Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N+](CC)([O-])=O.[Cl:15][S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17]>>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([Cl:15])(=[O:18])=[O:17])=[O:21])[N:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1nc(C)nc(N)n1
Solvent: CC[N+](=O)[O-]
Product: Cc1nc(C)nc(NC(=O)NS(=O)(=O)Cl)n1
Reaction time: 1 h

Procedure:
To a stirred suspension of 2-amino-4,6-dimethyl-1,3,5-triazine in 10 parts by volume of nitroethane at -10° to 0° is added dropwise an equivalent amount of chlorosulfonyl isocyanate. The mixture is stirred for one hour at -10° allowing for completion of the reaction to form [(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonyl]sulfamoyl chloride. The additional reagent such as pyrrole is then added and the preparation of the stable herbicidal compound is continued as described in Example 2 or for Equations 3 and 3A.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:26]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([O-:18])(=[O:17])=[O:15])=[CH:24][CH:23]=1.[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][N+:35]2[CH:36]=[CH:37][N:33]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:34]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCCCCCCn1ccnc1
Product: CCCCCCCn1cc[n+](CCCCc2ccc(NC(C)=O)cc2)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 5 h

Procedure:
Heat a mixture of 6.23 g (0.017 mole) 4-methylbenzenesulfonic acid 4-(4-acetylaminophenyl)butyl ester and 2.9 g (0.017 mole) 1-heptyl-1H-imidazole to 80° C., for 5 hours, following the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonium hydroxide, 90:10). At the completion of the reaction, triturate the cooled resultant material with petroleum ether. Recrystallize the material from 25 ml hot methyl ethyl ketone with hot filtration, chill and seed to obtain the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([F:21])[CH:14]=2.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([OH:20])=[C:10]([NH:9][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1cnc2cc(F)ccc2c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cnc2cc(F)ccc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.4 mL, 46.2 mmol) was added to a suspension of 3-amino-7-fluoro-4-quinolinol hydrochloride (3 g, 14.0 mmol) in tetrahydrofuran (50 mL). Butyryl chloride (1.6 mL, 15.4 mmol) was added dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 hours. Aqueous sodium bicarbonate was added and the reaction mixture was allowed to stir at ambient temperature for about 1 hour. The resulting biphasic mixture was filtered to remove solids. The solids were rinsed with diethyl ether to provide a slightly pink powder. The tetrahydrofuran layer was concentrated under vacuum to provide a dark pink solid. This solid was triturated with ether and then oven dried. The solids were combined to provide 3.0 g of N-(7-fluoro-4-hydroxyquinolin-3-yl)butanamide. A 300 mg portion was recrystallized from ethyl acetate/ethanol to provide a light gray fluffy solid, m.p. 306-308° C. Analysis: Calculated for C13H13FN2O2: % C, 62.90; % H, 5.28; % N, 11.28; Found: % C, 62.95; % H, 5.34; % N, 11.14.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:20][OH:21])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.Cl([O-])=[O:26].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.CC(=CC)C.O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:20][OH:21])[CH2:18][CH2:19]3)=[CH:15][CH:16]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:26])=[O:24])=[CH:5][NH:6]2
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(CO)CC4)cc3)c(F)c12
Agent: CC=C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(C4(CO)CC4)cc3)c(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
To a solution of 4,6-difluoro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde (70 mg, 0.214 mmol) in acetonitrile (4.6 mL), t-Butanol (4.6 mL) and 2-methyl-2-butene (3.0 mL) was added a solution of sodium chlorite (289 mg, 4.28 mmol) and NaH2PO4 (590 mg, 4.28 mmol) in water (4.6 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a solution of sodium sulfate (674 mg, 5.35 mmol) in water (5.0 mL), and extracted with ethyl acetate (20 mL×3). The organic layers were washed with brine (20 mL×1) and dried over sodium sulfate, filtered, concentrated, and purified which was purified by preparative HPLC to give the title compound (17.4 mg, 24%) as a white solid. MS (AP+) 343.9 (M+1)+. 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1 H), 7.48 (d, 2 H), 7.39 (d, 2 H), 7.11 (d, 1 H), 3.71 (s, 2 H), 0.91 (s, 4 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(=O)C(F)(F)F)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:12]=[CH:11][C:10]=2[CH2:34][C:35]([NH2:37])=[O:36])[CH:2]=1>CO.[OH-].[Na+].O>[N:22]1([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:34][C:35]([NH2:37])=[O:36])=[C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:14]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCN(C(=O)C(F)(F)F)CC3)cc2)cc1NCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccnc1
