Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([NH:29][C:30]([CH3:32])=[O:31])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.[N+:39]([C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1N)([O-:41])=[O:40]>C(OCC)(=O)C.[OH-].[Na+]>[N+:39]([C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[C:21]1[C:22]([NH:29][C:30]([CH3:32])=[O:31])=[C:23]([CH:27]=[CH:28][C:20]=1[O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:24]([NH2:2])=[O:26])([O-:41])=[O:40]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(N)=O)ccc(OCc2ccccc2)c1-c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
28.5 g (0.39 mole) dry dimethylformamide in 910 mL dry ethyl acetate are mixed dropwise at 2° C., under an atmosphere of nitrogen, with 21.5 g (0.17 mole) oxalyl chloride. After stirring for 30 minutes at 2°-5° C., a suspension of 37.2 g (0.13 mole) 4-benzyloxyacetaminobenzoic acid and 14.4 g (0.18 mole) pyridine in 65 mL ethyl acetate are added thereto and the ice bath is removed. After stirring for 2.5 hours at ambient temperature, the reaction mixture is mixed with a solution of 19.8 g (0.14 mole) o-nitroaniline and 14.4 g (0.18 mole) pyridine in 65 mL ethyl acetate. After stirring for 1 hour at ambient temperature, the reaction mixture is heated to the boil for 3 hours. After cooling, it is mixed with 500 mL IN aqueous sodium hydroxide solution and the phases are separated. The aqueous phase is shaken out twice with ethyl acetate. The combined organic phases are washed neutral with water and dried over anhydrous sodium sulfate. The solvent is evaporated to 150 mL and the precipitated crystals are filtered off with suction and recrystallized from 700 mL ethanol. Yield 13 g (24.7% of theory); m.p 128°-130° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58.4 %

Procedure:
To a solution of Intermediate A (374 mg, 2.29 mmol) in dry DMF (3 mL) under N2 was added NaH (60% dispersion in oil, 183 mg, 4.58 mmol) and the resulting opaque brown solution was stirred at RT for 45 min (CARE: gas evolution). A solution of Intermediate 81c (537 mg, 2.29 mmol) in dry DMF (7 mL) was added and the dark brown solution stirred at 60° C. under N2 for 90 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (3 mL) and AcOH (0.10 mL) and then applied to an SCX-2 cartridge (20 g), washing with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave a dark brown solid. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave the title compound as a pale brown foam (505 mg, 58%). LCMS (Method 3): Rt 2.29 min, m/z 378 [MH+].
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=1.[OH-].[Na+].Cl.C(O)C>CN(C)C=O>[O:18]=[C:15]1[NH:14][CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:19])=[O:2])[CH:17]=[CH:16]1
Reactant: COC(=O)c1ccccc1NCc1ccc(=O)[nH]c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccccc1NCc1ccc(=O)[nH]c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
3.5 g (12.7 mmol) of 2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid-methyl ester is mixed in 15 ml of dimethylformamide with 30 ml of 6N sodium hydroxide solution and stirred for 1.5 hours at room temperature. While being cooled with ice, it is then mixed with about 50 ml of 4N hydrochloric acid, the precipitation is suctioned off, and it is washed with water. 3.1 g, which is taken up in 29.3 ml of 1N sodium hydroxide solution and 142 ml of ethanol, is obtained, and it is heated for 1.5 hours to a bath temperature of 120° C. The ethanol is then drawn off in a vacuum, it is made acidic with 2N hydrochloric acid, and the precipitated product is suctioned off and dried well. 2.9 g (93.5% of theory) of 2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid is obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Li].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:2][CH2:3]1.[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: O=C(CCc1ccc(F)cc1)NC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCNCCCc1ccc(F)cc1
Product: Fc1ccc(CCCNC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-cyclopropyl-3-(4-fluorophenyl)propionamide (4.3 g, 20.8 mmoles) in 30 mL of dry tetrahydrofuran at 0° C. was added 1 equivalent of lithium aluminumhydride in tetrahydrofuran dropwise, and the mixture was refluxed for 2 hours. After cooling to room temperature was added sodium sulfate decahydrate slowly and the mixture was stirred for 0.5 hours. It was filtered through a plug of Celite® and evaporated to give an oily residue. It was purified by clolumn chromatography on silica gel with elution by 6:94 methanol-methylene chloride followed by 0.6:5.4:94 cNH4OH-methanol-methylene chloride to give 1.4 g of N-cyclopropyl-3-(4-fluorophenyl)propylamine and 1 g of N-propyl-3-(4-fluorophenyl)propylamine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:7]2.C([O-])([O-])=O.[Na+].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH2:23]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:7]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc2cccc(O)c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2cccc(OCc3ccccc3)c2c1

