Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][NH2:6])[CH2:4][CH2:3]1.[CH3:7][N:8]([CH3:29])[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=S)N)[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].CC[O-:32].[Na+]>C(O)C.C(OCC)(=O)C>[CH:2]1([CH2:5][NH:6][C:26]([C:23]2[CH:22]=[CH:21][C:20]3[S:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH:10]([CH3:11])[CH2:9][N:8]([CH3:29])[CH3:7])[C:25]=3[CH:24]=2)=[O:32])[CH2:4][CH2:3]1
Reactant: CC(CN(C)C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NCC1CC1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(CN(C)C)N1c2ccccc2Sc2ccc(C(=O)NCC3CC3)cc21
Reaction time: 5 h

Procedure:
A suspension of cyclopropylmethylamine hydrochloride (5.4 g) dispersed in ethanol (25 cc) containing 10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbothioamide (3.43 g) is added to a 0.05 M solution of sodium ethylate in ethanol (10 cc). The mixture is brought to 200° C. for 5 hours and then diluted with ethyl acetate (150 cc), washed with distilled water (2×100 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residual solid is purified by chromatography on a column (height: 18 cm; diameter: 2.5 cm) of silica gel (0.6-0.02 mm), eluting with mixtures of ethyl acetate and cyclohexane in proportions (by volume) of 30:70 (2.5 liters) and 50:50 (1.1 liters), collecting 60-cc fractions. Fractions 50 to 59 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give N-cyclopropylmethyl-10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarboxamide (0.42 g), m.p. 90° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCCl.C1COCC1>[CH3:14][C:15]1[N:20]=[C:19]([NH:21][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[CH:18]=[CH:17][C:16]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:24]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(-c2cc(Oc3ccc(N)nc3C)ccn2)on1
Reactant: CC(C)(C)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3C)ccn2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
A suspension of 2,2,2-trimethylacetamide (0.086 g, 0.850 mmol) in DCE (3.5 mL) was treated drop-wise with oxalyl chloride (0.074 mL, 0.850 mmol), stirred at RT for 0.5 h, then warmed to 85° C. for 1 h. The solution was cooled to RT, added drop-wise to a solution of Example A7 (0.2 g, 0.708 mmol) and pyridine (0.069 mL, 0.850 mmol) in THF (3.5 mL) and stirred at RT for 2.5 days. Satd. NaHCO3 was added, the mixture extracted with EtOAc (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The white solid was dissolved in MeOH, treated with water until a precipitate formed and the solid was collected via filtration, dissolved in MeCN/H2O, frozen and lyophilized to afford N-((6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (51 mg, 18%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.41 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 7.93-7.91 (m, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.97-6.95 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.20 (s, 9H); MS (ESI) m/z: 410.2 (M+H+).
Reaction SMILES: C1(P(=[C:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[CH:35]=[C:34]2[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=1[O:52][CH3:53])=O.[C:54](OCC)(=O)C>O1CCOCC1>[C:24]([O:23][C:21](/[C:20](/[CH3:28])=[CH:54]/[C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH3:40])[CH:35]=[C:34]2[CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=1[O:52][CH3:53])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CC(C(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C=O)cc23)c(OC)c1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)OC(C)(C)C)cc23)c(OC)c1
Yield: 90 %

