Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11]([C:13]1[S:27][C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:24]([OH:26])=O)=[CH:21][C:22]=3[S:23][C:15]=2[C:14]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:9][O:10][C:11]([C:13]1[S:27][C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:24](=[O:26])[NH:8][CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:21][C:22]=3[S:23][C:15]=2[C:14]=1[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:12]
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NCC3CCCCC3)ccc12
Reaction time: 48 h
Yield: 55.7 %

Procedure:
Cyclohexanemethyamine (29 μl, 0.22 mmol) was added to a mixture of 1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2,6-dicarboxylic acid 2-methyl ester (42 mg, 0.11 mmol), HATU (49 mg, 0.13 mmol), and Et3N (50 1) in DMF (0.5 ml). The mixture was stirred for 2 days. Addition of EtOAc, washing with water, drying organic layers over MgSO4, filtration, and reoval of solvent in vacuo left crude material. Purification by column chromatography yielded 30 mg (58%) of 6-(cyclohexylmethylcarbamoyl)-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.C(NCC)C>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CCN(CC)CC
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 193.5 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and diethylamine (9.6 ml) is added thereto at the temperature within 20 min, the above mixture is reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50 for 5 h to obtain solid purin (12.3 g). The yield is about 75.1%.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](Cl)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:38]([N:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]([N:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][CH:17]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)c1ccccc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
A mixture of 75 mg (0.166 mmole) of N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl chloride (from Step B), 46 mg (0.25 mmole) of N-phenylbenzylamine, 58 μL (43 mg, 0.33 mmole) of N,N-diisopropylethylamine, and 1 mL of dry toluene was stirred under N2 at 110° C. for 48 hours. The cooled reaction mixture was concentrated by rotary evaporation. Flash chromatography of the residual oil on silica gel (elution with 4:1 and then 3:1 hexane-EtOAc) gave 91 mg (92%) of the title compound as a tacky foam, homogeneous by TLC in 3:1 hexane-EtOAc; FAB-MS m/e 599 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][O:36][CH2:37][C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: COCC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was dissolved in dimethylformamide (3 ml) and triethylamine (153 μl, 1.1 mmol) was added followed by methoxyacetic acid (31 μl, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) and 1-hydroxybenzotriazole (54 mg, 0.40 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) and the product was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (112 mg) as a white solid.
Reaction SMILES: [CH:1]1[N:9]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@@H:11]2[OH:18])[C:8]2[C:3](=[C:4]([NH2:20])[N:5]=[C:6]([F:19])[N:7]=2)[N:2]=1.[P:21]([O-:25])([O-:24])([O-:23])=[O:22].C(=O)([O-])[O-].[K+:30].[K+].CC(C)=O>O>[CH:1]1[N:9]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@@H:11]2[OH:18])[C:8]2[C:3](=[C:4]([NH2:20])[N:5]=[C:6]([F:19])[N:7]=2)[N:2]=1.[K+:30].[K+:30].[P:21]([OH:25])([O-:24])([O-:23])=[O:22]
Reactant: O=P([O-])([O-])[O-]
Agent: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=P([O-])([O-])O
Temperature: 25 °C

Procedure:
5.0 g of fludarabine-phosphate at a purity of 96.1% is dissolved in 30 ml of water, and 6.5 ml of a potassium carbonate solution (18.5% by weight) is added to this solution below 30° C. It is stirred for 15 more minutes, then solid material is filtered out. The clear solution that is thus obtained is poured into acetone at 50° C., cooled to room temperature and stirred for 2 more hours. The deposited precipitate is filtered and washed twice with acetone. 4.5 g of fludarabine-phosphate dipotassium salt is obtained.
Reaction SMILES: N1C=CN=CC=1[N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.ClCC([N:18]1[CH2:22][C:21](F)(F)C[C@H:19]1[C:25]#[N:26])=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl>C(#N)C.C(OCC)C>[N:18]1[CH:19]=[CH:25][N:26]=[CH:21][C:22]=1[CH:12]1[CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8][NH:7]1
Reactant: N#C[C@@H]1CC(F)(F)CN1C(=O)CCl
Reactant: NC1CCN(c2cnccn2)CC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: NC1CCNC(c2cnccn2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 145.5 %

