Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=3)[CH:3]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3ccc(O)cc23)cc1
Yield: 52 %

Procedure:
This compound was prepared from 6b using 4-cyanophenylboronic acid according to method P. Yellow powder; Yield: 52%; mp 266–267° C.; 1H-NMR (400 MHz, DMSO-d6) δ 6.97 (d, J=2.7 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.34 (dd, J=9.0, 2.6 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.92 (s, 1H), 7.95–8.00 (m, 2H), 8.07–8.10 (m, 3H), 10.00 (s, 1H), 10.21 (s, 1H); MS (ESI) m/z 355 ([M−H]−), 357 ([M+H]+); Anal. Calcd for C22H13FN2O2: C: 74.15, H: 3.68, N: 7.86. Found: C: 73.69, H: 3.53, N: 7.86.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[N:10]([CH2:23][C:24](OC)=[O:25])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].CO.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[N:10]([CH2:23][CH2:24][OH:25])[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cn1nc(-c2ccnc(Br)c2)c2cc(OC)c(OC)cc2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(-c3ccnc(Br)c3)nn(CCO)c(=O)c2cc1OC
Yield: 75.9 %

Procedure:
To a solution of 2-bromo-4-(6,7-dimethoxy-2-methoxycarbonylmethylphthalazin-1(2H)-on-4-yl)pyridine (4.34 g) in tetrahydrofuran (20 ml) is added sodium borohydride (0.76 g), and further thereto is added dropwise with heating a mixture of methanol (3.2 ml) and tetrahydrofuran (5 ml) under reflux over a period of one hour. The reaction mixture is allowed to stand for cooling, and thereto is added water under ice-cooling. The mixture is extracted with chloroform, and the extract is washed, dried and concentrated. The residue is recrystallized from isopropyl ether to give 2-bromo-4-(6,7-dimethoxy-2-hydroxyethylphthalazin-1(2H)-on-4-yl)pyridine (3.08 g).
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[N:7]([CH3:19])[C:6]=2[C:5]([C:20]#[N:21])=[CH:4][N:3]=1.CS(O)(=O)=[O:24]>>[NH2:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:16])[F:17])=[CH:9][C:8]=3[N:7]([CH3:19])[C:6]=2[C:5]([C:20]([NH2:21])=[O:24])=[CH:4][N:3]=1
Reactant: Cn1c2cc(C(F)(F)F)ccc2c2c(N)ncc(C#N)c21
Reactant: CS(=O)(=O)O
Product: Cn1c2cc(C(F)(F)F)ccc2c2c(N)ncc(C(N)=O)c21
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A suspension of the product of Step 3 in a 1:1 (mass/mass) mixture of PPA/CH3SO3H (0.034 M) was stirred for 90 min at 120° C. The resulting mixture was then added to ice-cold saturated NaHCO3 solution, stirring until all the reagent was consumed and the pH was 7-8. The crude material was collected by filtration, and was purified by preparative TLC, eluting with 1:20 MeOH:EtOAc to give the title compound as a white solid.
Reaction SMILES: Br.Br[CH:3]1[C:8](=[O:9])[CH:7](Br)[C:6]([CH3:12])([CH3:11])[NH:5][C:4]1([CH3:14])[CH3:13].[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][NH2:22])[CH2:18][O:17]1.CC([O-])(C)C.[K+]>C(O)(C)C>[CH3:15][C:16]1([CH3:23])[O:20][CH:19]([CH2:21][NH:22][C:8]([C:7]2[C:6]([CH3:11])([CH3:12])[NH:5][C:4]([CH3:3])([CH3:13])[CH:14]=2)=[O:9])[CH2:18][O:17]1
Reactant: CC1(C)OCC(CN)O1
Reactant: CC1(C)NC(C)(C)C(Br)C(=O)C1Br
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1(C)C=C(C(=O)NCC2COC(C)(C)O2)C(C)(C)N1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Under agitation, cooling between -5° and 0° C., and covering with argon, 68.94 g (175 mmol) of 3,5-dibromo-2,2,6,6-tetramethylpiperidin-4-one hydrobromide is added in portions to a solution of 22.93 g (175 mmol) of (2,2-dimethyl-1,3-dioxolan-4-yl)methylamine and 58.9 g (525 mmol) of potassium tert-butylate in 700 ml of isopropanol. A white paste is thus obtained which is stirred for one hour without cooling, suctioned off from the solid matter, and concentrated to dryness under vacuum. The residue is distributed between dichloromethane and water. The organic phase is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized. After recrystallization from pentane, 30.1 g (60.9% of theory) of 2,2,5,5-tetramethyl-3-pyrroline-3-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amide is obtained, mp 55°-57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][O:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O1CCOCC1.[Br:26]Br.O>C(OCC)C>[Br:26][CH:6]([O:5][CH2:4][C:3]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=1[Cl:1])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(COCc1ccc(Cl)cc1Cl)c1ccccc1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccccc1)C(Br)OCc1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2-(2,4-Dichlorobenzyloxy)acetophenone (29.52 g, 100 mmole) was dissolved in a mixture of diethyl ether (100 ml) and 1,4-dioxane (100 mmole) and bromine (16 g, 100 mmole) was added dropwise over 1 hour. After stirring at the same temperature for additional 1 hour, water (200 ml) was added and the mixture was separated into layers. The aqueous layer was extracted with diethyl ether (200 ml). The organic layers were combined, washed with 1% aqueous solution of sodium bicarbonate (180 ml) and dired over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and a mixture of benzene/n-hexane was added to the residue to crystallize. The crystals were filtered off to obtain a crude product of the title compound (28.57 g). The crude product (1 g, 2.67 mmole) was recrystallized from benzene/n-hexane to obtain the title compoud (0.79 g, 79%), m.p. 89°-91° C.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)=O>[CH2:20]([N:27]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:1]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: NNCc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)cc1
Yield: 24.9 %