Procedure:
A solution of ethyl 5-hydroxyquinoline-3-carboxylate (2.17 g, 10 mmol) prepared in stage D of example 2, Na2CO3 (2.12 g, 20 mmol) and benzylbromide (1.71 g, 10 mmol) in DMF (20 mL) was stirred for 12 hours at room temperature. The reaction mixture was diluted with water (50 mL) and then extracted with AcOEt (3×25 mL). The combined organic layers were washed water, and dried over Magnesium sulfate and evaporated under reduced pressure. The obtained residue was chromatographed over silica-gel.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][NH2:11]>O1CCOCC1>[Cl:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: NN
Reactant: Clc1cnc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: NNc1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a 500 mL flask, 2,3,5-trichloropyridine (20.00 g, 0.110 mol), 80% hydrazine (34.30 g, 0.550 mol) and dioxane (200 mL) were added sequentially. The reaction mixture was heated to reflux for 20 hours. Then the reaction mixture was cooled down to room temperature overnight and white crystal was precipitated. The white crystal was isolated via filtration and dried to give the product (14.0 g) as a white solid in 72% yield. Melting point: 187-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:27]4[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=4)([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)O)[CH:16]=3)[N:11]3[N:33]=[N:34][N:35]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:38])=O>>[ClH:1].[Cl:38][C:18]([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]1[N:33]=[N:34][N:35]=[C:10]1[N:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Product: Cc1ccc(C(Cl)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of intermediate 25 (0.0083 mol) in thionyl chloride (80 ml) was stirred at 60° C. for 3 hours, then cooled and the solvent was evaporated. The residue was taken up in DCM. The solvent was evaporated, yielding 7-[chloro(1-methyl-1H-imidazol-5-yl)(4-methylphenyl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline. hydrochloride (1:1) (intermediate 26). This product was used directly in the next reaction step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([N:20]=[CH:21][C:22]3[S:26][CH:25]=[N:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[S:26][CH:25]=[N:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(N=Cc3cncs3)c2CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3cncs3)c2CC1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
Dissolve 3-(t-butoxycarbonyl)-7-chloro-6-(thiazol-5-ylmethyleneamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (228 mg, 0.58 mmol) in methanol (10 mL), add sodium borohydride (263 mg, 7 mmol) and reflux for 28 h. Cool to ambient temperature, dilute with EtOAc and add slowly water. Separate the organic layer, extract the aqueous layer three times with EtOAc. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:3) to give the desired intermediate as a colorless oil (134 mg, 58%). MS (ES+) m/z: 394 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]#[N:9])[NH:4][C:3]=1[C:10](Cl)=[O:11].Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]#[N:9])[NH:4][C:3]=1[C:10]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[CH2:17][CH2:16]1)=[O:11]
Reactant: COC(=O)c1cc(N2CCC(N)CC2)c2ccccc2n1
Reactant: N#Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl
Agent: Cl
Product: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C#N)c(Cl)c3Cl)CC2)c2ccccc2n1

Procedure:
The title compound was prepared by an analogous procedure to Example 271 starting from 3,4-dichloro-5-cyano-1H-pyrrole-2-carbonyl chloride (Intermediate 132) and methyl 4-(4-aminopiperidin-1-yl)quinoline-2-carboxylate hydrochloride (Intermediate 136).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.ClCCl>[N:1]1[CH:2]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH:5]1[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C1CCNCC1
Product: c1cncnc1
Reaction time: 16 h

