Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)OC(=O)C=1.[Na+].[Cl-:9].[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[OH-:15].[Na+]>O>[CH2:10]([CH:12]1[O:14][CH2:13]1)[Cl:11].[Cl:9][C:10]([Cl:11])([OH:15])[CH2:12][CH3:13]
Reactant: [OH-]
Reactant: [Cl-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: O
Solvent: ClCC1CO1
Product: CCC(O)(Cl)Cl

Procedure:
A sulfonation flask is charged with 87.5 pans of hydrolysed polymaleic anhydride (0.5 COOH equivalents, molecular weight 500-2,000, e.g. Belclene® 200), 80 parts of water and 3 parts of NaCl. After 31 parts of epichlorohydrin have been added, the reaction mixture is heated to 80°-85° C. for about 1 hour, cooled down to room temperature and neutralised with sodium hydroxide solution (pH about 6.8). Excess epichlorohydrin and dichloropropanol formed in the course of the reaction are then distilled off azeotropically. After adjustment to a solids concentration of 50%, the product is a mixture of 35% of polymer, 15% of 3-chloro-1,2-propanediol and 50% of water.
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])=[CH:10][C:4]=2[O:3]1.[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:15]=[C:13]([CH:12]=[CH:11][C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:1])([F:16])[O:3][C:4]=3[CH:10]=2)[O:14][CH:20]=1
Reactant: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: FC1(F)Oc2ccc(C=Cc3nc(CCl)co3)cc2O1

Procedure:
6.90 g (30.4 mmol) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide, 4.76 g (37.5 mmol) dichloro acetone and 50 ml toluene were kept at reflux temperature for 48 h with continuous removal of water by applying a Dean-Stark trap. After removal of solvents in vacuo, the residue was treated with 60 ml of a 1:1 mixture of water/isopropanol. After filtration the precipitate was washed first with isopropanol, then with heptane. Drying at 40° C. in vacuo gave 4-Chloromethyl-2-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazole.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[N:9][N:8]=1>CO>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([S:5][CH2:2][CH:3]=[CH2:4])=[N:8][N:9]=1
Reactant: C=CCS
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(Cl)c2ccccc12

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml (0.01 mol) of allylmercaptan. To this mixture was added 1.99 g(0.01 mol) of 1,4-dichlorophthalazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale white needle crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](Cl)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccn2)nc2cc(Br)sc12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, triethylamine (0.42 mL) and tetrahydrofuran (15 mL) was added pyridine-2-carbonylchloride hydrochloride (214 mg) with stirring at room temperature. The mixture was stirred at room temperature for 30 min and at 50° C. overnight. Triethylamine (0.42 mL) and pyridine-2-carbonylchloride hydrochloride (214 mg) were added to the reaction mixture. 2 hr later, aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with water and brine (5 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol (10 mL) and 2M aqueous sodium hydroxide solution (3.0 mL) were added to the residue, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was neutralized with 6M hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine (10 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product (300 mg) of the title compound as a pale-orange solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:21][NH2:22].O>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:14][CH:15]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Yield: 90.1 %

Procedure:
(2-Chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine (3.58 g, 12.1 mmol) was dissolved in tetrahydrofuran (50 mL). Hydrazine monohydrate (26 mL, 536 mmol) was added and the reaction mixture was heated to reflux over night. The next day water was added and the resulting solid was collected by filtration, washed with water and dried to give (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine (3.16 g, 90%) as a white crystalline compound.
Reaction SMILES: CC1(C)C2C=CC(C#CC3C=CC(C(O)=O)=CC=3)=CC=2C(C(C)(C)C)=CC1.[CH2:28]([C:32]1[C:33]2[CH:34]=[C:35]([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([O:52]CC)=[O:51])=[CH:48][CH:47]=3)[CH:36]=[CH:37][C:38]=2[C:39]([CH3:43])([CH3:42])[CH2:40][CH:41]=1)[CH2:29][CH2:30][CH3:31].C(C1C2C=C(C#CC3C=CC(C([O-])=O)=CC=3)C=CC=2C(C)(C)CC=1)CCC>>[CH2:28]([C:32]1[C:33]2[CH:34]=[C:35]([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([OH:52])=[O:51])=[CH:48][CH:47]=3)[CH:36]=[CH:37][C:38]=2[C:39]([CH3:42])([CH3:43])[CH2:40][CH:41]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Agent: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CCCCC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Product: CCCCC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid (Compound 80), 22.6 mg (0.06 mmol) of ethyl 4-[(5-butyl-7,8-dihydro-8,8-dimethylnaphth-3-yl)-ethynyl]benzoate (Compound 74) was converted into the title compound using 6.1 mg (0.146 mmol) of LiOH in H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][C:21](OC)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CCOCC.C1COCC1>[CH2:10]([N:17]1[CH2:22][C:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC1=CC(=O)CN(Cc2ccccc2)C1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1C=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of p-chlorophenyl magnesium bromide (0.17 M) in ether (100 ml) was treated with a solution of 1-benzyl-1,6-dihydro-5-methoxy-3-[2H]pyridone (32.5 g, 0.25 M) in THF (150 ml). The reaction was stirred 1 hour, poured onto cold 2 N hydrochloric acid (250 ml) and stirred 30 min. Removal of the resulting precipitate by filtration, followed by air-drying and recrystallisation from methanol gave the title compound as the hydrochloride hydrate (24.1 g) m.p. 166°-8°.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH2:18])=[O:10])[CH2:6]1
Reactant: [NH4+]
Reactant: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(Cl)c1OC1CN(C(N)=O)C1
Reaction time: 72 h
Yield: 77.6 %

