Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][C:8]([I:15])=[CH:7][CH:6]=2.[N+](C1C=CC=CC=1)([O-])=O.CCN(C(C)C)C(C)C>>[I:15][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([OH:1])=[CH:11]2
Reactant: O=C(O)c1c(O)cnc2ccc(I)cc12
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Oc1cnc2ccc(I)cc2c1
Temperature: 210 °C
Reaction time: 3 h

Procedure:
3-hydroxy-6-iodoquinoline-4-carboxylic acid (22 g, 70 mmol) was suspended in 1-nitrobenzene (143 ml, 1397 mmol) followed by adding Hunig's base (25 mL)-the suspension was completely dissolved. The resulting mixture was heated to reflux (210° C.) under N2. After 3 h, LC/MS showed no sign of starting material mass. The reaction mixture was cooled to rt; solvent was removed as much as possible in vacuo. The crude product was redissolved in DCM/MeOH and the solid was collected by filtration. The solid was rinsed with hexane and either and dried as brownish solid. The filtrate was removed excess solvent and purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-058, 330 g SiO2, solvent system: hexanes:acetone=80%:20%, Flow=100 mL/min) to afford the desired product as brown solid. MS m/z: 272.3 (M+H). Calc'd. for C9H6INO−271.05.
Reaction SMILES: [CH:1]([C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=O.Cl.[NH2:24][OH:25].C[O-].[Na+]>CO>[OH:25][N:24]=[CH:1][C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cccc(C2=C(C=O)CCc3ccccc32)c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(C2=C(C=NO)CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 77.8 %

Procedure:
Methyl 3-(2-formyl-3,4-dihydro-1-naphthyl)benzoate (0.44 g) was added to a mixture of hydroxylamine hydrochloride (0.11 g) and 28 methanolic sodium methoxide (0.31 ml) in methanol (10 ml) and the whole was stirred for 19 hours at ambient temperature. The solvent was removed by concentration. To the residue was added a mixture of ethyl acetate, tetrahydrofuran and water and adjusted to pH 2 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting a mixture of chloroform and methanol (50:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(2-hydroxyiminomethyl-3,4-dihydro-1-naphthyl)benzoate (0.36 g).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:22][O:23][C:24]([C:37]1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(OC(=O)C)(=[O:45])C>N1C=CC=CC=1>[CH2:1]([O:17][CH2:18][CH:19]([CH2:22][O:23][C:24](=[O:45])[CH3:37])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCOCC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(CO)COC(C)=O
Yield: 84 %

Procedure:
A solution of compound 4 (2.80 g, 4.90 mmol) in acetic anhydride (5 ml) and pyridine (5 ml) was stirred at room temperature for 6 hours. The solution was concentrated and the oil was dissolved in 4:3:1 glacial acetic acid-ethanol-water (20 ml) and heated on a steam bath. After 2 hours the solution was concentrated and the residue was chromatographed on silica gel using 10% ethylacetatehexane to afford 1.53 g (84%) of the title compound (6) as a waxy white solid, m.p. 33°. NMR (CDCl3, (CH3)4Si); δ0.90 (t, 3H, J=6 Hz, --CH3), 1.25 (s, 26H, --CH2 --), 1.54 (m, 2H, --OCH2CH2R), 2.03 (s, 3H, CH3), 2.16 (m, 1H, CH), 2.54 (t, 1H, J=6.5 Hz, --OH), 3.41 (t, 3H, J=6.5 Hz, --OCH2R), 3.53, 3.56 (ABX, 2H, JAB =8.5, /J 5 Hz, --CH2OR), 3.73 (t, 2H, J=5 Hz, CH2OH), 4.18 (d, 2H, J=6.5 Hz, CH2OAc).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)=[CH:7][CH:6]=1)([O-])=O.CC(O)=[O:26].O>[Zn]>[CH3:6][CH:5]([OH:26])[CH3:14].[ClH:23].[NH2:2][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(NCc1cccc(Cl)c1)CC2
Reactant: CC(=O)O
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CC(C)O
Product: Nc1ccc2c(c1)CC(NCc1cccc(Cl)c1)CC2
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To 7-nitro-2-(((3-chlorophenyl)methyl)amino)-1,2,3,4-tetrahydronaphthalene hydrochloride (1.34 g, 3.80 mmol) in 85% AcOH/H2O (75 ml) was added zinc metal (2.48 g, 38.0 mmol). The mixture was stirred for 5 min. filtered through celite, and evaporated to an oil. The oil was dumped into basic water and extracted with chcloroform (3×20 ml). The combined extracts were washed with water, dried over MgSO4, filtered and concentrated to an oil. Treatment with IPA/HCl yielded 7-amino-2-(((3-chlorophenyl)methyl)amino)-1,2,3,4-tetrahydronaphthalene (1.4 g, 99%); M.S. (M+H)+ =288.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:20]([F:21])=[CH:19][C:10]([C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])=[C:9]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:8]=2)[CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].O.C(OC(C)C)(C)C>C(Cl)(Cl)Cl>[C:31]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:20]([F:21])=[CH:19][C:10]([C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])=[C:9]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:8]=2)[CH2:3]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(N)C2)nc1Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Yield: 72.8 %