Procedure:
A mixture of ethyl 4-benzoylbenzoate (13.7 g, 54 mmole), benzylhydrazine (8 g, 65 mmole), ethanole (50 mL) and HOAc (1 mL) was refluxed for 12 hours and then treated with the procedure described in Example 1 to yield a crude product that was purified by column chromatography (silica gel-benzene), and recrystallized from n-hexane to give 4.8g 1-benzyl-3-(4′-ethoxycarbonylphenyl)indazole in a yield of 25.5%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][N:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18]>>[ClH:13].[OH:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:27]1[CH:26]=[C:16]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:18])[CH:15]=[CH:14][N:28]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: CN1CCN(C(=O)c2ccnc(Cl)c2)CC1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Product: CN1CCN(C(=O)c2ccnc(-c3c(O)[nH]c4ccc(C#N)cc34)c2)CC1
Product: Cl
Yield: 2 %

Procedure:
The reaction was performed as described in Example 49 using 5-cyanooxindole and 1-(2-chloroisonicotinoyl)-4-methylpiperazine. The crude product was purified on a silica gel column using chloroform/ethanol/conc. NH3(aq), (100:10:1), as the eluent. The base (20 mg) was dissolved in chloroform and a solution of HCl in diethyl ether was added until acidic pH. The formed precipitation was filtered and washed with diethyl ether. Drying in vacuo afforded 10 mg the title compound as a red solid. Yield: 2%: 1H NMR (D2O, 400 MHz) δ 7.82-7.77 (m, 1 H), 7.18-7.11 (m, 1 H), 7.09-7.05 (m, 1 H), 7.04-6.98 (m, 1 H), 6.78-6.71 (m, 1 H), 6.67-6.61 (m, 1 H), 4.05-3.94 (m, 1 H), 3.93-3.82 (m, 1 H), 3.67-3.48 (m, 2 H), 3.48-3.37 (m, 1 H), 3.35-3.04 (m, 3 H), 2.92-2.80 (m, 3 H); MS (TSP) m/s 362 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)#[N:31].O>O1CCOCC1>[Cl:23][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[N:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:22])[C:9]([OH:14])([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C#N)nc3)cc2Cl)C(F)(F)F)ccn1