Procedure:
63 mg of 1-(2-pyrazinyl)-4-amino-piperidine (0.32 mmol) and 62 mg (2S)-1-(2-chloroacetyl)-4,4-difluoro-2-pyrrolidine carbonitrile (0.32 mmol) and 285 mg of polymer-bound 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (PBEMP) (0.73 mmol) are dissolved in 20 ml dry acetonitrile and stirred at 55° C. for 8 hours. The resin is removed by filtration, the filtrate is concentrated by vacuum and the residue is purified by column chromatography using chloroform—methanol (9:1) as eluent to result an oil, which is treated with hydrochloric acid in diethylether result in 83 mg (60%) of title compound, as white crystals. M.p.: 158-160° C. 1H-NMR (400 MHz, DMSO-d6): δ 1.54 (m, 2H), 2.15 (m, 2H), 2.80-2.95 (m, 4H), 4.20-4.25 (m, 4H), 4.55 (d, 2H,), 5.20 (t, 1H), 7.00 (d, 1H), 7.87 (dd, 1H), 8.50 (d, 1H); 9.38 (br, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:13])[C:8](=[O:9])[N:7]([CH3:10])[C:6](=[O:11])[NH:5][C:4]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]=12.CCN(CC)CC>CC(O)=O>[CH3:10][N:7]1[C:8](=[O:9])[C:3]([CH3:13])([N:2]2[C:21](=[O:22])[C:20]3[C:19](=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=3[F:14])[C:24]2=[O:23])[C:4](=[O:12])[NH:5][C:6]1=[O:11]
Reactant: CN1C(=O)NC(=O)C(C)(N)C1=O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Temperature: 25 °C

Procedure:
A mixture of 5-amino-1,5-dimethylbarbituric acid hydrochloride (0.31 g, 1.50 mmol), tetrafluorophthalic anhydride (0.40 g, 1.80 mmol) and Et3N (0.21 mL, 0.15 g, 1.50 mmol) in glacial AcOH (11 mL) was stirred under reflux for 3 hours. The yellow solution was then allowed to cool down to room temperature and evaporated to dryness under reduced pressure. The oily residue was recrystallized from 70% EtOH to give 1,5-dimethyl-5-(tetrafluorophthalimido)-barbituric acid (19a) as white crystals.
Reaction SMILES: [CH:1]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH:4]2[C:7]([O:9][C:10](=[O:11])[CH:3]2[CH2:2]1)=[O:8].C([OH:18])CC>>[CH:1]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([OH:18])=[O:8])[CH:3]([C:10]([OH:9])=[O:11])[CH2:2]1
Reactant: O=C(O)C1CCC2C(=O)OC(=O)C2C1
Reactant: CCCO
Product: O=C(O)C1CCC(C(=O)O)C(C(=O)O)C1

Procedure:
Into a four-necked flask equipped with a thermometer, a stirring device, a condenser and a temperature controller, 198 parts by weight of cyclohexane-1,3,4-tricarboxylic 3,4-anhydride and 300 parts by weight of n-propyl alcohol were charged and allowed to react at 100° C. for 3 h. After the reaction, the excess n-propyl alcohol was distilled off under reduced pressure to obtain monopropyl ester of cyclohexane-1,3,4-tricarboxylic acid as a colorless and transparent liquid. The product was identified by confirming the disappearance of the characteristic absorption of acid anhydride group (1850 and 1790 cm−1) and the appearance of the characteristic absorption of ester group (1735 cm−1) on infrared absorption spectra, and by determining the molecular weight using a gas chromatograph-mass spectrometer.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[CH:10][CH:9]=1.[CH3:25][C:26]1([CH3:32])[NH:30][C:29](=O)[CH2:28][CH2:27]1.C(N(CC)CC)C.ClC(Cl)C.[OH-].[Na+]>ClCCCl>[ClH:3].[CH3:25][C:26]1([CH3:32])[N:30]=[C:29]([N:14]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH2:28][CH2:27]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(NCc2c[nH]c3ccccc23)cc1
Reactant: CC1(C)CCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(Cc2c[nH]c3ccccc23)C2=NC(C)(C)CC2)cc1
Product: Cl
Reaction time: 6 h
Yield: 19.8 %