Procedure:
A stirred solution of 3.9 g (0.015 mole) of 3-(2-chloro-6-methylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 2.8 mL (0.045 mole) of 57% ammonium hydroxide. After stirring for 72 h the reaction mixture was diluted with 200 mL of water and the precipitated product collected by filtration (3.6 g of pale yellow product). Recrystallization from benzene yielded 2.8 g (69.2%) of fine white crystals, mp 256°-157° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])=[CH:5][C:4]=1[F:22])#[CH:2].[N:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N+:24]=[N-:25].N1C(C)=CC=CC=1C>C(#N)C.[Cu](I)I>[CH2:26]([N:23]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][N:15]4[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]4)[O:11][C:10]3=[O:21])=[CH:5][C:4]=2[F:22])[N:25]=[N:24]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C#Cc1ccc(N2C[C@H](Cn3cc(C)nn3)OC2=O)cc1F
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4cn(Cc5ccccc5)nn4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Yield: 26 %

Procedure:
(5R)-3-(4-Ethynyl-3-fluorophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Intermediate 9, 40 mg, 0.133 mmol), azidomethyl-benzene(21.2 mg, 0.16 mmol), copper iodide (2.5 mg, 0.013 mmol) and 2,6-lutidine were mixed in dry acetonitrile (2 mL) and stirred at room temperature for over night. The reaction mixture was filtered through a 0.45 μm membrane, the filtrate was concentrated to an oil and purified by reverse phase chromatography with 5%˜95% MeCN in H2O (0.1% TFA). The product was obtained as a colourless solid (15 mg).
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-bromophenyl (2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1I>>[NH2:9][C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: Fc1ccccc1I
Product: Nc1cc(Br)ccc1-c1ccccc1F

Procedure:
2,5-Dibromo-1-nitrobenzene and o-fluoroiodobenzene were reacted under Ullmann conditions to give 4-bromo2'-fluoro-2-nitrobiphenyl, b.p. 125°-140°C./0.2mm (m.p. 71°-73°C. after recrystallisation from industrial methylated spirits). This was reduced to give 2-amino-4-bromo-2'-fluorobiphenyl, m.p. 52°-54°C., which was deaminated to give the product, b.p. 105°-115°C./0.5mm (m.p. 40°-42°C. after recrystallisation from petroleum, b.p. 40°-60°C.).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[Na].[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([CH2:34][C:35]([O-])=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([C:34]3[C:35](=[O:36])[N:12]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[C@@H:11]4[C@H:6]([C:4]=3[OH:3])[C@@H:7]3[CH2:21][C@H:10]4[CH2:9][CH2:8]3)=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2cc(Br)cnc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(Br)cnc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reaction time: 0.02 h
Yield: 60.3 %

