Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:24])=O.C([Li])CCC.Cl>C(Cl)Cl>[CH2:1]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([Cl:24])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCc1ccccc1C(=O)Cl
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2-Dodecylbenzoyl chloride was prepared from 2-dodecylbenzoic acid (4.06 g, 14 mmoles) and excess thionyl chloride in methylene chloride at 23° C. for 1 hour. Following evaporation of the solvents, the acid chloride was used without purification. A solution of this acid chloride in tetrahydrofuran (15 ml) was added to the cold solution of dianion prepared above, followed by an additional amount of 2.12M n-butyl lithium (6.6 ml). The solution was warmed to -20° C., stirred for 1 hour and poured into cold 1N hydrochloric acid. The mixture was extracted with diethyl ether. The extracts were washed with water, dried and evaporated. The crude product was recrystallized from acetonitrile.
Reaction SMILES: Br[C:2]1[C:3]2[CH:4]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][CH:5]3[N:6](C(OC(C)(C)C)=O)[C:7]=2[CH:8]=[CH:9][CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:38]1[C:42](B(O)O)=[CH:41][C:40]2[CH:46]=[CH:47][CH:48]=[CH:49][C:39]1=2.N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[O:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[CH:41]=[C:42]1[C:2]1[C:3]2[C@@H:4]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C@@H:5]3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCC2c3c(Br)cccc3N(C(=O)OC(C)(C)C)C2CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: c1cc2c(c(-c3cc4ccccc4o3)c1)[C@@H]1CCNCC[C@@H]1N2
Temperature: 80 °C
Yield: 64.5 %

Procedure:
A 30-mL shaker vial was charged with di(tert-butyl) 10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate (0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol), benzo[b]furan-2-boronic acid (0.104 g, 0.642 mmol), and DMF (2 mL). The vial was purged with N2, and tetrakis(triphenylphosphine)palladium (0.025 g, 0.02 mmol) was added and the mixture was agitated at 250 RPM with heating at 80° C. overnight. The mixture was filtered through Celite, washing with MeOH (3-5 mL), and sulfonic acid resin (DOWEX®50W-X2, washed and dried, 4.8 meq/g dry weight) was added (1 g). The vial was then purged with N2, capped and agitated at 250 RPM with heating at 65° C. for 36 h. The mixture was filtered through a scintered funnel and the resin was washed 1:1 methylene chloride/methanol and then consecutively washed with MeOH and THF to ensure that all excess reagent was removed from the resin (the methanol and THF washes are alternated to swell and then shrink the resin to help expel reagents from inside the resin). The resin was then washed with 4 M ammonium hydroxide in methanol (4×2 ml) and THF (2×2 ml) into an accurately weight round-bottomed flask. The filtrate was concentrated to give 0.042 g (65%) of a beige solid, which was dissolved in methylene chloride and crystallized to give 0.020 g of the title compound as beige solid: MS (EI) m/z 304 (M+), 302, 260, 259, 258, 247, 246, 207, 195, 153; 1H NMR (CDCl3) δ 7.64 (d, J=7 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.35-7.22 (m, 3 H), 7.15 (t, J=8 Hz, 1H), 6.63 (d, J=8 Hz, 1H), 4.38-4.27 (m, 1H), 4.16-4.06 (m, 1H), 3.28-3.22 (m, 1H), 3.17-3.11 (m, 1H), 2.95-2.79 (m, 2H), 2.38-2.26 (m, 1H), 2.10-1.89 (m, 2H), 1.81-1.72 (m, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:16]([OH:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:16]([O:32][C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: CCCCCCCCCCCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 90 %

