Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[C:7]([Cl:21])=[C:8]([Cl:20])[C:9]2[O:13][CH:12]([C:14]([O:16]CC)=[O:15])[CH2:11][C:10]=2[CH:19]=1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[C:7]([Cl:21])=[C:8]([Cl:20])[C:9]2[O:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]=2[CH:19]=1)(=[O:4])=[O:5]
Reactant: CCOC(=O)C1Cc2cc(S(=O)(=O)N(C)C)c(Cl)c(Cl)c2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 94 %

Procedure:
To a solution of 1 g of ethyl 5-(N,N-dimethylsulfamoyl)-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate (Ia-1) dissolved in 9 ml of tetrahydrofuran is added 14 ml of 15% aqueous potassium carbonate and the mixture stirred for 72 hours at room temperature. The reaction mixture is condensed under reduced pressure to leave residue, which is made acid (pH 5.0) with 10% hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and evaporated under reduced pressure to leave an oil, which is then recrystallized from either to give 0.868 g of 5-(N,N-dimethylsulfamoyl)-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (I b-28), yielded in 94%, m.p. 154° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(O)(=O)C>ClC(Cl)C>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Sodium triacetoxyborohydride (3.3 g, 15.4 mmol, 1.1 eq.) was added at room temperature to a solution of 4-chlorobenzaldehyde (2 g, 14 mmol), tert-butyl 2-aminoethylcarbamate (4.5 mL, 28.5 mmol, 1.2 eq.) and acetic acid (2.5 mL) in dichloroethane (20 mL). The reaction mixture was allowed to stir overnight before being quenched with 0.5M HCl (30 mL). The mixture was then extracted with dichloromethane one time and then brine was added. The precipitate was filtered and dried to give tert-butyl 2-(4-chlorobenzylamino)ethylcarbamate (3.58 g, 90%), MS (ESI) m/e (M+H+) 285.
Reaction SMILES: [OH:1][C@H:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[OH:1][C@H:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[CH:33]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4ccc(C(=O)O)cc4)CC3)cc2)ccc1O
Yield: 26 %

Procedure:
Methyl 4-{[4-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-phenyl}ethyl)amino]ethyl}anilino)-1-piperidinyl]carbonyl}benzoate (0.127 g, 0.208 mmol) was dissolved in methanol (12 mL) and 1N sodium hydroxide (0.416 mL) added. The reaction was stirred at reflux for 24 hours. A further portion of 1N sodium hydroxide (0.1 mL) was added and the reaction stirred at reflux for a further 24 hours. The solvent was removed in vacuo. The residue was extracted with ethyl acetate and the solvent removed in vacuo. The residue was extracted with methanol, filtered through Celite and the solvent removed in vacuo to furnish the title compound (0.032 g, 0.054 mmol).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)(=O)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[C:20]1([NH:19][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCCOS(C)(=O)=O)cc1
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(OCCNc2ccccc2)cc1
Reaction time: 64 h
Yield: 82.2 %