Procedure:
In 1 ml of chloroform was dissolved 100 mg of ethyl 2-[6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate, and 26 mg of acetic anhydride was added thereto, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, the reaction mixture was added to a mixture of 1 ml of water and 1 ml of chloroform, and the organic layer was separated, washed successively with 1 ml of water and 1 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 0.5 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 80 mg (yield 72.8%) of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 19.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[OH:13])[CH3:3].[SH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].C([O-])(O)=O.[Na+]>ClCCl>[S:22]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][S:14][CH:9]1[C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:2][CH3:3])=[C:6]([OH:13])[CH:7]=1
Reactant: SCc1ccccc1S
Reactant: CCOc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(C2SCc3ccccc3S2)cc1O
Yield: 71.2 %

Procedure:
Hydrogen chloride gas was bubbled for three minutes at 22° C. through a solution of 4-ethoxy-3-hydroxybenzaldehyde (0.50 g, 3.0 mmol) and 2-(mercaptomethyl)benzenethiol (0.52 g, 3.3 mmol) in dichloromethane (15 ml). After an additional 15 min. the reaction mixture was poured into saturated NaHCO3 (50 ml) and extracted with dichloromethane (2×75 ml). The combined organic layer was washed with brine (30 ml), dried (Na2SO4), filtered and concentrated providing a crude solid. This solid was triturated with hexane and then purified by flash chromatography using a gradient of hexanes (100%) up to hexanes (70%:30%). Concentration of the product containing fractions provided the above subtitle compound (0.65 g, 70%) as a cream colored solid. 1H NMR (300 MHz, CDCl3, ppm) δ 1.46 (t, J=7 Hz, 3H), 3.98 (s, 3H), 4.13 (q, J=7 Hz, 2H), 5.44 (s, 1H), 5.68 (br s, 1H), 6.80 (d, J=8 Hz, 1H), 6.99 (dd, J=8 Hz, J2=2 Hz, 1H), 7.13 (d, J=2 Hz, 1H), 7.15-7.35 (m, 4H); 13C NMR (75 MHz, CDCl3, ppm) δ 15.1, 34.4, 51.2, 64.9, 111.6, 114.6, 120.0, 126.2, 127.7, 128.6, 129.4, 132.2, 135.1, 135.9, 146.0, 146.2; MS calculated for C16H16O2S2-H 303 observed 303.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][O:11][CH2:12][CH2:13]Br.O>CN(C)C=O>[CH3:10][O:11][CH2:12][CH2:13][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCBr
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 4.70 g of phenol and 35 mL of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 1.30 g of sodium hydride (95%, dispersion in mineral oil) in 15 mL of dry N,N-dimethylformamide at 5° C. Stirring was continued for 2 hours at 5° C., followed by dropwise addition of 5.20 mL of 2-bromoethyl methyl ether (technical grade, 90%) at 5° C. The mixture was allowed to come to room temperature and stirring was continued for 72 hours. The mixture was poured into water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (sodium sulfate) and concentrated to give 5.90 g of (2-methoxy-ethoxy)-benzene as an oil. EI-MS: 159 (M+).
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].Cl.C1COCC1.CN1CCOCC1.[NH:42]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:43](C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:44][CH2:45][CH2:46][CH2:47][NH:48]C(OCC1C=CC=CC=1)=O>CN(C=O)C>[NH:42]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:43]([C:22]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:24])[CH2:44][CH2:45][CH2:46][CH2:47][NH2:48]
Reactant: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Boc-Asn-Ala-OBzl (XXIII) (27.54 g, 70 mmol) was treated with 4 N HCl/THF (875 ml) for 30 minutes at room temperature. Evaporation and treatment with dry ether provided 23.08 g (100%). The hydrochloride salt was dissolved in DMF (250 ml), cooled to 0° C and NMM (4.9 ml, 70 mmol) was added under stirring followed by Boc-Lys(Z)-OPfp (39.5 g, 72.3 mmol). The mixture was stirred for 1 hr at 0° C and 3 hr at room temperature. After evaporation of the solvent to a smaller volume, 0.5 N HCl was added and the precipitated product was collected by filtration and washed on the funnel with H2O, (5%) NaHCO3 and H2O. After drying, it was triturated with EtOAc and then with petroleum ether, yield 41.5 g (90.4%); mp 148°-150° C; [α]D25 -15.3° (c 2, DMF). Anal. Calcd for C33H45N5O9 (655.76): C, 60.44; H, 6.92; N, 10.68. Found: C, 60.50; H, 6.97; N, 10.70.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[S:14][CH:13]=[N:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:32]4[CH2:35][CH:34]([OH:36])[CH2:33]4)[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: OC1CNC1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CC(O)C2)c(C#N)c1-c1cncs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.206 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 45 mg (0.411 mmol) of azetidin-3-ol hydrochloride and 53 mg (0.411 mmol) of N-ethyl-N-(1-methylethyl)propan-2-amine, were dissolved in 1.5 ml of THF. The mixture was stirred at room temperature for two hours, and the product was then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 40 mg (37% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:20][C:21](=O)[CH3:22]>CN(C)C=O>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]2[C:21]([CH3:22])=[CH:20][O:9][C:5]=2[CH:4]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1coc2cc(N(C)C)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.1 %