Procedure:
A mixture of t-butyl (triphenylphosphoranylidene)propionate (10.41 g) and methyl 4-(5-formyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate (4.5 g) in dry dioxane (60 ml) was stirred and heated at 100° for 18 hr, under an atmosphere of nitrogen. After ethyl acetate (100 ml) was added to the cooled reaction solution, solids were removed by filtration and the filtrate evaporated. The residual dark oil was purified by flash chromatography, eluting with 45:50:5 hexane: methylene chloride:ethyl acetate, to give methyl E-4-[5-[2-(t-butoxycarbonyl)-1-propenyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (5.4 g, 90%) as a white foam: partial NMR (250 MHz, DMSO-6): 1.49 (s, 9H, t-butyl), 2.01(d, J=1.0 Hz, 3H, CCH3), 3.74(s, 3H), 3.82(s, 3H), 3.90(s, 3H), 4.05(s, 2H, ArCH2Ar').
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:40].[CH3:41][N:42]=[C:43]=[O:44].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[CH3:41][NH:42][C:43](=[O:44])[O:40][C:3]1[CH:4]=[C:5]([C@:8]([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([F:26])[CH:17]=2)([NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CN=C=O
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(O)c1)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1cc([C@@](Cc2ccccc2)(NC(=O)c2cccc(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of (R)—N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide, prepared as described in Example 264, (15 mg, 0.027 mmol), methylisocyanate (0.01 mL), and Et3N (0.02 mL) in CH2Cl2 (0.3 mL) was heated at 80° C. under microwave irradiation for 10 min. After cooling, the reaction mixture was diluted with EtOAc and the organic layer was washed with H2O, sat. NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO flash chromatography (silica gel, hexanes/EtOAc) to yield (R)-2-fluoro-5-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(3-(trifluoromethyl)-benzamido)-ethyl)phenyl methylcarbamate (Example 272, 11 mg, yield: 61%). LCMS: RT=2.13 min [M+H] 623.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10](Cl)[C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4][C:3]=2[O:2]1.Cl(O)(=O)(=O)=O.C(O)C>[H][H].C(OCC)(=O)C.[C].[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C(Cl)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Yield: 89 %

Procedure:
A mixture of 7.0 g of 1-(3,4-methylenedioxyphenyl)-1-chloro-2-methyl-2-nitropropane, 7.7 g of 70% perchloric acid, 2.8 g of 10% palladium-carbon and 100 ml of ethanol is shaken at room temperature for 3 hours in hydrogen gas atmosphere under 3 atmospheres. After the reaction, insoluble materials are removed by filtration, and the filtrate is condensed. The residue is dissolved in ethyl acetate, and the solution is washed with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, successively. The washed solution is dried and then evaporated to remove solvent. 5.4 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropane are thereby obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.C(Br)C.[Mg].[CH3:12][C@H:13]1[CH2:18][C:17](=[O:19])[CH2:16][CH2:15][O:14]1.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Br:1][C:2]1[S:3][C:4]([C@@:17]2([OH:19])[CH2:16][CH2:15][O:14][C@@H:13]([CH3:12])[CH2:18]2)=[CH:5][CH:6]=1
Reactant: C[C@H]1CC(=O)CCO1
Reactant: Brc1ccc(Br)s1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Solvent: C1CCOC1
Product: C[C@H]1C[C@@](O)(c2ccc(Br)s2)CCO1
Temperature: 40 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of a mixture of 2,5-dibromothiophene (1.9 g) and ethyl bromide (2.56 g) in THF (6 ml) was added dropwise to a stirred suspension of magnesium (0.29 g) in diethyl ether (3 ml) and the mixture was warmed gently to promote the formation of a Grignard Reagent. The mixture was heated to 40° C. for 1 hour. The mixture was cooled in an ice-bath and a solution of (2S)-2-methyltetrahydropyran-4-one [European Patent Application No. 0385662 (Example 20 thereof); 0.61 g] in THF (5 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and diethyl ether as eluent. There was thus obtained, as a less polar isomer, (2S,4R)-4-(5-bromothien-2-yl)-4-hydroxy-2-methyltetrahydropyran (0.248 g, 19%) as an oil, having the 2-methyl and 4-hydroxy groups in a trans-relationship.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[Se](=O)=[O:20]>CC(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH:15]=[O:20])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: O=[Se]=O
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)c2c(C=O)nccc2c2ccc(Cl)cc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a solution of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.387 mmol), prepared as described in Example 16, Part G, in AcOH (4 mL) was added selenium dioxide (51.5 mg, 0.464 mmol). The reaction mixture was allowed to stir at 70° C. for 3 h. Volatiles were removed under reduced pressure and the residue so obtained was dissolved in dichloromethane (2 mL). The mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure to afford the title product (0.1 g, 0.202 mmol, 52% crude yield) as pale yellow solid. The material was carried on without further purification. LC/MS, (ESI) m/z 273.0 [(M+H)+, calcd for C14H10ClN2O2, 273.0]; LC/MS retention time (method H): tR=1.89 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH:7]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)Br)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:30][NH:31][CH3:32]>>[C:1]([O:5][C:6](=[O:24])[CH:7]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[N:31]([CH3:32])[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(C(=O)OC(C)(C)C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Intermediate 19 (0.8654 g, 2.17 mmol) in 8 mL, THF was bubbled in dimethylamine. The reaction was stirred at ambient temperature overnight. The solvent was removed in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The crude product was chromatographed on silica eluting with 5% to 20% EtOAc/hex. The resulting yellow oil crystallized to a yellow solid under high vacuum overnight
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[CH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=1)[CH2:2]2.[CH2:22]([Br:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[Br-:29].[CH3:21][S:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:9]=[C:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:8][CH2:7]3)[CH2:2]2)=[CH:12][CH:13]=1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)Nc1ccc(CC=C2CN3CCC2CC3)cc1
Reactant: CCCCCCCBr
Product: CCCCCCC[N+]12CCC(CC1)C(=CCc1ccc(NS(C)(=O)=O)cc1)C2
Product: [Br-]