Procedure:
To a solution of methyl 4-[2-(methanesulfonyloxy)ethoxy]benzoate (2.74 g, 10 mmol) in MeCN (50 ml), was added aniline (9.1 ml, 100 mmol) at rt. The reaction was stirred for 64 hours at reflux. The mixture was poured into H2O (200 mL), extracted with EtOAc (100 mL×2), dried over MgSO4. After removal of the solvent in vacuo, the unreacted aniline was removed in vacuo by co-evaporation with toluene (10 mL×3) at 80° C. The residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, f50 mm×150 mm, CHCl3) to give methyl 4-[2-(N-phenylamino)ethoxy]benzoate (2.23 g, 82%) as a colorless oil. 1H-NMR (CDCl3) δ3.56 (t, J=5.1 Hz, 2 H), 3.90 (s, 3 H), 4.21 (t, J=5.1 Hz, 2 H), 6.68 (dd, J=1.0 Hz, 8.6 Hz, 2 H), 6.75 (t, J=7.3 Hz, 1 H), 7.20 (AB type d, J=7.3 Hz, 2 H), 8.00 (d, J=9.1 Hz, 2 H); MS (ESI) m/z 272 (M++1).
Reaction SMILES: I.CS[C:4](=[NH:18])[CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[C:19]([NH:27][NH2:28])(=O)[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>CC(O)C>[N:23]1[CH:24]=[CH:25][C:20]([C:19]2[NH:18][C:4]([CH2:5][CH2:6][N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])=[N:28][N:27]=2)=[CH:21][CH:22]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CSC(=N)CCN1C(=O)c2ccccc2C1=O
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1CCc1nnc(-c2ccncc2)[nH]1
Temperature: 85 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a suspension of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiopropionimidic acid methyl ester hydroiodide (880 mg, 2.34 mmol) in 2-propanol (16 mL) were added isonicotinohydrazide (337 mg, 2.46 mmol) and sodium carbonate (248 mg, 2.34 mmol). The reaction mixture was stirred at 85° C. for 1 h. Acetic acid (32 mL) was added and the reaction mixture was stirred at 130° C. for 3 h. After cooling down to ambient temperature, all volatiles were evaporated. The residue was dissolved in acetic acid (30 mL) and the reaction mixture was stirred at 130° C. for 16 h. The reaction mixture was cooled down to RT and concentrated in vacuo. The residue was poured into saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was washed water (40 mL) and brine (40 mL), dried over MgSO4 and concentrated in vacuo. The residue was suspended in dichloromethane, filtered, washed with dichloromethane and dried in vacuo to give the product as brown solid (480 mg (purity 80%), 0.96 mmol, 41%). The filtrate was evaporated and pure product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light brown solid (180 mg, 562 μmol, 24.0%). MS: M=321.1 (M+H)+
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.CO>C(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1csc(N2CC[C@@H](O)C2)n1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCN(c2nc(C(N)=O)cs2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
To a solution of (3R)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (290 mg, 1.36 mmol) (obtained as described in Reference Example 18(6)) suspended in methylene chloride (9 ml) were added methanesulfonyl chloride (0.684 ml, 8.85 mmol) and triethylamine (1.24 ml, 8.85 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature overnight. After checking the completion of the reaction, methanol (0.33 ml) was added to the reaction mixture in an ice bath, and then the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate→10% methanol in ethyl acetate as the eluant to afford (3R)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (148 mg, yield 40%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH2:13][CH2:14][CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][CH2:21][P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24].C(N(CC)CC)C.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([CH:21]([P:22](=[O:27])([O:25][CH3:26])[O:23][CH3:24])[NH2:20])=[O:18])[CH2:13][CH2:14][CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COP(=O)(CN)OC
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](NC(=O)OCc1ccccc1)C(=O)C(N)P(=O)(OC)OC
Temperature: -12 °C
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
(i)(b) 45.4 g (180 mmol) of N-benzyloxycarbonyl-L-norvaline were stirred in 200 ml of methylene chloride while 31.76 g (180 mmol) of dimethyl aminomethylphosphonate hydrochloride were added. The resulting suspension was cooled to -12° C. and 25.3 ml (180 mmol) of dry triethylamine were added dropwise. After completion of the addition, the cold mixture was stirred for 0.25 hour. 56.8 g (230 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline in 100 ml of methylene chloride were then added rapidly. The mixture was stirred in the cold for 2 hours and then at room temperature overnight. The mixture was washed with 100 ml of water and then with four 100 ml portions of 1-N hydrochloric acid. The combined acid washings were back-extracted with two 50 ml portions of methylene chloride. The combined organic solutions were washed with 100 ml of water and finally with three 100 ml portions of 15% potassium bicarbonate solution, then dried over anhydrous sodium sulphate, filtered and evaporated. The residual oil was re-evaporated with benzene to give an oil which was triturated with 200 ml of anhydrous ether. There were obtained 58.2 g of crude product of melting point 77°-80° C. Recrystallization from 200 ml of ethyl acetate gave 50.6 g of dimethyl N-benzyloxycarbonyl-L-norvalyl-aminomethylphosphonate of melting point 82°-84° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[CH2:19]1[CH2:23]OC[CH2:20]1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[C:20]#[C:19][CH3:23])=[CH:17][CH:18]=1
Reactant: C1CCOC1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Reaction time: 0.25 h

Procedure:
An oven-dried 3 L 3-neck flask equipped with a mechanical stirrer, nitrogen inlet, nitrogen outlet and placed in a room-temperature water bath. After purging with nitrogen for 20 minutes, a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) was added by cannula. In a separate oven-dried and nitrogen-flushed 500 mL RB flask, compound 1.1 (35 g, 142 mmol) was dissolved in anhydrous THF (350 mL) with gentle warming. The solution of 1.1 was then added over 15 minutes. Over the course of the addition, the reaction mixture changed to a thick, yellow suspension. After the addition was complete, the reaction mixture was stirred for 15 minutes and then quenched with aqueous NH4Cl (0.6N, 750 mL) and diluted with hexanes (800 mL). The layers were separated and the organic layer discarded. The aqueous layer was acidified to pH ˜2 with saturated aqueous KHSO4 and extracted with ethyl acetate (2×400 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (37 g, 91%). 1H NMR (500 MHz)(acetone-d6) δ 8.26 (s, 1H); 7.39 (d, 2H, J=8.5 Hz); 6.76 (d, 2H, J=8.4 Hz); 4.73 (br s, 1H); 4.46 (d, 1H, J=2.4 Hz); 1.82 (s, 3H); 1.81 (s, 3H); 1.64 (s, 3H). MS ESI (pos.) m/e: 599.0 (2M+Na).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br-].[Mg].C([O:12][CH3:13])=O>C1COCC1.O>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][CH:13]([OH:12])[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5]
Reactant: FC(F)(F)CCBr
Reactant: COC=O
Agent: [Br-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCC(F)(F)F)CCC(F)(F)F
Temperature: 0 °C

