Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:18]([C:22]1[CH:26]=[C:25]([CH2:27][NH2:28])[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[N:23]=1)([CH3:21])([CH3:20])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[C:18]([C:22]1[CH:26]=[C:25]([CH2:27][NH:28][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)[CH3:17])[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: CC(C(=O)O)c1ccc(CS(C)(=O)=O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.4 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoic acid (60 mg, 0.231 mmol) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.231 mmol) in THF (1.8 mL) were added O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluorborat (73 mg, 0.231 mmol), 1-hydroxybenzotriazole (30 mg, 0.231 mmol) and N-ethyldiisopropylamine (0.078 mL, 0.462 mmol). The reaction mixture was stirred for 48 h at room temperature, concentrated in vacuo and the residue was purified by CC (eluent: ethyl acetate/cyclohexane (3:2)) to give N-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(methylsulfonyl-methyl)-phenyl]-propionamide (94 mg, 80%).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:8]=[CH:7][C:6]=2[N:23]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:24]([N:4]1[C:5]2[C:10](=[O:11])[N:9]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:8]=[CH:7][C:6]=2[N:23]=[C:3]1[S:2][CH3:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2n1Cc1ccccc1
Yield: 54.7 %

Procedure:
A solution of 1.0 g (3.10 mmol) of 2-methylsulphanyl-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 15 ml of dimethylformamide was combined with 547 mg (3.20 mmol) of benzylbromide and then with 442 mg (3.20 mmol) of potassium carbonate and stirred overnight at ambient temperature. Then it was diluted with approx. 40 ml of water and extracted three times with 15 ml of ethyl acetate. The organic extracts were washed with water, dried over sodium sulphate and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant:petroleum ether with 10–20% ethyl acetate).
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](Cl)=[O:23])[CH:20]=1.O>N1C=CC=CC=1>[N:11]1[C:6]([C:5]2[O:28][C:18]([C:19]3[CH:27]=[CH:26][CH:25]=[C:21]([C:22]4[O:23][C:5]([C:6]5[N:11]=[C:10]([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=6)[CH:9]=[CH:8][CH:7]=5)=[N:4][N:3]=4)[CH:20]=3)=[N:3][N:4]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)nc1
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(-c2cccc(-c3nnc(-c4cccc(-c5nnc(-c6cccc(-c7ccccn7)n6)o5)c4)o3)n2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
0.63 g of 6-(2H-tetrazol-5-yl)-2,2′-bipyridine was dissolved in 10 ml of dehydrated pyridine, and 0.29 g of isophthaloyl dichloride was gradually added. Temperature was elevated to 115° C., and stirring was conducted for 6 hours under reflux. After cooling to room temperature, the reaction solution was poured into water, and a precipitated white solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 80° C. for 20 hours, and purified with column chromatography (carrier: silica gel, eluting solution: chloroform/methanol=20/1) to obtain 0.62 g (yield 81%) of BpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.071 ppm (1H), 8.639-8.714 ppm (6H), 8.325-8.477 ppm (4H), 8.037 ppm (2H), 7.756-7.854 ppm (3H), 7.330 ppm (2H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.[OH-].[Na+]>C(Cl)Cl.O>[N:15]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(CN2CCCC2)cc1
Yield: 58.5 %

Procedure:
NaB(OAc)3H (43.4 g, 0.21 mol) was added in portions during 30 min to a mixture of pyrrolidine (17 mL, 0.21 mol) and 4-hydroxybenzaldehyde 1 (20 g, 0.16 mol) in CH2Cl2 (200 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 3 h and cooled. Then 10 N NaOH (20.5 mL) and water (300 mL) were added. The organic layer was separated, the aqueous one was extracted with chloroform (3×200 mL). The organic fractions were evaporated. The residue was dissolved in water, concentrated HCl (15 mL) was added, and the mixture was extracted with ether (3×200 mL). The organic fractions were discarded. The aqueous layer was alkalized with 10 N NaOH (16 mL) and extracted with CH2Cl2 (3×200 mL). The combined extracts were washed with brine, dried with Na2SO4, and evaporated. The title compound (16.6 g, 57%) was obtained as yellow crystals. 1H NMR-data (DMSO-d6): 9.18 (br.s, 1H, OH); 7.00 (d, 2H, Ph, J=8.6 Hz); 6.68 (d, 2H, Ph, J=8.6 Hz); 3.43 (s, 2H, CH2); 2.33-2.42 (m, 4H); 1.62-1.71 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[O:8])[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1(C)C(C)=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[O:32][CH2:31][CH2:30][O:8]1
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1cccnc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Clc1ccc(CC2(c3cccnc3)OCCO2)c(Cl)c1