Procedure:
A mixture of 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (Example 60 step 1, 40 mg), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palldadium(II) (7 mg), Cs2CO3 (96 mg) and 2-cyanopyridine-5-boronic acid pinacol ester (CAS Reg. No. 741709-63-7, 45 mg) in dioxane (2 ml) and water (0.2 ml) was heated at 100° C. for 10 min in a sealed tube. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (32 mg) as a yellow solid. MS (m/e)=432.2 [M+H+].
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH3:6])[CH3:3].C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[ClH:20].[CH2:2]([N:4]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([Cl:1])=[O:13])=[CH:15][CH:16]=1)[CH2:5][CH3:6])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)Cc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To a well-stirred suspension consisting of 1.34 g. (5.0 mmole) of 4-(N,N-diethylaminomethyl)benzoic acid hydrochloride (the product of Preparation G) in 25 ml. of methylene chloride under a nitrogen atmosphere, there was added over a five-minute period a solution consisting of 1.5 g. (0.0118 mole) of oxalyl chloride dissolved in 5 ml. of methylene chloride. The resulting reaction mixture was refluxed for a period of 17 hours and then cooled to room temperature (~20° C.). The colorless solution so obtained was evaporated under reduced pressure, and the resulting residue was washed twice with methylene chloride and then stripped free of solvent to give a white solid product. In this way, there was readily obtained substantially pure 4-(N,N-diethylaminomethyl)benzoyl chloride hydrochloride, which was used in the next reaction step without any further purification being necessary. The yield of product was assumed to be quantitative.
Reaction SMILES: [Na].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Cl:13])=[N:5][N:4]=1.[CH3:14][CH2:15][OH:16]>>[Cl:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:16][CH2:15][CH3:14])=[N:4][N:5]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: CCO
Agent: [Na]
Product: CCOc1nnc(Cl)c2ccccc12

Procedure:
Sodium (33.8 mg, 1.470 mmol) was allowed to react with EtOH (10 mL), then 1,4-dichlorophthalazine (279 mg, 1.4 mmol) was added and the reaction mixture was refluxing for 30 min. The hot solution was filtered and evaporated. The crude product was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 200 mg of the crude product 1-chloro-4-ethoxyphthalazine. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.29-8.18 (m, 2H), 7.99-7.90 (m, 2H), 4.73 (q, J=7.1 Hz, 2H), 1.57 (t, J=7.2 Hz, 3H); MS: MS m/z 209.06 (M++1).
Reaction SMILES: C([O:4][C@@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH2:7][CH2:6]1)(=O)C.[Li+].[OH-]>>[OH:4][C@@H:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCCCCCN1CC[C@H](OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCCCCCN1CC[C@H](O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
The title compound was prepared from (S)-ethyl 7-(8-acetoxy-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) and LiOH analogously to Example 9.1;
Reaction SMILES: [ClH:1].N[C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1.N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:1][C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,260 ml of 36% hydrochloric acid were charged in a 5-l four-necked flask and then cooled to 0° C. After 180 g (1.16 moles) of 2-amino-4,6-dimethoxypyrimidine were added in small portions into the flask, the resulting mixture was stirred for about 1 hour until the reaction mixture changed into a syrupy form. After the reaction mixture was cooled to -15° C., 260 ml of 159 g (2.3 moles) of NaNO2 in H2O were added dropwise over about 1 hour under vigorous stirring. After completion of the dropwise addition, the resulting mixture was stirred at -15° to -10° C. for additional 1 hour so that the reaction was brought to completion. While the reaction mixture was retained at -5° C., 1.5 l of a 30% aqueous solution of NaOH were charged dropwise so that the reaction mixture was neutralized to pH 7. By filtration under reduced pressure, a clay-like material of a purple color was collected. The target compound was extracted from the clay-like material using 3 l of ethyl acetate. Through the procedures of washing with water, drying over anhydrous sodium sulfate and removal of the solvent, 63 g of bluish crude crystals were obtained. They were crystallized further by silica gel chromatography to obtain 60.8 g of white crystals (yield: 29.9%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:16])[CH2:13][O:14][CH3:15])[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]=2[C:23]=1[F:24].Cl[C:26]1[N:34]=[CH:33][N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.CCN(C(C)C)C(C)C>CC(O)CC>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:16][C:26]3[N:34]=[CH:33][N:32]=[C:31]4[C:27]=3[N:28]=[CH:29][N:30]4[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH2:13][O:14][CH3:15])[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:8]=2[C:23]=1[F:24]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COC[C@H](N)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Agent: Cl
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(F)c2n1-c1ccccc1
Temperature: 90 °C