Procedure:
Commercially available dichloropyrimidines were reacted with a 4-aminopiperidine in tetrahydrofuran in the presence of potassium carbonate at room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and the potassium carbonate was filtered off. The solvent was removed and the crude reaction mixture was purified by column chromatography on silicagel to give a pyrimidine-piperidine intermediate. Further the intermediate was reacted with the desired diamine compound in refluxing butanol. The compound of Formula I was isolated after column chromatography on silicagel.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:10]=2[NH2:23])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:24]([O-])=O.[Na+].CO.[Sn](Cl)Cl>Cl.O.C1COCC1>[C:1]1([C:7]2[C:9]3[C:10](=[CH:11][CH:12]=[C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:14]=3)[NH:23][N:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(COc2ccc3[nH]nc(-c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2-amino-5-(phenylmethoxy)phenyl phenyl ketone (2.6 g, 8.0 mmol) in 6N HCl (70 mL) at 0° C. was added a solution of sodium nitrite (NaNO2) (650 mg, 9.4 mmol) in water (2 mL). To this solution was added methanol and THF to keep it homogeneous. A solution of tin (II) chloride (SnCl2) (5.3 g, 23.6 mmol) in concentrated HCl (20 mL) was then added. The solution was stirred at room temperature overnight. The solid was then filtered and the solution concentrated and chromatographed on silica gel eluting with 20% ethyl acetate in hexane to give the title compound (1.15 g, 48% yield). 1H NMR (DMSO-d6) δ 13.1 (s, 1H), 7.95 (d, 2H), 7.56-7.48 (m, 6H), 7.44-7.3 (m, 4H), 7.14 (d, 1H), 5.12 (s, 2H); ES-MS (m/z) 301 [M+1]+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[C:11]1[N:12]=[CH:13][C:14]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:15]=2[N:16]=1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[NH2:36].O>CN1CCCC1=O>[C:23]([O:22][C:20]([N:18]1[CH2:19][C:14]2[CH:13]=[N:12][C:11]([NH:36][CH:28]3[CH2:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:27]3)=[N:16][C:15]=2[CH2:17]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(Cl)nc2C1
Reactant: NC1Cc2ccccc2C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 80 °C
Yield: 74.5 %

Procedure:
Charge 450 mL (2.58 mol) of N-ethyl-N-isopropylpropan-2-amine into a 15° C. solution of tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (220 g, 860.37 mmol) and 2,3-dihydro-1H-inden-2-amine (137.7 g, 1.03 mol) in 1-methylpyrrolidin-2-one (3.6 L). Heat the resulting mixture to 80° C. for 16 h, then cool to 30° C. and transfer the resulting mixture into 5 L of water at 25° C. Filter the resulting solid and rinse the filter cake with water (2×300 mL). Reslurry the solid in ethyl acetate (350 mL) for 45 min at 15° C. Filter the slurry, rinsing with 15° C. ethyl acetate (2×250 mL), and dry to give the title compound (226 g, 75%) as an off-white solid. 1H NMR (d6-DMSO) 1.45 (s, 9H), 2.87 (dd, J=7.2, 15.8 Hz, 2H), 3.24 (dd, J=7.2, 15.8 Hz, 2H), 4.36 (d, 10.4 Hz, 2H), 4.44 (d, J=12.8 Hz, 2H), 4.60 (m, 1H), 7.14 (m, 2H), 7.20 (m, 2H), 7.55 (d, J=6.8 Hz, 1H), 8.27 (d, J=7.2 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>S1(CCCC1)(=O)=O.O>[CH2:18]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 32.3 %

Procedure:
2,4-Dihydroxybenzoic acid (48.0 g), anhydrous potassium carbonate (21.5 g), benzyl chloride (39.4 g) and dry sulpholane (400 ml) were heated together, with stirring, at 100° C. for 20 hours. The mixture was then poured into water (2 liters), the resulting oil was separated and the aqueous layer extracted with diethyl ether (300 ml). The ether extract was evaporated and its residue was combined with the said oil layer and washed with water (500 ml) to remove sulpholane, and then was washed with brine, the aqueous washings were extracted with diethyl ether (400 ml), and the combined oil and ether extract were dried and evaporated to give crude benzyl 2,4-dihydroxybenzoate (64 g), m.p. 83°-88° C. This ester (20 g) was treated with anhydrous potassium carbonate (17.0 g) and benzyl chloride (22.8 g) in dry sulpholane (300 ml) and the mixture was stirred and heated at 140° C. for 3 hours. It was allowed to cool and was then poured into water (1500 ml) and the mixture was neutralised to pH 7 by treatment with hydrochloric acid. The precipitated crude benzyl 2,4-dibenzyloxybenzoate was heated at reflux with a mixture of aqueous sodium hydroxide solution (2N; 400 ml) and ethanol (50 ml) for 10 hours. The solution was allowed to cool, and was then diluted with a large volume of water and acidified to pH 1 by treatment with hydrochloric acid (2N) to give a white solid which was filtered off and recrystallized from ethanol to give 2,4-dibenzyloxybenzoic acid (16.8 g), m.p. 126°-128° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:47])[C@H:7]([CH2:26][S:27][C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:8]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)([CH3:4])[CH3:3].N1CCCCC1>CN(C=O)C>[CH3:4][C:2]([O:5][C:6](=[O:47])[C@H:7]([CH2:26][S:27][C:28]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH2:8])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1cccc2c1Cc1ccccc1-2
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of N-fluorenylmethoxycarbonyl-S-trityl-L-cysteine 1,1-dimethylethyl ester (640 mg, 1 mmol) in 5 mL of DMF was added 2 mL of piperidine. The solution was stirred for 20 min., and the solvent was evaporated. The residual piperidine was removed by azeotroping the solid with DMF (3×20 mL) and drying under high vacuum for 1 hour to give S-trityl-L-cysteine 1,1-dimethylethyl ester as a solid. To this solid was added 5 mL of DMF followed by 1-(2-azidoethyl)cyclopentane carboxylic acid (6a) (183 mg, 1 mmol), HBTU (379 mg, 1 mmol), and DIPEA (0.18 mL, 1 mmol). The resulting solution was stirred for 5 hours, and the solvent was removed under high vacuum. The residue was purified by silica gel column chromatography usilng ethylacetate/hexanes (15/85) as eluent, to afford 500 mg (86%) of N-[[1-(2-azidoethyl)cyclopentyl]carbonyl]-S-triphenylmethyl-L-cysteinie 1,1-dimethylethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11]N(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][O:8][C:6]=2[N:7]=1.[CH:26]1[C:36]2[C:30](=[N:31][C:32]3[CH:40]=[CH:39][CH2:38][CH2:37][C:33]=3[CH2:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=1.[H-].[Na+].NC1N=C(N)C2C(CCl)=COC=2N=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][CH:37]3[C:33]4[CH2:34][CH:35]=[C:36]5[CH:26]=[CH:27][CH:28]=[CH:29][C:30]5=[N:31][C:32]=4[CH:40]=[CH:39][CH2:38]3)=[CH:9][O:8][C:6]=2[N:7]=1
Reactant: C1=CC2=C(CC=c3ccccc3=N2)CC1
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)coc2n1
Agent: Nc1nc(N)c2c(CCl)coc2n1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(N)c2c(CC3CC=CC4=C3CC=c3ccccc3=N4)coc2n1