Procedure:
Phosphorus oxychloride (1.53 g., 0.01 mole), 3-(p-anisidinomethyl)indole, (2.52 g., 0.01 mole), 5,5-dimethyl-2-pyrrolidinone (1.13 g., 0.01 mole), and triethylamine (1.01 g., 0.01 mole) in 50 ml. of 1,2-dichloroethane is reacted according to the procedure of Example 36. After standing for 6 hr. at ice bath temperature, the reaction mixture is filtered affording the crude hydrochloride salt (1.45 g.) of the product, m.p. 188°-191° C. The dichloroethane filtrate is made basic with 10% sodium hydroxide, separated, dried over magnesium sulfate, acidified with ethanolic hydrogen chloride, and concentrated under reduced pressure. Trituration of the residue thus obtained with acetone yields a second crop of the hydrochloride, (0.76 g.), m.p. 191°-194° C. The hydrochloride fractions are combined and converted to the free base (m.p. 83°-85° C.) in the usual manner by dissolving in water and making basic with sodium hydroxide followed by extraction with ether. The hydrochloride salt is reprepared by taking the free base up in ethanol and acidifying with ethanolic hydrogen chloride to provide analytically pure 3-[[N-(5,5-dimethyl-1-pyrrolin-2-yl)-p-anisidino]methyl]indole hydrochloride, m.p. 188.5°-190.5° C. (dec) (corr.)
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)([O-])=O>Cl.C(OCC)C>[NH2:8][C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of tin chloride dihydrate (5.44 g, 24.1 mmol) in concentrated hydrochloric acid (32 ml) was added slowly to a cooled, stirred solution of (4-nitro-phenyl)-(4-phenyl-piperazin-1-yl)-methanone (1.0 g, 3.2 mmol) in anhydrous diethyl ether (32 ml). The resulting mixture was stirred for 1 hour at room temperature, then cooled and quenched carefully with 10M sodium hydroxide (aq.) until slightly basic (˜pH 9). The aqueous mixture was extracted with ethyl acetate (100 ml) and the organic extracts dried over magnesium sulfate then concentrated in vacuo to the title compound as a cream solid (667 mg, 73% yield). HPLC retention time 6.2 min. Mass spectrum (ES+) m/z 282 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17].N1CCCCC1.[NH2:25][C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:27]=1[OH:33]>C(O)C.O>[C:16]([C:15]1[CH:7]([C:6]2[CH:5]=[C:4]([O:10][CH3:11])[C:3]([O:12][CH3:13])=[C:2]([Br:1])[CH:9]=2)[C:28]2[C:27](=[C:26]([NH2:25])[C:31]([NH2:32])=[CH:30][CH:29]=2)[O:33][C:14]=1[NH2:18])#[N:17]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Nc1cccc(O)c1N
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc(N)c3N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a mixture of 5-bromoveratraldehyde (980 mg, 4.0 mmol) and malononitrile (246 mg, 4.0 mmol) in ethanol (10 mL) was added piperidine (0.4 mL) and 2,3-diaminophenol (496 mg, 4.0 mmol). The mixture was stirred at room temperature under argon for 2 h then diluted with water (20 mL). The precipitate was filtered to yield brown solid, yielding 1.367 g (85%) of the title compound. 1H NMR (CD3OD): 6.25 (s, 1H), 6.18 25 (s, 1H), 6.34 (d, J=7.8, 1H), 6.10 (d, J=7.8, 1H), 4.43 (s, 1H), 3.68 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[CH3:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)c(C)c1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.851 g, 8.5 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.422 mL, 10.20 mmol). The solution was then cooled to 0° C. before 2,4-dimethylbenzoyl chloride (I53) (1.577 g, 9.35 mmol) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (40 mL) and the solution was washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered, and analysis by LCMS showed impurities still to be present. The solid was thus further purified by flash chromatography (Isolera 100 g cartridge) with a gradient of 0-10% MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo to yield the product in 1.482 g.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].Cl[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[C:23]([CH2:22][CH2:21][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:10]#[N:11])([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CCCl
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(C#N)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 37.5 %