Procedure:
To a solution of (R)-1-(6,7-difluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine dihydrochloride (0.20 g, 0.68 mmol) in 2-butanol (5 mL) was added 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (0.195 mg, 0.81 mmol) and DIPEA (233 μL, 1.36 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give the title compound as an off white solid (290 mg, 84%). LCMS (Method C): RT=3.48 min, [M+H]+=506.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH:26]([N:39]1[CH2:42][CH:41]([OH:43])[CH2:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH:26]([N:39]1[CH2:42][CH:41]([O:43][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:6]3[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(OC4CN(C(c5ccccc5)c5ccccc5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a tetrahydrofuran (1 ml) solution of 6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (30 mg, 0.073 mmol) and 1-benzhydrylazetidin-3-ol (53 mg, 0.22 mmol) was added potassium tertbutoxide (24 mg, 0.22 mmol). The combined reagents were stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness and the residue was extracted into ethyl acetate from saturated NaHCO3 solution. The organic layers were combined, dried (Na2SO4), filtered, and evaporated to dryness. The crude product was purified by chromatography on a preparative TLC plate using 4% methanol/methylene chloride as the solvent to give title compound 3A-1 as a yellow oil. A solution of the material in methylene chloride was treated with excess 1 N HCl in diethyl ether, stirred, evaporated to dryness, and then triturated in diethyl ether to afford the hydrochloride salt of compound 3A-1 (14 mg, 31%): +ESI MS (M+1) 612.2; 1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 7.65–7.30 (m, 17H), 5.85–5.77 (br m, 2H), 4.75–4.60 (br m, 2H), 4.55–4.30 (br m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2C(=CC=C[CH:18]=2)C[C@H:12]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=CC=C[CH:3]=1.N1C2C(=CC=CC=2)C[C@H]1C(O)=O.C(Cl)[Cl:36]>>[CH2:1]([O:8][C:9]([Cl:36])=[O:10])[CH:2]([CH3:7])[CH3:3].[CH3:9][N:11]1[CH2:12][CH2:20][O:22][CH2:18][CH2:19]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: ClCCl
Agent: O=C(O)[C@@H]1Cc2ccccc2N1
Product: CC(C)COC(=O)Cl
Product: CN1CCOCC1