Procedure:
3-Bromo-1,1,1-trifluoropropane (31 g, 0.175 mol) was dissolved in THF (175 mL). Mg (4.2 g, 0.175 mol) was placed in a 1 L, 3-necked round-bottom flask equipped with a condenser, nitrogen inlet and thermometer. The bromide solution (10 mL) was added to cover the magnesium and upon stirring a mild exotherm commenced. The temperature was kept <40° C. by immersing the flask in a bowl of water. The bromide was added slowly to maintain this mild exothermic reaction. When the exotherm had subsided the mixture was cooled in ice-water and methyl formate (7 mL, 0.11 mol) in THF (175 mL) was added. The mixture was stirred for 30 min and then quenched with NH4Cl (aq.soln. 100 mL). The mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:9]2)=[O:7])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](N)C2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: Cc1ccc(C(=O)N2CCC[C@@H](NC(=O)c3ccc(Cl)cc3)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 114.4 %

Procedure:
To the aqueous solution of (R)-1-(p-methylbenzoyl)-3-amino piperidine obtained in Example 13 (amount: 3 g), p-chlorobenzoyl chloride (0.18 g) was added. The pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and chlorobenzene (3 ml) and sodium chloride (0.5 g) were added thereto. The mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow crystal (0.42 g, yield: 84%).
Reaction SMILES: [CH:1](/[C:9]1[O:13][C:12]([C:14](OCC)=[O:15])=[N:11][CH:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-]>C(O)C>[OH:15][CH2:14][C:12]1[O:13][C:9](/[CH:1]=[CH:2]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:10][N:11]=1
Reactant: CCOC(=O)c1ncc(/C=C/c2ccccc2)o1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: OCc1ncc(/C=C/c2ccccc2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
150 mg of ethyl (E)-5-styryloxazole-2carboxylate Yakugaku Zasshi, vol. 91, page 425 (1971)) was suspended in 15 ml of ethanol, and at -10° C., 5 ml of an ethanol solution of 35 mg of sodium borohydride and 123 mg of calcium chloride was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl ether were added to the residue to perform extraction. The organic layer was separated, and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to give 120 mg (yield 97%) of the captioned compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:23]=1)[C:17]([NH:19][CH2:20][CH2:21][F:22])=[O:18]>>[N:9]1[O:8][N:7]=[C:6]2[CH:10]=[C:2]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:23]=3)[C:17]([NH:19][CH2:20][CH2:21][F:22])=[O:18])[CH:3]=[CH:4][C:5]=12
Reactant: Brc1ccc2nonc2c1
Reactant: O=C(NCCF)c1cncc(Br)c1
Product: O=C(NCCF)c1cncc(-c2ccc3nonc3c2)c1

Procedure:
Starting from 5-bromo-benzo[1,2,5]oxadiazole and 5-bromo-N-(2-fluoro-ethyl)-nicotinamide. Beige powder. MS(ES−): 285 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S.[OH2:12]>[Cu]>[OH:12][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O
Reactant: O=C(O)c1cncc(Br)c1
Agent: [Cu]
Agent: S
Product: O=C(O)c1cncc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To 10.1 g (0.05 mol) of 5-bromonicotinic acid was added 10 g of NaOh dissolved in 63 mL of water, 3.1 g of coppersulfate pentahydrate and 0.42 g of copper (0). The reaction mixture was vigorously stirred and heated under reflux for 30 hours. After cooling the mixture to room temperature, 4.8 g of Na2S.H2O was added and stirring was pursued overnight. The reaction mixture was heated to 70° C. and treated with H2S gas until disappearance of the white precipitate (3 h). After cooling to room temperature, the mixture was filtered and the pH of the filtrate was adjusted to 5.2 with concentrated hydrochloric acid. The precipitate was filtered and the pH of the % filtrate was adjusted to 4.6 with concentrated hydrochloric acid. The white precipitate was then filtered, washed with water and dried under reduced pressure giving 4.3 g (yield: 62%) of product of molecular formula C7H5NO3. Aspect: white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2(=[O:21])=[O:20])[CH:5]=[N:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25][N:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10](=[O:20])(=[O:21])[N:9]([C:4]2[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[C:14]1=[O:15]
Reactant: COc1cc(F)c(CBr)c(F)c1
Reactant: Cc1cc(N2C(=O)Nc3ccccc3S2(=O)=O)cnc1C
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3cnc(C)c(C)c3)S(=O)(=O)c3ccccc32)c(F)c1
Yield: 26.5 %