Procedure:
To a stirred suspension of sodium hydride (27 g of a 60% oil suspension) in 600 mL of dry dimethylformamide at room temperature was added over 1 hour a solution of diphenyl acetonitrile (130 g, o.67 mol) in 400 mL of DMF. the mixture was stirred until the evolution of hydrogen ceased, about 1 hour. Ethyl 3-chloropropionate (90 mL, 1 mol) was added dropwise over 1 hour and the resulting mixture was stirred for a further 1 hour, then it was partitioned between water and ether. The organic layer was washed with brine and dried. Concentration of the solvents afforded a residue which was vacuum distilled to give 4-carbethoxy-2,2-diphenylbutanenitrile (110 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(OCC)C>O1CCCC1>[C:11]1([NH:17][NH:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NNc1ccccc1)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
30 ml. (0.25 mole) of 4-fluorobenzoyl chloride is added dropwise over a 30 minute period to a mixture of 25 ml. (0.25 mole) of phenylhydrazine and 35 ml. (0.25 mole) of triethylamine in 500 ml. of anhydrous diethyl ether stirred at -10° C. under nitrogen. The reaction mixture is allowed to warm to 20°-25° C. and stirred under nitrogen for 3 hours. The obtained solids are collected by filtration, washed with diethyl ether and dissolved in about 600 ml. of methylene chloride. The methylene chloride solution is filtered and evaporated at reduced pressure to near dryness, and n-hexane is added to obtain the crude solid product (26 g.). The crude product is dissolved in tetrahydrofuran and filtered to remove the triethylamine hydrochloride, the tetrahydrofuran is evaporated at reduced pressure, and the obtained product is recrystallized from acetone (12 g.), m.p. 181°-186° C. A second crop is also obtained (6 g.).
Reaction SMILES: [CH:1]([C@@H:3]1[N:6]([Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[C:5](=[O:14])[C@H:4]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:2].[CH3:42][C:43]([CH3:45])=[O:44].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:43]1([CH:45]=[CH:1][C@@H:3]2[N:6]([Si:7]([C:10]([CH3:12])([CH3:11])[CH3:13])([CH3:8])[CH3:9])[C:5](=[O:14])[C@H:4]2[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH:5]=[CH:4][CH:3]=[CH:1][CH:42]=1.[C:1]([C@@H:3]1[NH:6][C:5](=[O:14])[C@H:4]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])([OH:2])=[O:44]
Reactant: CC(C)=O
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Product: O=C(N=C(NCCC[C@@H]1C(=O)N[C@H]1C(=O)O)NC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
The aldehyde 5a prepared in Step A was dissolved in acetone (75 mL). Freshly prepared Jones reagent was added dropwise to the acetone solution, maintaining the temperature between 20°-25° C., until the TLC indicated the disappearance of the starting aldehyde. The resultant suspension was concentrated to half of its original volume and partitioned between EtOAc and H2O. The organic phase was dried (Na2SO4) and concentrated. The residual solid was recrystallized from EtOAc/hexane to afford 8.8 g (54% from 4a) of the title compound as a greenish solid, mp 172°-173° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=2[Cl:17])[N:3]=1
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c(Cl)c1

Procedure:
2-Chloro-6-[(2,4-dichlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,4-dichlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[C:7]1([C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.CCOCC>[C:7]1([C:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:1][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nn1cncn1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: c1ccc(CC(=Nn2cncn2)c2ccccc2)cc1

Procedure:
A solution of 5.7 g (50.8 mmol) of 75% pure 1-amino-1H-1,2,4-triazole, 5.0 g (25.5 mmol) of deoxybenzoin and 0.6 g p-toluenesulfonic acid in 150 mL of benzene was heated at reflux with azeotropic removal of water for 7 days. Solvent was stripped and the residue was diluted with ether, which was washed with saturated aqueous Na2CO3, water and brine. Drying (MgSO4) and removal of solvent gave an off-white solid which was recrystallized from hexane affording 3.23 g of the desired product, m.p. 78°-80° C.