Procedure:
A suspension of 1.500 g (5.04 mmoles) of N-benzyloxycarbonyl-(S)-(-)-indoline-2-carboxylic acid (abbreviation Z-(S)-Dhi-OH, prepared from (S)-(-)-indoline-2carboxylic acid (Aldrich) according to the method of Wunsch E. Wunsch, W. Graf, O. Keller, W, Keller, G.Wersin: Synthesis, (11), 958 (1986)!) in 80 ml of dry methylene chloride (CH2Cl2) was brought under argon atmosphere to a temperature of approximately -20° C. On stabilization of the temperature, the following were added in quick succession: 0.680 ml (5.20 mmoles) of isobutylchloroformate (IBCF) and 0.580 ml (5.26 mmoles) of 4-methylmorpholine (NMM), leaving the system under stirring for approximately 2 minutes. A solution, precooled to approximately -15° C. for 30 minutes, of 1.840 g (5.00 mmoles) of (L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.560 ml (5.08 mmoles) of NMM in 25 ml of anhydrous N,N-dimethylformamide (DMF) was then added, leaving, under stirring and static argon, the temperature of the bath free to rise to room temperature. After approximately 5 hours of reaction, the white precipitate was then filtered away and washed with a little CH2Cl2. The latter was put back into the pale yellow coloured organic solution, which was extracted in succession using 5% NaHCO3 (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (3×30 ml) and finally saturated aqueous NaCl (3×30 ml), discarding the aqueous phases. The organic phase extracted, of a pale yellow colour, was left in a cold chamber under argon and on anhydrous Na2SO4 for 12 hours. The desiccant was then filtered away and the organic solution, concentrated to a small volume, was added dropwise under stirring to 200 ml of dry petroleum ether (30/50), obtaining an abundant white precipitate which, after several hours at rest in a cold chamber, was filtered, discarding the organic solution. The residual solid was left for 24 hours under vacuum on P2O5 2.440 g (79.9%) of an analytically pure white solid were recovered.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[N+:22]([C:25]1[CH:34]=[CH:33][C:28]([CH:29]=[CH:30][CH2:31]O)=[CH:27][CH:26]=1)([O-:24])=[O:23].CCOCC>C(#N)C>[N+:22]([C:25]1[CH:34]=[CH:33][C:28](/[CH:29]=[CH:30]/[CH2:31][Br:20])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(C=CCO)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(/C=C/CBr)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
In 35 mL of dry acetonitrile under nitrogen atmosphere was added 7.3 g (27.9 mmole) of triphenylphosphine. To the solution was added dropwise over 15 minutes 4.31 g of bromine (27.0 mmole) while cooling the reaction mixture to maintain the temperature between 0°-10° C. The solution was allowed to warm to room temperature (about 22°-25° C.) and 5.0 g (27.9 mmole) of p-nitrocinnamyl alcohol (Pfaultz & Bauer Chemical Co.) was added as a slurry in 50 mL of acetonitrile which caused an exothermic reaction, temperature about 45° C. The resulting dark red solution was heated for one hour at 60° C. with stirring and then poured into 500 mL of ether. Triphenylphosphine oxide precipitated from the solution after standing overnight (about 16 hours). The solution was filtered and 15 g of flash silica gel was added to the solution, followed by solvent removal. The resulting powder matrix was applied to a 3 in.×8 in. (7.6 cm×20.3 cm) flash column and the desired product was eluted with hexane, followed by 20% ethyl acetate in hexane to yield 5.8 g (23.9 mmole) of the desired pure trans product in 86% yield (MP=75°-76° C., Rf =0.81, 60:40 ethyl acetate:n-hexane) and was further characterized by:
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6](OCCN)=[S:7])C.C[C@@H:13]([OH:19])[C@H:14]([NH2:18])[C:15](O)=O.N>C(O)(C)C>[NH2:18][CH:14]([CH3:15])[C:13]([NH:3][CH2:4][CH2:6][SH:7])=[O:19]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: C[C@H](N)C(=S)OCCN
Agent: Cl
Agent: N
Solvent: CC(C)O
Product: CC(N)C(=O)NCCS

Procedure:
To a suspension of 22.1 g of the 2-aminoethyl thioalaninate dihydrochloride (0.1 mole), obtained above, in 50 cm3 of isopropanol, thre are slowly added, under an inert atmosphere, 20.4 cm3 (0.15) mole) of a 2.5% aqueous ammonia solution. The resulting solution is evaporated to dryness under reduced pressure. The residue is taken up in 100 cm3 of ethanol. The insoluble ammonium chloride is separated by filtration on fritted glass. The filtrate is evaporated to dryness and dried under a vacuum at 50° C. 17.5 g of 2-amino N-(2-mercaptoethyl) propionamide in the form of a white solid whose melting point is 141° C. are obtained.