Reaction time: 0.33 h
Yield: 95 %

Procedure:
66 mg of 4-[(pyridin-3-ylmethyl)amino}-6-({4-[4-(trifluoroacetyl)piperazin-1-yl]phenyl}amino}pyridine-3-carboxyamide (the compound of Example 354) was dissolved in 1 mL of methanol, to which 0.5 mL of 1 mol/L sodium hydroxide in water was added at room temperature, and stirred at the same temperature for 20 minutes. To the reaction mixture water was added, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:ammonia methanol=40:1 to 20:1) to obtain 51 mg (96%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:5][CH2:6][CH3:7])[CH3:4].[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12].[OH-].[K+]>O1CCOCC1>[CH2:3]([N:5]([CH2:6][CH3:7])[CH2:1][C:12]#[C:11][CH2:10][CH2:9][CH2:8][OH:13])[CH3:4]
Reactant: CCNCC
Reactant: C#CCCCO
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCN(CC)CC#CCCCO
Temperature: 60 °C
Yield: 73.9 %

Procedure:
A mixture of paraformaldehyde (7.14 g, 238 mmol), diethylamine (27.6 ml, 260 mmol) and cupric acetate monohydrate (1 g) in dioxane (40 ml) was heated in an oil bath of 60° C. for 1 hour. When the solid material disappeared, pent-4-yn-1-ol (20 g, 238 mmol) was added and the heating at 95° C. was continued until the greenish suspension had been completely replaced by the thin brown precipitate (approximately 3 hours). After cooling to 20° C., the reaction mixture was poured into 10% aqueous KOH (40 ml). The precipitate was filtered off and washed with ether (100 ml). The organic phase was washed with water (5 times 50 ml), dried (K2CO3) and evaporated to dryness to give crude product. The isolated product was distilled to yield 29.78 g (74%) of 6-diethylaminohex-4-yn-1-ol: bp 92°-94° C. (0.1 mm Hg), IR (neat) 3309 cm-1 ; 1H NMR (CDCl3) δ4.1(S, 1H), 3.6(t, 2H), 3.3(m, 2H), 2.7-2.0(m, 6H), 2.0-1.4(m, 2H), 1.0(t, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12](I)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.C[N:27]([CH:29]=[O:30])C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:29]([NH2:27])=[O:30])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.5 g, 3.8 mmol) and bis(triphenylphosphine) palladium(II) chloride (142 mg, 0.202 mmol), DMF (45 mL) and hexamethyldisilazane (4.34 mL, 20.6 mmol) were mixed. The entire solution was purged with a CO balloon and sealed with the CO balloon attached. The reaction flask was heated at 70° C. for 2 h. LC/MS indicated clean conversion. Cooled to room temp and poured into 1 N HCl (30 mL). Stirred for 5 min and neutralized with sat. aq. NaHCO3 soln. Extracted three times with EtOAc, dried over MgSO4, filtered and concentrated in vacuo. Triturated with IPA and the solids were collected after filtration and EtOAc wash. This provided 734 mg (62% yield) of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a tan solid. LC/MS (ESI+): m/z 310 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.5, 1H), 7.63 (s, 1H), 7.24 (dd, J=7.2, 4.2, 1H), 7.09-6.99 (m, 1H), 4.51-4.36 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:20]([F:21])([F:23])[F:22])[CH:4]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4ccc(F)c(C(F)(F)F)c4)ncnc23)c1F
Yield: 8.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4-fluoro-3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-17, 100 mg, 0.31 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 178 mg, 0.62 mmol), oxalyl chloride (118 mg, 0.93 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93 mmol) in CH2Cl2 (5 mL) to afford 16 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H), 10.15 (s, 1H), 8.82-8.79 (d, J=8.1 Hz, 1H), 8.69 (s, 1H), 8.33-8.30 (m, 3H), 8.16 (br t, 1H), 7.75-7.69 (t, J=8.4 Hz, 1H), 7.62-7.55 (d, J=10.2 Hz, 1H), 7.42-7.34 (m, 2H), 4.32-4.30 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 592.28 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]([Si:10]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)([CH3:9])[CH3:8].[CH2:22]=O.[OH-].[Na+]>C(O)(=O)C.O>[CH:19]([Si:10]([CH:7]([CH3:9])[CH3:8])([CH:16]([CH3:18])[CH3:17])[N:11]1[CH:15]=[CH:14][C:13]([CH2:22][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12]1)([CH3:21])[CH3:20]