Procedure:
(1S,2R,3S,4R)-3-(4-Fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 0.213 g, 0.73 mmol), sodium-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-acetate (0.25 g, 0.73 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.305 g, 0.803 mmol) were combined and dissolved in N,N-dimethylformamide (1.5 mL). The mixture was shaken vigorously for about 1 min until everything dissolved. The solution continued to stir for 1 h. Triethylamine (0.5 mL, 3.65 mmol) was added and the mixture was stirred at 50° C. for 16 h. The mixture was concentrated in vacuo to a volume of −5 mL. Water (˜20 mL) was added and the product precipitated. The solid was collected by vacuum filtration and purified by flash column chromatography (Merck silical gel 60, 40-63 μm; 35% ethyl acetate in hexanes) to afford the desired product, (0.24 g, 0.44 mmol, 60%) as a white, brittle foam. A portion of the product (0.07 g, 0.128 mmol) was recrystallized from n-propanol (0.5 mL) to afford the pure desired product, 5-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.044 g, 0.081 mmol, 63%), as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.23 (2H, m), 1.38-1.60 (4H, m), 2.51 (1H, s), 2.63 (1H, s), 3.00 (1H, d, J=8.4 Hz), 3.55 (1H, d, J=9.4 Hz), 4.41 (1H, d, J=14.7 Hz), 4.95 (1H, d, J=15.4 Hz), 7.14 (2H, t, J=9.0 Hz), 7.33 (2H, dd, J1=8.6 Hz, J2=5.5 Hz), 8.66 (1H, s), 8.82 (1H, s). LC-MS (ESI) calcd for C23H20BrFN4O4S 546.04, found 547.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[NH:6][C:7]([C:9]3[NH:10][N:11]=[C:12]4[C:17]=3[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=3)[CH2:13]4)=[N:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.[Pd].C([O-])([O-])=O.[Ca+2]>[CH3:1][C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[NH:6][C:7]([C:9]3[NH:10][N:11]=[C:12]4[C:17]=3[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:13]4)=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc([N+](=O)[O-])cn3)C4)[nH]c2cc1C
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc(N)cn3)C4)[nH]c2cc1C
Yield: 59.6 %

Procedure:
55 mg of Pd/CaCO3 10% are added to a solution of 545 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-(5-nitropyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine in 60 ml of ethanol. After stirring for 15 hours at 35° C. under 3 bar of hydrogen, the reaction medium is brought back to ambient temperature, filtered through celite and then concentrated under reduced pressure. 300 mg of 6-[3-(5,6-dimethyl-1H-benzimidazol-2-yl)-2,4,5,7-tetrahydropyrazolo [3,4-c]pyridin-6-yl]-pyridin-3-ylamine are thus obtained in the form of a brown powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:60]=[CH:59][C:11]([C:12]([O:27][CH2:28][C@@:29]2([CH:51]=[CH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][OH:58])[O:33][C@@H:32]([N:34]3[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]3=[O:36])[CH2:31][C@@H:30]2[O:43][SiH2:44][C:45]([CH3:50])([CH3:49])[CH:46]([CH3:48])[CH3:47])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([O:27][CH2:28][C@@:29]2([CH:51]=[CH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][O:58][S:2]([CH3:1])(=[O:4])=[O:3])[O:33][C@@H:32]([N:34]3[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]3=[O:36])[CH2:31][C@@H:30]2[O:43][SiH2:44][C:45]([CH3:49])([CH3:50])[CH:46]([CH3:47])[CH3:48])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]2[CH:59]=[CH:60][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C(OC[C@@]2(C=CCCCCCO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]2(C=CCCCCCOS(C)(=O)=O)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Methanesulfonyl chloride (96 μL, 1.22 mmole) was added dropwise to Compound (4) (250 mg, 0.32 mmole) in dry pyridine (3 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 hours and the reaction was quenched by the dropwise addition of methanol (1.5 mL). The yellow solution was poured into water (20 mL) and the layers were separated. The organic phase was washed with brine (20 mL), dried over magnesium sulfate and concentrated to a white solid (0.41 g) under reducedpressure. (Routinely, this crude material was used directly in the next step). The crude product (0.41 g) was purified by column chromatography onsilica gel using ethyl acetate/hexane mixtures for elution. 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-methanesulfonyloxy-1-hepten-1-yl)-thymidine (241 mg, 87.5%) was obtained as a white solid. Recrystallization from hexane/dichloromethane gave a sample with m.p. 72°-75° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](O)=[C:11]2[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:27]>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([Cl:27])=[C:11]2[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1c(Nc1ccccc1)nn2Cc1ccccc1
Product: Clc1ncnc2c1c(Nc1ccccc1)nn2Cc1ccccc1
Temperature: 25 °C