Procedure:
Using 3,5-dinitrobenzoyl chloride (60.6 g, 263.0 mmol) and hexadecyl alcohol (63.9 g, 263.9 mmol), n-hexadecyl-3,5-dinitrobenzoate was obtained (103.2 g, yield: 90%) in the same manner as in Example 1.
Reaction SMILES: [O-]CC.[Na+].S.Cl[CH2:7][C:8]1[NH:9][C:10]([CH3:33])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].O[S:35](O)(=O)=O>COCCOC.O>[SH:35][CH2:7][C:8]1[NH:9][C:10]([CH3:33])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC[O-]
Agent: S
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A stirred ethanolic solution (200 ml) of an alkaline alkoxide, for example sodium ethoxide (20 g), is saturated, at +10° C., with dry hydrogen sulfide, cooled to -15° C., and added with a solution of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine (25 g) in DME (70 ml). After one hour, the reaction mixture is warmed to 0° C., acidified with H2SO4 (10% water solution; 100 ml) and diluted with water (1400 ml). The precipitate is filtered off, dried in vacuum, and recrystallized from Et2O to give 23 g of 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine, m.p. 145°-147° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Cl.[OH:6][C:7]1[CH:8]=[C:9]2[CH:12]([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=O)[CH2:11][C:10]2=[CH:21][CH:22]=1.[OH-].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:2]([C:12]1([CH2:13][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:9]2=[CH:8][C:7]([O:6][CH2:11][CH2:12][CH2:13][NH2:15])=[CH:22][CH:21]=[C:10]2[CH2:11]1)[CH:3]=[CH2:4]
Reactant: ClCCCBr
Reactant: O=C(C1Cc2ccc(O)cc21)N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCC1(CN2CCCCC2)Cc2ccc(OCCCN)cc21
Reaction time: 1 h

Procedure:
Tetrabutylammonium chloride (4.48 g) and 1-bromo-3-chloropropane (127.8 ml) are added to a stirred solution of 5-hydroxy-1-(1-piperidinylcarbonyl)benzocyclobutene (31.8 g) in methylene chloride (250 ml) and potassium hydroxide (18.85 g, 45% in H2O) which has been stirred vigorously under nitrogen for one hour. The reaction mixture is stirred at RT overnight, diluted with methylene chloride, extracted with H2O, sat'd aqueous NaCl and the organic layer dried over sodium sulfate. The solution is filtered, evaporated in vacuo and chromatographed (silica gel: ethyl acetate/hexane) yielding the desired product as an oil which is identified by NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([CH2:21][NH2:22])[OH:20]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][CH2:19][OH:20])=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCO
Product: O=C(NCCO)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.39 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.50 mmol of ethanolamine. LC/MS [3.42 min; 402 (M+1)]
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH2:4][CH2:3][O:2]1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C1COCC1>[OH:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:1]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:11]
Reactant: COc1ccc(CN)cc1
Reactant: O=C1OCCc2cnccc21
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2ccncc2CCO)cc1

Procedure:
3,4-Dihydro-1H-pyrano[4,3-c]pyridin-1-one (I-67e: 100 mg, (0.666 mmol) in THF (1 mL) was refluxed with p-methoxybenzylamine (0.9 mL, 6.66 mmol) to afford 220 mg of the crude product. LCMS: 95.54%, m/z=287.1 (M+1)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>C(O)C>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH:15]=[C:29]3[O:25][C:26](=[O:31])[NH:27][C:28]3=[O:30])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1sc(CCc2ccc(C=CC=O)cc2)nc1-c1ccccc1
Reactant: O=C1COC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1sc(CCc2ccc(C=CC=C3OC(=O)NC3=O)cc2)nc1-c1ccccc1

Procedure:
A mixture of 4-[2-(5-methyl-4-phenyl-2-thiazolyl)ethyl]cinnamaldehyde (2.5 g), 2,4-oxazolidinedione (1.14 g), piperidine (0.211 g) and ethanol (50 ml) was refluxed under heating conditions for 4 hours. After the reaction mixture was concentrated, chloroform was added to the residue; the mixture was washed with 2 N HCl and water. The chloroform layer was washed with water, dried (MgSO4) and then concentrated to yield 5-[4-[2-(5-methyl-4-phenyl-2-thiazolyl)ethyl]cinnamylidene]-2,4-oxazolidinedione[mixture of the (E)- and (Z)- configurations](0.81 g, 26%), which was then recrystallized from ethyl acetate to yield light yellow prisms having a melting point of 161°-162° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CC(C)(C)C(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)C(C)(C)C)C3)cc1