Procedure:
140 g of 3-dimethylaminophenol are dissolved in 700 ml of dimethylformamide. 152 g of potassium carbonate and 28 g of potassium iodide are added. 101.8 g of chloroacetone are then added dropwise in the course of one hour; afterwards the mixture is stirred at room temperature for 20 hours. The reaction solution is filtered and the dimethylformamide and unconverted chloroacetone are distilled off (30° C., 1 mm Hg). Water is added to the residue, and the mixture is basified with concentrated sodium hydroxide solution and filtered. The crude product is taken up in 1 litre of ethanol, 115 ml of concentrate hydrochloric acid are added, and the mixture is heated to 80° C. 40 hours later the mixture is cooled down, treated with active carbon and filtered. The alcohol is removed, water is added to the residue, and the mixture is basified with concentrated sodium hydroxide solution. The crude product is filtered off and recrystallized from a mixture of hexane and diethyl ether (10:1) to give 36 g of 6-dimethylamino-3-methylbenzofurane.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:8][C:7]1[C:2]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:13]3[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=3)[CH2:22][CH2:21]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(NC2CCNCC2)cc1
Reactant: Clc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(NC2CCN(c3ncccc3Br)CC2)cc1
Yield: 57.1 %

Procedure:
2-Chloro-3-bromopyridine (0.25 g, 1.3 mmol), D2 (0.25 g, 1.3 mmol) and potassium carbonate (0.23 g, 2.9 mmol) in DMF (5 ml) were heated at 120° C. for 16 h. The mixture was concentrated and the residue partitioned between EtOAc and water (50 ml each). The aqueous was re-extracted with EtOAc (50 ml) and the combined organics washed with water, dried (Na2SO4) and concentrated. Purification by column chromatography on silica (0-50% diethyl ether\40-60 pet. ether gradient) gave the title compound as a yellow solid (0.26 g). δH (CDCl3) 1.64 (2H, m), 2.17 (2H, d), 2.98 (2H, m), 3.43 (2H, m), 3.74 (2H, m), 6.58 (2H, m), 6.77 (1H, m), 6.89 (2H, m), 7.78 (1H, d), 8.22 (1H, dd). MS (ES): MH+ 351.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[N:18]=1>>[Cl:16][C:17]1[N:18]=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[N:20]=[C:21]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CC(C)Oc1nc(Cl)nc(Cl)n1
Product: COc1cc(Nc2nc(Cl)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 41 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,4-dichloro-6-isopropoxy-[1,3,5]triazine (Synth. Commun. 24, 2153 (1994)) in analogy to example 2a. The compound crystallized from methanol as a slightly brownish solid in 41% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][NH:17][C:16](=[O:19])[N:15]1[CH3:20])=[O:13].Cl.[CH3:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH2:28]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[CH2:10][NH:11][C:12]([CH:14]1[CH2:18][N:17]([CH2:28][C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH3:22])[C:16](=[O:19])[N:15]1[CH3:20])=[O:13]
Reactant: Cc1nc[nH]c1CO
Reactant: CN1C(=O)NCC1C(=O)NCc1ccc(F)c(F)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc[nH]c1CN1CC(C(=O)NCc2ccc(F)c(F)c2Cl)N(C)C1=O
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A solution of N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-4-imidazolidinecarboxamide (152 mg, 0.5 mmol) (prepared as described in Example 28), (4-methyl-1H-imidazol-5-yl)methanol hydrochloride (93 mg, 0.625 mmol) and p-toluene sulfonic acid monohydrate (19 mg, 0.100 mmol) in N-methyl-2-pyrrolidone (1 ml) was heated at 130° C. under argon for 3 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The solution was washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC, followed by trituration with ether to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-2-oxo-4-imidazolidinecarboxamide (147 mg, 74%). LC/MS [M+H]+=398, retention time=1.57 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.Br[CH2:25][CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:21][CH:22]=1
Reactant: BrCCCOC1CCCCO1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccccc2Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccccc2Cl)s1
Temperature: 60 °C
Yield: 95.4 %