Procedure:
The title compound (58 mg, 0.13 mmol) was prepared from 2-(5,6-dimethylpyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (IntA29) (150 mg, 0.49 mmol), 2,6-difluoro-4-methoxybenzyl bromide (129 mg, 0.54 mmol) and K2CO3 (102 mg, 0.74 mmol) in DMF (3 mL) at 50° C. using the methods of (115).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][C:8](=[O:30])[NH:7][C:6]=2[CH:31]=1)=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=4.Cl[CH2:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[C:13]4[C:18]([C:10]=3[CH2:9][C:8](=[O:30])[N:7]([CH2:33][C:34](=[O:35])[N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:6]=2[CH:31]=1)=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=4
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2NC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CC(=O)N2CCCCC2)C(=O)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a suspension of ethyl 3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (772 mg, 1.77 mmol) in N,N-dimethylformamide (7.7 ml) were added a solution of 1-(2-chloroacetyl)piperidine (343 mg, 2.12 mmol) in N,N-dimethylformamide (2 ml) and potassium carbonate (488 mg, 3.53 mmol), and the mixture was stirred at 90° C. for 1 hr. Furthermore, a solution of 1-(2-chloroacetyl)piperidine (171 mg, 1.06 mmol) in N,N-dimethylformamide (1 ml) and potassium carbonate (244 mg, 1.77 mmol) were added, and the mixture was stirred at 90° C. for 1.5 hr. The mixture was allowed to cool to room temperature, water (10 ml) was added, and the precipitated solid was collected by filtration. The obtained solid was washed with water (10 ml) and dried in vacuo to give ethyl 3-chloro-12-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (911 mg, yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[N:23]([CH2:29][CH3:30])[C:22]=2[CH:31]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[CH:26]1([C:24]2[N:23]([CH2:29][CH3:30])[C:22]3[CH:31]=[C:18]([N:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]5[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=5)=[CH:9][C:10]4=[O:14])[CH:19]=[CH:20][C:21]=3[N:25]=2)[CH2:28][CH2:27]1
Reactant: CCn1c(C2CC2)nc2ccc(Br)cc21
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 120 °C
Yield: 61.4 %

Procedure:
The mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg), 6-bromo-2-cyclopropyl-1-ethyl-1H-benzimidazole (133 mg), copper iodide (87 mg), N,N′-dimethylethylenediamine (0.051 ml), potassium carbonate (158 mg) and DMSO (2.5 ml) was heated 120° C. for 1 h under microwave irradiation. The mixture was quenched with 28% NH3 solution at room temperature and extracted with EtOAc and THF. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc). The solid was crystallized from IPA-hexane to give the title compound (113 mg) as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][CH:7]([CH3:11])[CH2:8][CH2:9][SH:10].[O-]CC.[Na+].[Na]>C(O)C>[CH2:9]([S:10][CH2:2][CH2:3][CH2:4][Cl:5])[CH2:8][CH:7]([CH3:11])[CH3:6]
Reactant: ClCCCBr
Reactant: CC(C)CCS
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(C)CCSCCCCl
Temperature: 0 °C
Reaction time: 72 h
Yield: 52.3 %

Procedure:
Mix 1-bromo-3-chloropropane (5.0 g, 31.76 mmol), absolute ethanol (25 mL), and 3-methyl-l-butanethiol (3.3 g, 31.76 mmol). Place under nitrogen atmosphere and cool to 0° C. In a separate flask, generate sodium ethoxide by carefully adding sodium metal (736 mg, 32 mmol) to absolute ethanol (25 mL) and stirring under nitrogen atmosphere until evolution of nitrogen gas ceases. Add the sodium ethoxide, by dropwise addition, to the above mixture and stir at room temperature for 72 hours. Partition between water and ethyl ether and separate the organic phase. Extract the aqueous phase with ethyl ether (2×50 mL), combine the organic phases and dry (MgSO4). Evaporate in vacuo to yield 3.0 g (52%)3 -chloropropyl isopentyl sulfide as a clear oil; MS (CI/CH4) m/z 181(M+1).