Procedure:
Method as example 18 using 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and pivaloyl chloride as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[C:6]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=4)[N:21]=[CH:20][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[OH-].[Na+:39]>C(O)C.O>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[C:6]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([O-:31])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=4)[N:21]=[CH:20][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[Na+:39]
Reactant: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)[O-]
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirred suspension of Compound Formula (II) (98.0 g, 190 mmol) in ethanol (2.0 L) was added 1.044 M Sodium hydroxide in water (199 mL). The resultant homogeneous solution was stirred for 1 hour, during which time a thick precipitate formed. The product was collected by filtration, and washed with ethanol (0.5 L) and diethyl ether (1.0 L). The resultant solid was dried in vacuo at 60-70° C. for 4 days to provide 88.6 g (86.8%) of compound Formula (I) as a light tan solid, mp 225° C. (decomp). 1H NMR (DMSO-d6) δ 9.86 (s, 1H), 8.60 (s, 1H), 8.29 (d, 1H), 7.79 (dd, 1H), 7.60 (br s, 1H), 7.40 (dd, 1H), 7.29 (d, 1H), 7.25-7.15 (m, 2H), 6.9 (br s, 2H), 4.9 (br s, 1H), 3.8 (br s, 1H), 3.70 (s, 3H), 3.35 (br s, 3H); MS m/z 519 (M+−Na+H, 100%); CHN Anal. Calcd. for C27H19ClFN4NaO40.33 EtOH1.3H2O: C, 57.33; H, 4.10; N, 9.67. Found C, 57.14; H, 3.99; N, 9.65.
Reaction SMILES: [Si:1]([CH:8]([OH:24])[C@H:9]1[O:13][C@@H:12]([N:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[NH:16][C:15]2=[O:22])[CH2:11][C@@H:10]1[OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:31](Cl)(=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Si:1]([CH:8]([OH:24])[C@H:9]1[O:13][C@@H:12]([N:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[NH:16][C:15]2=[O:22])[CH2:11][C@:10]1([C:31](=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[OH:23])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CN1CN([C@H]2C[C@H](O)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O2)C(=O)NC1=O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCC(=O)[C@]1(O)C[C@H](N2CN(C)C(=O)NC2=O)O[C@@H]1C(O)[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 88.7 %

Procedure:
To a solution consisting of 3.59 gm. (0.010 mole) of 1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione and 30 ml. A.R. pyridine that had been cooled to 5° C. was added, with stirring, 2.55 gm. (0.0116 mole) of freshly distilled lauroyl chloride. This reaction mixture was stirred for 18 hours at 25° C. Then it was cooled to 10° C. and 3 ml. water was added. This mixture was stirred at 25° C. while the solvents were removed by evaporation under reduced pressure. The residue thus obtained was dispersed in a solvent mixture consisting of 100 ml. chloroform and 50 ml. saturated aqueous sodium bicarbonate. The aqueous and organic phases were allowed to stabilize and the organic phase was saved. It was washed two times with 50 ml. portions of saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The dried chloroform solution was filtered and the filter was washed with chloroform. The filtrate and washings were combined and the chloroform was removed by evaporation under reduced pressure. There was thus obtained 4.8 gm. (88.7% yield) of 1-(5-tert-butyldimethylsilyl-3-lauroyl-2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.
Reaction SMILES: ClC1N=CN=C2N(C3C=CC=CC=3)N=CC=12.CCN(CC)CC.N[C@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][OH:27]>C(O)C>[C:29]1([CH2:28][CH2:25][CH2:26][OH:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Agent: Clc1ncnc2c1cnn2-c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCCCc1ccccc1
Yield: 74 %