Procedure:
2.25 g of 2,4-dichlorobenzyl 3-pyridyl ketone, 2.2 g of p-toluenesulfonic acid monohydrate and 1.0 g of ethylene glycol are heated at reflux for 24 hours in 20 ml of xylene, the resulting water being separated in a water separator. The mixture is then cooled, poured into 2N sodium hydroxide and extracted with diethyl ether, the organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel with n-hexane/ethyl acetate (1:1) to yield 3-[2-(2,4-dichlorobenzyl)-1,3-dioxolan-2-yl]pyridine, which melts at 76°-78°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](Br)[C:9]#[CH:10]>C(O)C>[CH2:10]([NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:9]#[CH:8]
Reactant: Nc1ncccn1
Reactant: C#CCBr
Solvent: CCO
Product: C#CCNc1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-aminopyrimidine (2 g, 20.67 mmol) and propargyl bromide (23 mL, 20.67 mmol) in ethanol (30 mL) was heated to reflux for about 23 hours. The formed precipitate was collected by filtration, washed with ethanol and was recrystallized from ethanol. To the vacuum dried crystals was added water (10 mL) and 10% aqueous sodium hydroxide (5 mL) and the mixture was stirred at room temperature for about 30 min. The solid was collected by filtration, washed with water and was re-crystalized from water to provide Example 642. MS (ESI): m/z 134 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1c(CBr)cccc1OC
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a solution of ethyl 2-methoxy-6-methylbenzoate (0.813 g, 4.19 mmol) in CCl4 (8 mL) was added recrystallized N-bromosuccinimide (0.751 g, 4.22 mmol) followed by benzoyl peroxide (52 mg, 0.22 mmol). The resultant mixture was heated to reflux for 90 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (8:1 hexanes-EtOAc) provided 0.68 g (60%) of ethyl 6-(bromomethyl)-2-methoxybenzoate as a colorless oil. 1H NMR (CDCl3) δ 1.42 (t, 3H, J=7.2 Hz), 3.84 (s, 3H), 4.45 (q, 2H, J=7.2 Hz), 4.50 (s, 2H), 6.89 (d, 1H, J=8.4 Hz), 7.01 (d, 1H, J=7.2 Hz), 7.34 (dd, 1H, J=7.2, 8.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1.C(N(CC)CC)C.[CH3:35][CH:36]([OH:43])[CH2:37][NH:38][CH2:39][CH:40]([OH:42])[CH3:41].COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:38]([CH2:39][CH:40]([OH:42])[CH3:41])[CH2:37][CH:36]([OH:43])[CH3:35])[CH:19]=1
Reactant: COC(=O)c1cc(N2CCCC2=O)ccc1NC(=O)c1cccc(CCl)c1
Reactant: CC(O)CNCC(C)O
Agent: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(N2CCCC2=O)ccc1NC(=O)c1cccc(CN(CC(C)O)CC(C)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
Subsequently, 2-(3-chloromethyl-benzoylamino)-5-(2-oxo-pyrrolidin-1-yl)benzoic acid methyl ester (14 mg) was dissolved in anhydrous methylene chloride (5 ml). Triethylamine (7 mg: dissolved in 2 ml of anhydrous methylene chloride) and diisopropanolamine (compound B′) (10 mg: dissolved in 2 ml of anhydrous methylene chloride) were added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 24 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-{[bis-(2-hydroxy-propyl)-amino]-methyl}-benzoylamino)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (8.0 mg, yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.CN(C)C=O>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccc(Cl)cc2)cn1)c1ccccc1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide (0.50 g, 2.01 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.01 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.22 g, 0.34 mmol) in dimethylformamide (10 mmol) was stirred at room temperature for 2 hours. Water (100 mL) was added and a thick oil was being formed. The water was decanted and the residue dissolved in dichloromethane, dried over sodium sulphate, filtered and evaporated in vacuo. Ethyl acetate was added and the solution was heated briefly (some of the compound does not dissolve). The solvent was decanted and heptane was added to it. After standing overnight, the crystals were isolated by suction, washed with heptane and dried in a vacuum oven at 45° C. Further purification by flash column chromatography (SiO2, ethyl acetate:heptane 50:50), yielded the title compound (0.41 g, 53% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].CCCC[Sn]([C:25]1[N:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(CCCC)CCCC>C1COCC1.CN(C=O)C>[F:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[CH:25][N:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1