Procedure:
In a manner similar to Example II, Method A, react N-[4-(2-(1-azabicyclo[2.2.2]oct-3-ylidene)ethyl)phenyl]methanesulfonamide with heptyl bromide to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]1[C@@H:46]2[C@@H:41]([CH2:42][CH2:43][CH2:44][CH2:45]2)[CH2:40][NH:39]1>O1CCCC1>[CH2:16]([C@@H:11]([CH2:12][C:13]([N:39]1[CH2:40][C@H:41]2[C@H:46]([CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:38]1)=[O:15])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1CC[C@H]2CNC[C@H]2C1
Reactant: O=C(O)C[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
To a solution of (S)-3-benzyloxycarbonyl-4-phenylbutyric acid (671 mg) in anhydrous tetrahydrofuran (15 ml) were added N-methylmorpholine (0.5 ml) and isobutyl chloroformate (0.38 ml) with stirring at -20° C. for 20 minutes. To the mixture was added a solution of cis-hexahydroisoindoline (313 mg) in anhydrous tetrahydrofuran (5 ml) with stirring at -10 - -20° C. After 1 hour, the deposit was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate solution, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was recrystallized from dichloromethane-hexane to give 772 mg of benzyl (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate.
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:7][CH2:6][N:5]([O:8][CH3:9])[CH2:4][CH2:3]1.[CH2:12](ON1CCC(=O)CC1)C>>[NH2:1][C:2]1([C:10]#[N:11])[CH2:3][CH2:4][N:5]([O:8][CH2:9][CH3:12])[CH2:6][CH2:7]1
Reactant: CON1CCC(N)(C#N)CC1
Reactant: CCON1CCC(=O)CC1
Product: CCON1CCC(N)(C#N)CC1

Procedure:
4-Amino-1-ethoxy-piperidine-4-carbonitrile is prepared analogously to the synthesis of 4-amino-1-methoxy-piperidine-4-carbonitrile (preparation example 1, Step 1) starting from N-ethoxy-4-piperidone (Journal of Organic Chemistry (1961), 26, 1867-74).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].C[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=1[CH3:42])=[O:30].O>CN(C=O)C>[F:20][CH:2]([F:1])[C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([S:8][CH2:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=2[CH3:42])=[O:30])=[N:6][N:7]=1
Reactant: CCC(=O)Nc1ccc(S(N)(=O)=O)cc1C
Reactant: Cc1ccc(-n2c(S)nnc2C(F)F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CSc1nnc(C(F)F)n1-c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
In a solution of 5-difluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol(53 mg, 0.18 mmol), K2CO3 (27.0 mg, 0.20 mmol) in DMF (1.5 mL) was added 2-methyl-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide (47 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (4.0 mL) was added to the reaction and stirred until precipitation occurred and filtered off product (77.0 mg, 83% yield). 1H NMR (DMSO, 300 MHz) δ 9.84 (broad s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.70-7.53 (m, 7H), 7.18 (t, J=51.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 4.26 (s, 2H), 2.82 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]3[N:14]=[N:15][N:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[C:17]=3[CH3:18])[CH:10]=2)[C:5]1=[O:27])([CH3:3])[CH3:2].C([O-])(=[O:30])C.[Na+].O.C(=O)(O)O.C(OCC)(=O)C>C(O)(=O)C.BrBr>[CH:1]([N:4]1[C:12](=[O:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]3[N:14]=[N:15][N:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[C:17]=3[CH3:18])[CH:10]=2)[C:5]1=[O:27])([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Cc1c(-c2ccc3c(c2)CN(C(C)C)C3=O)nnn1-c1ccc(F)cc1F
Agent: BrBr
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(-c2ccc3c(c2)C(=O)N(C(C)C)C3=O)nnn1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
37 mg of the compound obtained in Example 119 was dissolved in 2.0 ml of acetic acid, then 41 mg of sodium acetate and 3 drops of bromine were added and the mixture was stirred at room temperature for 20 min. After adding saturated hydrogen carbonate water and ethyl acetate, organic layer was separated, and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents under reduced pressure were purified by thin-layer silicagel chromatography (hexane:ethyl acetate=50:50) to obtain 19.5 mg of the above compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([CH3:38])=[C:17]([NH:19][C:20](=[O:37])[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])=[O:25])[CH:18]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:27]([NH:26][C:24](=[O:25])[CH2:23][O:22][CH2:21][C:20]([NH:19][C:17]2[CH:18]=[C:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:14]=[CH:15][C:16]=2[CH3:38])=[O:37])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30]
Reactant: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(C)c(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)c1