Procedure:
2.3 g of the compound obtained in stage 23E), 1.95 g of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 1.2 g of potassium carbonate are added to 15 ml of DMF and then the mixture is heated at 60° C. for 7 hours. It is poured onto ice-cold water, extraction is carried out with ether and the extract is dried and concentrated to dryness. After purifying by chromatography on silica (heptane and then heptane/AcOEt 80/20), 3.1 g of the expected compound are obtained.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=1.[C-:20]#[N:21].[Na+].CC(C)=O>C(O)C>[Br:1][C:2]1[O:3][C:4]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:20]#[N:21])[CH:8]=1
Reactant: Clc1ccc2oc(Br)c(-c3cccc(CBr)c3)c2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: N#CCc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1

Procedure:
The product of Step D, 2-bromo-3-(3-bromomethylphenyl)-5-chlorobenzofuran is reacted with sodium cyanide by heating to reflux in a solvent mixture of acetone and ethanol. Evaporation provides the desired product, 2-bromo-5-chloro-3-(3-cyanomethylphenyl)benzofuran.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][CH2:22][CH2:23]Br.CC(C)=O>O>[Cl:20][CH2:21][CH2:22][CH2:23][O:11][C:7]1[C:6]([O:12][CH3:13])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[C:9]([OH:10])[CH:8]=1
Reactant: COc1cc(C(C)=O)c(O)cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(C)=O)c(O)cc1OCCCCl
Yield: 70.3 %

Procedure:
A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol), K2CO3 (1.4 g, 10.0 mmol), 3-chlorobromopropane (1.6 g, 10.0 mmol) and acetone (25 mL) was stirred and refluxed under N2 for 16 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with ethyl acetate. The extract was washed (H2O, brine) dried (MgSO4) and concentrated to yield 1.4 g of an off-white solid. Recrystallization twice from ethanol afforded 0.4 g of the alkylated phenol as a solid, m.p. 99-101° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.O>C(#N)C>[C:8]([N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution containing 1 g (10.4 mmol) of 1H-imidazole-4-carbaldehyde and 3.18 g (11.4 mmol) of trityl chloride suspended in 28 mL of acetonitrile are added dropwise 2.5 mL (17.7 mmol) of triethylamine. After stirring for 2 hours at room temperature, 30 mL of water are added and the crude reaction product is filtered. 3.2 g in the form of a beige-coloured powder are obtained and used in the following step without further purification.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1.Br[C:13]1[CH2:17][CH:16](C2C=CC(OC(F)(F)F)=CC=2)[O:15][N:14]=1.C(=O)([O-])O.[Cs+].O1C=CCN1>CN(C)C=O>[N:5]1[CH:4]=[CH:9][CH:8]=[C:7]([O:10][C:13]2[CH2:17][CH2:16][O:15][N:14]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: FC(F)(F)Oc1ccc(C2CC(Br)=NO2)cc1
Agent: C1=CONC1
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cncc(OC2=NOCC2)c1
Temperature: 130 °C

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-96a and I-96b were prepared in 1 step from racemic compound I-14 and 5-hydroxypicolinic acid methyl ester according to the following procedure: 3-bromo-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole (1.0 equiv), 5-hydroxypicolinic acid methyl ester (1.2 equiv), and cesium hydrogencarbonate (1.50 equiv) are suspended in N,N-dimethylforamide (0.32 M with respect to dihydroisoxazole. The mixture is then degassed with argon after which it is heated to 130° C. for 4 h after which point there is only desired product and corresponding acid visible by LC/MS. The reaction is allowed to cool to room temperature and quenched by pouring into a solution of ammonium chloride in water (30% by weight, 0.08 M with respect to dihydroisoxazole). The aqueous phase is extracted with ethyl acetate (2×), dried over sodium sulfate, filtered and concentrated to product a brown solid which could be recystallized from absolute ethanol to provide racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-96 that was isolated by filtration as a white solid (25% yield). These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=383.8 m/z. Activity: A