Procedure:
A mixture of 2-bromo-1-fluoro-4-nitrobenzene (2.0 g, 9.1 mmol) and 2-(1,1,1-tributylstannyl)pyridine (3.36 g, 9.11 mmol) in THF (80 ml) and DMF (10 ml) was degassed with nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (200 mg, 3 mol %) was added, and the mixture was heated at reflux for 24 h. More 2-bromo-1-fluoro-4-nitrobenzene (0.60 g, 2.7 mmol) and catalyst (100 mg, 1.5 mol %) were added, and the mixture was heated as before for another 24 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 50% dichloromethane in isohexane, then 100% dichloromethane, then 100% ethyl acetate (UV detection). 2-(2-Fluoro-5-nitrophenyl)pyridine was isolated as a colourless solid (2.11 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.30-7.37 (2H, m), 7.80-7.87 (2H, m), 8.27 (1H, m), 8.78 (1H, m), 9.01 (1H, dd, J 3.1, 6.7 Hz); MS (ES+) m/z 219 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][C:19]([Cl:22])=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:23]#[N:24])=[C:4](I)[CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1>>[Cl:22][C:19]1[S:18][C:17]([NH:16][S:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=3[C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[C:8]([C:23]#[N:24])[CH:9]=2)(=[O:15])=[O:14])=[N:21][CH:20]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(Cl)cc1I
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(Cl)cc1-c1cn[nH]c1

Procedure:
The title compound was prepared according to the same method as that used for Example 785 above using 4-(4-chloro-2-iodophenoxy)-N-(5-chloro-1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide (Preparation 219) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials. Purification by preparative HPLC afforded the title compound. Yield 7.8 mg 17%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:51][CH2:50][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:54][CH2:53]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: B(Br)(Br)Br.ClCCl.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][C:18]3[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1>CO>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([NH2:27])=[O:26])[C:18]=3[N:17]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nc3cccc(C(N)=O)c3[nH]2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cccc2[nH]c(-c3ccc(O)cc3)nc12

Procedure:
Under an argon atmosphere 1M boron tribromide in dichloromethane (3.8 ml, 3.79 mmol) was transferred to a flask containing 2-(4′-methoxyphenyl)benzimidazole-4-carboxamide (NU 1076 from Example 5) (202.4 mg, 0.758 mmol). The resulting solution was refluxed for 24 hours using an air condenser. The solvent was removed by distillation to complete dryness. The solid residue was treated with 10% NaOH (10 ml), followed by dropwise addition of concentrated hydrochloric acid to neutralise (pH 7). The white precipitate was collected by filtration and dissolved in ethyl acetate (0 ml). The organic solvent was washed with water (2×3 ml), dried over MgSO4, and the product was obtained by removal of the solvent under reduced pressure. (109.5 mg, 57%). mp 266-267° C.; Found C 63.27, H 4.37, N 15.67 C14H11N3O2.0.75 MeOH requires C 63.04 H 4.69 N 15.76; vmax(cm−1) 3424.01, 3384.16, 3309.20, 3249.55, 3155.62, 1642.35, 1618.02, 1594.50, 1577.74; δH 7.03-7.07 (2H, d, J=8.5), 7.34-7.42 (1H, t), 7.75-7.79 (1H, d), 7.85 (1H, br s), 7.90-7.94 (1H, d), 8.15-8.19 (2H, d, J=8.5), 9.4-9.6 (1H, br s), 10.0-10.4 (1H, br s), 13.0-13.4 (1H, br s); m/z (EI) 253 (M+), 236, 208, 93.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.CN1CCOCC1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[F:38])[C:32](Cl)=[O:33].C(O)C(N)(CO)CO>CN(C)C=O>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:32]([C:31]3[CH:35]=[CH:36][C:37]([F:38])=[C:29]([F:28])[CH:30]=3)=[O:33])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccc(F)c(F)c4)CC3)cccc2n1
Reaction time: 2 h
Yield: 157.8 %