Reactant: C1COCCN1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of morpholine (98.5 mmoles) in acetic acid (100 ml) at 0° C. there are added 1-triisopropylsilanyl-1H-pyrrole (89.5 mmoles) and formaldehyde (89.5 mmoles) 37% in water. The reaction mixture is stirred overnight at ambient temperature. The solution is brought to alkaline pH (10-12) using 20% aqueous NaOH solution and is then extracted with DCM. The organic phase is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is purified by flash chromatography on silica gel (SiO2; gradient DCM/AcOEt) to yield the title product, which is used directly in the next Step.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:2]([O:6][C:7]([NH:9][C@H:10]([C:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of N-tert-butoxycarbonyl-L-phenylalanine hydrochloride (2.65 g) and aniline (1.02 g) in dimethylformamide (DMF, 50 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) and hydroxybenzotriazole (HOBT, 1.5 g) at room temperature, and the mixture was stirred for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure to give N-tert-butoxycarbonyl-L-phenylalanylaminobenzene. To a solution of the obtained compound in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml) at room temperature, and the mixture was stirred for 1 hour. Toluene (10 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. A 1M hydrogen chloride-ether solution (10 ml) was added to the residue, and crystallization gave the title compound (1.45 g, yield 52%).
Reaction SMILES: C(CC(=O)C)(=[O:3])C.[H][H].[N:10]#[N:11].[O:12]=[O:13]>>[O:12]=[O:13].[N:10]#[N:11].[OH2:3].[N:10]#[N:11].[O:12]=[O+:13][O-:3].[N:10]#[N:11]
Reactant: CC(=O)CC(C)=O
Reactant: [H][H]
Agent: N#N
Agent: O=O
Product: O
Product: O=[O+][O-]
Reaction time: 2 h

Procedure:
In the liquid phase method of manufacturing a phosphor from aqueous solution, organic metal salt or nitrate that contains elements composing the phosphor is dissolved in water, and then hydrolyzed to produce coprecipitation (hydrate) material. Here, the organic metal salt is alkoxide or acetylacetone, for example. The coprecipitation material is hydrothermally synthesized (crystallized in an autoclave), sintered in the air, or sprayed into a high temperature furnace, thereby obtaining powder. The powder is sintered for two hours at 1000 to 1400° C. in reducing atmosphere such as H2/N2=5/95 (%), crushed, and classified. Next, the resultant powder is sintered at 350 to 1000° C. in O2, O2—N2, H2O—N2, or O3—N2 to produce the phosphor.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:20][CH:21]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)nc1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-chloro-5-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Br:14][C:15]1[C:16](Cl)=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([NH2:21])=[N:19][CH:20]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:14][C:15]1[C:16]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12]2)=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([NH2:21])=[N:19][CH:20]=1
Reactant: Cn1ccnc1CN1CCNCC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cn1ccnc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 65 °C
Reaction time: 17 h
Yield: 51 %

Procedure:
The resulting 1-((1-methyl-1H-imidazol-2-yl)methyl)piperazine (supposedly 0.320 g, 1.78 mmol, 1 eq) was suspended in iPrOH (5.4 mL) and DIPEA (1.4 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.400 g, 1.62 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×6 mL), Et2O (2×6 mL) and dried to give the title compound as a bright yellow powder (0.370 g, 51%); 1H-NMR (500 MHz, DMSO-d6): δ 2.97-3.08 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2), 3.66 (s, 3H, imidazole Me), 6.75 (s, 1H, imidazole H-4), 6.96 (s, 2H, NH2), 7.08 (s, 1H, imidazole H-5), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.07 min—396/398 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1O.[NH2:9][C:10]([NH2:12])=[S:11]>C(O)CCCCC>[N:9]1[C:10](=[S:11])[N:12]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=12
Reactant: NC(N)=S
Reactant: OC1CCCCC1O
Solvent: CCCCCCO
Product: S=C1N=C2CCCCC2=N1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
Part A. A solution of 2-hydroxycyclohexanol (2.28 g, 0.02 mol), thiourea (1.52 g, 0.02 mol) and hexanol (30 ml), equipped with a column of 4Å sieves and a condenser, was heated to 160° for five hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature and was concentrated in vacuo to give a solid. The solid was triturated with ethyl ether (3×50 ml) to give 4,5,6,7-tetrahydrobenzimidazol-2-thione (0.6 g, 0.0039 mol) which was not purified but was taken on to the next step as a crude solid.