Procedure:
Under argon, 200 mg of 1-benzyl-4-hydroxy-3-phenylamino-pyrazolo[3,4-d]-pyrimidine are heated under reflux for 5 hours with 2 ml of POCl3, during which time the suspension slowly becomes a solution. The light-brown solution is cooled to room temperature, concentrated to dryness by evaporation and stirred with ice-water. The crude product is filtered off with suction and recrystallized from ethanol/water, yielding fine needles of 1-benzyl-4-chloro-3-phenylamino-pyrazolo[3,4-d]pyrimidine; m.p. 135° C., FAB-MS: (M+H)+ =336 (C18H14ClN5).
Reaction SMILES: ClCCC1N=CC=CN=1.OCCC1N=CC=CN=1.S(Cl)(Cl)=O.[NH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.[C:35]([NH:37][C:38](=[N:41][CH3:42])SC)#[N:36]>>[C:35]([NH:37][C:38]([NH:41][CH3:42])=[N:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)#[N:36]
Reactant: CN=C(NC#N)SC
Reactant: NCCSCCc1ncccn1
Agent: ClCCc1ncccn1
Agent: OCCc1ncccn1
Solvent: O=S(Cl)Cl
Product: CNC(=NCCSCCc1ncccn1)NC#N

Procedure:
By the procedure of Example 17 using 2-(2-chloroethyl)pyrimidine, prepared by treating 2-(2-hydroxyethyl)pyrimidine with thionyl chloride, as the starting material, 2-[2-(2-aminoethyl)thioethyl]pyrimidine is prepared, which when treated with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a) gives the title compound.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]([N:21]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:28]2[CH2:29][CH2:30][CH:25]([N:21]([CH:18]([CH3:20])[CH3:19])[C:22](=[O:24])[CH3:23])[CH2:26][CH2:27]2)=[CH:11][CH:10]=1)=[O:9]
Reactant: O=Cc1ccc(CCBr)cc1
Reactant: CC(=O)N(C(C)C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(C(C)C)C1CCN(Cc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.6 %

Procedure:
To a mixture of 4-(bromoethyl)benzaldehyde (0.840 g, 4.2 mmol) and K2CO3 (1.75 g, 12.6 mmol) in DMF (15 mL) was added N-isopropyl-N-(piperidin-4-yl)acetamide (0.92 g, 4.2 mmol) and the reaction was stirred at room temperature 5 hours, then concentrated in vacuo. The resulting mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 1% to 10% MeOH/CH2Cl2, afforded N-(1-(4-formylbenzyl)piperidin-4-yl)-N-isopropylacetamide (0.770 g, 61%).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[Br:25][C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[Cl:33]>ClCCl>[Br:25][C:26]1[N:31]=[C:30]([NH:32][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:29]=[CH:28][C:27]=1[Cl:33]
Reactant: Nc1ccc(Cl)c(Br)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reaction time: 16 h
Yield: 69.4 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (0.878 g, 3.37 mmol) was placed in an oven-dried flask which was allowed to cool under nitrogen. Dichloromethane (10 mL), triethylamine (1.42 mL, 10.1 mmol) and 6-bromo-5-chloropyridin-2-amine (10.1 mmol) were added and the reaction mixture was stirred for 16 hours. The reaction mixture was then washed with a saturated aqueous solution of sodium chloride, evaporated to near dryness, and then purified on 40 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.01 g, 69%). ESI-MS m/z calc. 429.9. found; 431.3 (M+1)+ Retention time 2.33 minutes.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[F:12][C:13]([F:21])([F:22])[C:14]1[CH:15]=[C:16]([NH:17][C:2]([CH2:9][CH2:10][CH3:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:18]=[CH:19][CH:20]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCC(=CC(=O)OCC)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
0.85 g (5.4 mmol) Ethyl 3-oxohexanoate, 1.0 g (6.21 mmol) 3-trifluoromethylaniline and 5 mg (0.08 mmol) acetic acid are dissolved in 15 ml ethanol, and 0.78 g (6.5 mmol) magnesium sulfate are added. The reaction mixture is stirred at reflux overnight. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([S:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N:10][N:9]=[C:8]2[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1.[C:24]1(=[O:34])[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>O1CCCC1>[CH2:18]([C:8]1[N:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:24](=[O:34])[C:25]3[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=3[C:27]([OH:29])=[O:28])=[CH:3][CH:4]=2)[C:11]([S:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N:10][N:9]=1)[CH2:19][CH2:20][CH3:21]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 566 mg (1.69 mmole) of 4-(4-aminobenzyl)-3-n-butyl-5-(carbomethoxymethylthio)-4H-1,2,4-triazole in 15 ml of dry tetrahydrofuran (THF) was treated with 250 mg (1.69 mmole) of phthalic anhydride dissolved in 2 ml of dry THF. The resulting solution was stirred overnight at room temperature in a stoppered flask. The solid which had precipitated was collected on a filter and washed with ether to yield (after vacuum-drying at 30° C.) 629 mg (77%) of a white solid, mp 161°-162° C., homogeneous by TLC in 90:10:1CH2Cl2 --MeOH-AcOH; mass spectrum (FAB) m/e 483 (M+1)+.