH:20]=[C:21]([S:27]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:13][CH:12]=3)[C:8]([CH3:14])=[CH:9]2)(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])(=[O:17])[CH3:16]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1NC(C)=O
Reactant: COc1ccc2[nH]cc(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C)cn2S(=O)(=O)c1ccc(OC)c(NC(C)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (2.15 grams, 49.3 mmol) was taken into a 250 mL three-necked round bottom flask containing tetrahydrofuran (50 mL) under nitrogen atmosphere. Added a solution of 5-methoxy-3-methyl indole solution (5.3 grams, 32.9 mmol) in tetrahydrofuran (25 mL) to the above mixture at 25° C., over a period of 15 minutes. The above reaction mass was stirred further for a period of 1 hour and mass was cooled to 0° C. and a solution of 3-acetamido-4-methoxy benzenesulfonyl chloride (13.01 grams, 49.3 mmol) in tetrahydrofuran (65 mL) was added through a dropping funnel over a period of 20 minutes. This mass was allowed to cool to room temperature and stirred over night (˜24 hours). The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction it was quenched into ice water (100 mL) under stirring and extracted the product with ethylacetate (2×250 mL). Organic phase was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain thick syrupy mass, which was used as such for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH3:25])=[CH:20][C:19]=1[N+:32]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].O>[NH2:32][C:19]1[CH:20]=[C:21]([N:24]([CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])[CH3:25])[CH:22]=[CH:23][C:18]=1[C:17]([NH:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:38]=[C:37]([F:39])[CH:36]=3)[CH:8]=2)[NH:12][N:11]=1)=[O:35]
Reactant: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(N)c1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
N-[5-(3,5-Difluoro-benzyloxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-2-nitro-benzamide (424 mg, 0.79 mmol) in DCM (5 mL) was treated with nBu4NCl (149 mg, 0.54 mmol). Na2S2O4 (969 mg, 4.73 mmol) in water (5 mL) was added drop-wise, with stirring. After 1 hour, the volatiles were removed by evaporation, the residue was taken twice in water, filtered and treated with 4N HCl in dioxane (12 mL). The volatile components were removed by evaporation. The solid was dissolved in DCM (100 mL), washed with saturated NaHCO3 solution and brine. After drying over sodium sulfate and removal of the solvent, the crude was purified over silica gel (DCM: NH3 7N in MeOH 9:1) to afford 260 mg of title compound in 65% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:24][NH2:25]>O1CCOCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH3:24])=[O:5]
Reactant: CN
Reactant: Nc1cc(Br)ccc1C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a mixture of 2-amino-4-bromobenzoic acid (5.0 g, 23.1 mmol) and dioxane (50 mL) was added triphosgene (2.3 g, 7.75 mmol). The reaction mixture was heated to reflux and stirred for 4 h. Methylamine (40% in water, 2 mL, 23.1 mmol) was added dropwise after the mixture was cooled to room temperature. After stirring for 30 min, the solution was evaporated under reduced pressure and the residue was redissolved in DCM which was washed with sat. NaHCO3 aqueous solution, dried over Na2SO4, filtered, and evaporated to give 4.6 g of the target compound. MS (ESI): 229, 231 (MH+).
Reaction SMILES: CS([S:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[Cl-].[Cl-].[Cl-].[Al+3]>[N+](C)([O-])=O>[CH3:20][C:10]1[C:9]2[O:8][CH2:7][CH2:6][S:5][C:19]=2[CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cccc(OCCSS(C)(=O)=O)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)c1ccc2c(c1C)OCCS2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.0 g (3.4 mmol) of ethyl 3-(2-methylsulfonylthioethoxy)-2-methylbenzoate are dissolved in 5 ml of nitromethane. 0.42 g (3.14 mmol) of aluminum trichloride is added. The mixture is stirred for 45 minutes at room temperature. Working-up is carried out by adding 10 ml of 2 N hydrochloric acid and subsequent extraction using MTB ether. The combined organic phases are washed with water and sodium carbonate solution, and dried over sodium sulfate, and the solvent is distilled off.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:22]([S:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:5]2[C:4]3[C:8](=[C:9]([C:11]#[N:12])[CH:10]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:14][CH2:15]1)(=[O:21])=[O:20])[CH3:23]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccc(F)cc4)cc23)CC1

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carbonitrile (Intermediate 10) (50 mg, 0.102 mmols), 4-fluorophenyl boronic acid (42 mg, 0.306 mmols), potassium carbonate (84 mg, 0.612 mmol), and Pd(PPh3)4 (10 mg) in dioxane/water (6/1, 3.5 mL) were reacted to give the crude title compound.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([C:40](O)=O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:40]([C@@H:36]3[CH2:37][CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH2:35]3)[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Product: CON=C1C[C@@H](c2noc([C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 85 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (3R)-1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid, the title compound, tert-butyl (3R)-3-{3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}-1-piperidinecarboxylate, was obtained in 85% yield (96.5% purity by HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3([C:19]4[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=4)[C:16]4[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:18])=[N:9]3)[CH:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cccc(F)c21
Reactant: OB(O)c1cccc(Cl)c1
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cccc(Cl)c3)c2)c2cccc(F)c21
Yield: 38 %

Procedure:
The title compound was synthesized as described for Example 1 in 38% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.21 mmol) and 3-chlorophenylboronic acid (39.3 mg, 0.25 mmol).