Reaction SMILES: [CH3:1][CH:2]1[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.[OH-].[Na+].Cl.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1>O>[CH3:1][CH:2]1[O:3][C:4]2=[CH:13][C:8]3[NH:9][C:10]([S:12][CH2:25][C:22]4[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=4)=[N:11][C:7]=3[CH:6]=[C:5]2[O:14]1
Reactant: CC1Oc2cc3nc(S)[nH]c3cc2O1
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)OC(C)O4)nc1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To 3.9 g of 2-methyl-5H-1,3-dioxolo-(4,5-f)benzimidazole-6-thiol, suspended in 60 ml of alcohol, were added dropwise while stirring 1.57 g of sodium hydroxide in 30 ml of water and, after 30 minutes, there were added 3.44 g of 5-methyl-2-chloromethylpyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in 500 ml of ethyl acetate. This was washed with 100 ml of sodium hydroxide three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/petroleum ether (low boiling) and there were obtained 4.8 g (81.7% of theory) of 2-methyl-6-[[(5-methyl-2-pyridyl)methyl]-thio]-5H-1,3-dioxolo(4,5-f)benzimidazole of melting point 147°-148° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][O:13][CH3:14])[N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[N:7]=1)=[CH2:5])C.O.Cl>O1CCOCC1>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:8]2[N:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[C:10]([CH2:12][O:13][CH3:14])[N:9]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: C=C(OCC)c1cc(COC)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COCc1cc(C(C)=O)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-(methoxymethyl)pyrimidin-2-amine (172 mg, 0.43 mmol) in 1,4-dioxane (30 mL) were added water (2 mL) and hydrochloric acid (conc., 0.11 mL, 1.30 mmol). The mixture was stirred at 50° C. for 20 min. The solvents were evaporated. Sodium bicarbonate (aq, 50% saturated) was added and the mixture was extracted with DCM. The organic phase was separated on phase separator and the solvents were evaporated to give the title compound, 160 mg (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([NH:14][C@@H:15]([CH2:19][C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)[C:16]([OH:18])=[O:17])[CH:3]=1
Reactant: COc1cc(C[C@H](N)C(=O)O)cc(OC)c1OC
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound is prepared by heating a suspension of 3-bromo-biphenyl (1.47 mL, 8.54 mMol, Aldrich 25,538-6), (S)-2-amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid (3,4,5-OCH3-phe-OH) (3.27 g, 12.81 mMol), K2CO3 (1.189, 8.54 mMol) and CuI (163 mg, 0.854 mMol) in DMF abs. (10.6 mL) for 24 h at 90° C., under an argon atmosphere. The resulting mixture is allowed to cool to rt, then concentrated in vacuo and purified by MPLC (CH3CN/H2O/TFA) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:20][CH2:19]2)=[N:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=1)=[O:6].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[C:31]([NH:35][C:25]([CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:9]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][CH:12]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[N:10]=2)[CH2:19][CH2:20]1)=[O:27])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)c1ccc(NC(=O)c2cccc(Cl)c2)c(N2CCC(CC(=O)O)CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)NC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
A mixture of 0.023 g (0.226 mmol) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.011 g (0.15 mmol) of tert-butyl amine, 0.021 g (0.066 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.021 mL (0.15 mmol) of triethylamine in N,N-dimethylformamide (2 mL) is stirred at room temperature for 2 hours. The mixture is diluted with water and purified using preparative reverse phase HPLC to give 0.016 g (62%) of the title compound (286) as colorless foam. [M+H]+=507.2.