Procedure:
5-(Piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was shaken for 60 hours at room temperature in the presence of 3-(morpholino)propyl polystyrene sulfonamide (PS-NMM) (160 mg; 0.4 mmol) and 3,4-difluorobenzoyl chloride (65.3 mg; 0.37 mmol) in 4 mL N,N-dimethylformamide. Tris-(2-aminoethyl)aminomethyl polystyrene (PS-Trisamine) (112 mg; 0.4 mmol) was then added to the mixture and continued to shake for an additional 2 hours. Resins were filtered off and rinsed with methanol. Filtrate was concentrated at reduced pressure, and residue was triturated with 2 mL 1 N NaOH and ethanol (1:1). Solids were collected by filtration to yield [4-(2,4-diamino-quinazolin-5-yloxymethyl)-piperidin-1-yl]-(3,4-difluorophenyl)-methanone (117.4 mg; 76% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.51 (m, 2H), 7.35 (t, J=8.4 Hz, 1H), 7.26 (m, 3H), 6.77 (d, J=8.4 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 5.94 (br s, 2H), 4.50 (br s, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.60 (br s, 1H), 3.11 (br s, 1H), 2.82 (br s, 1H), 2.22 (s, 1H), 1.87 (br s, 1H), 1.75 (br s, 1H), 1.31 (m, 2H). MS m/z (ESI) 414 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[CH:17][C:18]4[C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]=4[CH:24]=3)[CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].I[CH3:33].O>CN(C=O)C>[CH3:33][O:3][C:4]1[CH:13]=[C:12]([C:14]2[CH:27]=[CH:26][C:25]3[C:16](=[CH:17][C:18]4[C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]=4[CH:24]=3)[CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1OC

Procedure:
130 mg (4.2 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 1.6 g (4.2 mmol) of methyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate in 50 ml of DMF was added dropwise and the mixture was stirred until gaseous emission ceased. 340 μl (5.5 mmol) of iodomethane were then added and the mixture was stirred at room temperature for two hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted, dried over magnesium sulfate and evaporated. 1.6 g (96%) of the expected compound was recovered in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([O:16]C)=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1.[OH-].[Na+].CO.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([OH:16])=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: COC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2c(C(=O)O)[nH]c3cc(OC)c(OC)cc23)cc1OC
Yield: 85.3 %

Procedure:
A mixture of methyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (0.54 g), 2N-NaOH (10 ml) and methanol (25 ml) was refluxed for 3 hours under stirring. The reaction mixture was poured into water, acidified with 6N-HCl and extracted with chloroform. The chloroform layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from methanol to give 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylic acid (0.443 g, 85%) as pale red prisms.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:7]([C:9]2[C:10](Cl)=[N:11][CH:12]=[N:13][C:14]=2[Cl:15])=O)[CH2:6][CH2:5]1>C1COCC1>[Cl:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[NH:2][N:3]=[C:7]([CH:4]3[CH2:6][CH2:5]3)[C:9]=12
Reactant: NN
Reactant: O=C(c1c(Cl)ncnc1Cl)C1CC1
Solvent: C1CCOC1
Solvent: O
Product: Clc1ncnc2[nH]nc(C3CC3)c12
Reaction time: 4 h

Procedure:
Add hydrazine hydrate (2.67 g, 53.4 mmol) slowly to cyclopropyl-(4,6-dichloro pyrimidin-5-yl)-methanone (9.66 g, 44.5 mmol) dissolved in 300 mL THF at room temperature and stir for 4 hours. Upon completion, partition the reaction mixture between water and ethyl acetate, collect the organic layer, wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate under vacuum. Purify the resultant title compound by passing through a short silica gel (60-120 mesh) pad using Chloroform/methanol (97:3) as eluent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.[NH2:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18].O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][S:18]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(c1ccccn1)c1ccccn1
Solvent: CCO
Solvent: O
Product: O=C(O)C1CSC(c2ccccn2)(c2ccccn2)N1
Yield: 11 %

Procedure:
A mixture of 3.68 g of di-2-pyridyl ketone, 2.42 g of L-cysteine, 25 ml of water and 25 ml of ethanol was refluxed for 3.5 hours. After allowing the mixture to cool, the insoluble matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed in sequence with ethyl acetate and ether to give 0.63 g of 2,2-di(2-pyridyl)thiazolidine-4-carboxylic acid.