Procedure:
Using the same method as in Example 19-(ii), 3-methoxybenzene boronic acid was reacted with the 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 38-(i) to give 5-chloro-2-[((2-[(3′-methoxy-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 63%).
Reaction SMILES: [CH3:1]CN=C=NCCCN(C)C.[C:12]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][C:36](O)=[O:37])[C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C1COCC1.ClCCl>[CH3:1][C:36]([CH2:35][N:31]1[CH2:32][CH2:33][CH2:34][N:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:22])[CH2:24][CH2:25]2)[C:30]1=[O:39])=[O:37]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CN1CCCN(C2CCN(C(=O)OC(=O)c3ccccc3)CC2)C1=O
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
WSC (0.39 g) was added to a solution of [3-{1-[(benzoyloxy)carbonyl]piperidin-4-yl}-2-oxotetrahydropyrimidin-1(2H)-yl]acetic acid (0.70 g) obtained in Example 36a), a solution of methylamine in THF (1.85 mL) and HOBt (0.31 g) in THF/dichloromethane (1/1, 30 mL) and the mixture was stirred at room temperature overnight. The solvent were distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain the title compound (0.70 g, 97%) as a white powder.
Reaction SMILES: [CH2:1]([CH:5]1[CH:9](O)[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4].C(O)C.S(=O)(=O)(O)O>O>[CH2:1]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Oc2ccc([N+](=O)[O-])cc2C1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCCCc1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
300 mg of 2-(n-butyl)-5-nitro-2,3-dihydrobenzofuran-3-ol were introduced into ethanol in a 50 ml flask, and 1 ml of concentrated sulphuric acid was added. The mixture was then heated to reflux for 4 hours. After cooling, 10 ml of water were added, the ethanol was distilled off, and the mixture was extracted with dichloromethane. Washing of the organic phase with sodium bicarbonate solution, drying over sodium sulphate and removal of the solvent in vacuo resulted in 220 mg (80% of theory) of 2-(n-butyl)-5-nitrobenzofuran as yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:5]=[CH:4][C:3]1=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](O[C:36](=O)[CH3:37])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:19])[C:3]2[C:8](=[N:7][C:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:20]3[CH2:25][CH2:24][N:23]([C:1]4[CH:2]=[CH:3][CH:8]=[C:37]5[C:36]=4[N:7]=[CH:6][CH:5]=[CH:4]5)[CH2:22][CH2:21]3)=[CH:5][CH:4]=2)[NH:9][C:10](=[O:12])[CH2:11]1
Reactant: C1CNCCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC1(C)CC(=O)Nc2nc(OCCCC=O)ccc21
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(=O)Nc2nc(OCCCCN3CCN(c4cccc5cccnc45)CC3)ccc21
Reaction time: 0.17 h

Procedure:
The aldehyde (0.3 mmol) and the piperazine (60.306 mmol) were combined in methylene chloride and stirred in a vial over sieves for 10 min. Sodium triacetoxyborohydride (0.42 mmol) was added and the reaction was stirred overnight. The reaction was quenched by slowly adding water and then the mixture was filtered. The residue was partitioned between CH2Cl2 and water and the organic layer was concentrated. Purification by liquid chromatography (MPLC, gradient of 100% CH2Cl2 to 100% of a 10% MeOH in CH2Cl2 solution) gave the title compound. The final products were made into hydrochloride salts by treatment with a solution of saturated HCl in MeOH.