Procedure:
9-[(2,4-Diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-9,10-dihydrodibenz-[b,f]azepine (Formula I: Ar=2,4-diaminofuro[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=CH2CH2; m=n=0) is prepared similarly to N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10-dihydrodibenz[b,f]azepine (158 mg, 0.8 mmol), sodium hydride (50 mg, 2.1 mmol), and 2,4-diamino-5-chloromethylfuro[2,3-d]pyrimidine (60 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.O1CCCC1.CO.[BH4-].[Na+]>O>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12](=[O:30])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: O=C(Nc1ccc(C(=O)N2CCC(=O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)N2CCC(O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To 4-oxo-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline(0.7 g) are added tetrahyrdofuran (10 ml) and methanol (10 ml). To the mixture is added sodium borohydride (0.1 g) in portions and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the mixture is extracted with dichloromethane. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=20:1), and recrystallized from ethanol to give 4-hydroxy-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. 215°-217° C.
Reaction SMILES: [C:1]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11].[C:35]([O:39]O)([CH3:38])([CH3:37])C>[Mo](=O)(=O)=O.C1C2C(CCCC2)CCC1>[C:1]([O:24][CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([O:39][CH:35]2[CH:38]3[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7]3)[CH2:2][CH2:1][CH2:37]2)[C:27]([CH3:34])([CH3:33])[CH2:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:39][CH:35]2[CH:38]3[CH:14]([CH2:13][CH2:18][CH2:17][CH2:19]3)[CH2:15][CH2:21][CH2:37]2)[C:15]([CH3:21])([CH3:22])[CH2:14]1)=[O:11]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Solvent: C1CCC2CCCCC2C1
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC3CCCC4CCCCC43)C(C)(C)C2)CC(C)(C)N1OC1CCCC2CCCCC21
Yield: 141.1 %

Procedure:
A mixture of 25.0 g (0.052 mol) of bis(2,2,6,6-tetramethylpiperdin-4-yl) sebacate, 55.0 g (0.427 mol) of 70% aqueous tert-butyl hydroperoxide, 1.5 g (0.01 mol) of molybdenum trioxide and 180 ml of decahydronaphthalene (decalin) is heated at reflux for 4.5 hours till the red color disappears. Water is collected in a Dean-Stark trap. The molybdenum trioxide is removed by filtration and the filtrate is stirred with a solution of 26 g of sodium sulfite in 500 ml of water to decompose unreacted tert-butyl hydroperoxide. The 2-phase mixture is diluted with 200 ml of ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated at reduced pressure to give an oil. Purification by flash chromatography (silica gel, 19:1 heptane:ethyl acetate) affords 28.8 g (71% yield) of the title compound as a pale yellow oil.