Procedure:
First, 1.13 g of the starting material 4-chloro-1-phenylpyrazolo[3,4-d]pyrimidine was combined with 0.67 ml Et3N, 0.74 g of (R)-(+)-2-amino-3-phenyl-1-propanol in 60 ml absolute ethanol and heated in a steam bath for four hours. The solvent was then removed under vacuum and the residue was purified by flash chromatography (10-20% isopropyl alcohol/hexane) to yield 1.24 g of (R)-β-[1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol (74% yield).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:9][CH2:10]O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:9][CH2:10][Br:2]
Reactant: BrP(Br)Br
Reactant: Cc1ccc(CCO)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(CCBr)cc1C
Temperature: 25 °C

Procedure:
Phosphorus tribromide (0.82 g) was added dropwise to a solution of 3,4-dimethylphenethyl alcohol (1.27 g--see Preparation 17) in carbon tetrachloride (10 ml). The mixture was heated under reflux for 2.5 hours then cooled to room temperature and basified (pit 8) by the dropwise addition of 10% aqueous sodium carbonate (5 ml). The mixture was then diluted with water (20 ml) and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a colourless oil, yield, 0.5g.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[CH3:17][C:18](OC(C)=O)=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:18](=[O:19])[CH3:17])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1n[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)n1nc(C)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
3-Methylindazole (1.00 g, 7.6 mmol) (J. Med. Chem. 2706 (1997)] was dissolved in 10 ml THF and stirred at room temperature under a blanket of argon. Pyridine (0.64 ml, 7.9 mmol) was added, followed by Ac2O (0.79 ml, 8.3 mmol) and catalytic DMAP (90 mg, 0.7 mmol). The reaction proceeded for 2 h and was then partitioned between 1N HCl and dichloromethane. The organic phase was dried over MgSO4 and concentrated under vacuum to a tan solid (1.2 g, 91% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1>O1CCCC1>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@H:16]([C:32]([OH:34])=[O:33])[CH2:15]1)(=[O:11])=[O:10]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.67 h

Procedure:
12.20 ml of triethylamine and 6.81 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 12.41 g of trans-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 100 ml of dry tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 40 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with 350 ml of ethyl acetate and 50 ml of 1N aqueous hydrochloric acid. The mixture was then stirred at room temperature for 2.5 hours, after which the organic layer was separated and washed three times with an aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 12.57 g of the title compound, as a powder.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[C:5](=[CH:13][C:14]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[O:15])[NH:4][C:3]1([CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([S:44]([N:10]2[CH2:11][CH2:12][CH:8]([CH2:7][N:6]3[C:2](=[O:1])[C:3]([CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)([CH2:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[NH:4][C:5]3=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[O:15])[CH2:9]2)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNC2)cc1
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCN(S(=O)(=O)c3ccccc3)C2)cc1

Procedure:
According to the procedure of Example 13, the title compound of 46B (100 mg, 0.20 mmol) and benzenesulfonyl chloride (0.04 ml, 0.198 mmol) were reacted to generate the title compound of Example 46 as a white solid (25 mg, 0.037 mmol, 37% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[N:11]([O-])=O.[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][NH2:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NN)cc1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a mixture of 100 g of 4-aminobenzonitrile, 500 ml of water and 360 g of concentrated hydrochloric acid, a liquid mixture of 60.2 g of sodium nitrite and 240 ml of water was added at 0° C., and the resulting mixture was stirred for 30 minutes. The mixture was added to a liquid mixture of 382 g of stannous chloride dihydrate and 480 g of concentrated hydrochloric acid at 15° C., and the resulting crystals were collected by filtration, washed with water and then suspended in 1,000 ml of water. 300 ml of 5N aqueous sodium hydroxide was added to the suspension, and the resulting mixture was stirred for 1.5 hours. The resulting crude product was washed with water and recrystallized in benzene to give 70.2 g of the title compound as pale brown crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1.[C-:18]#[N:19].[Na+].[Cl-].[Na+]>CN(C)C=O>[C:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([O:16][CH3:17])[CH:4]=1)#[N:19]
Reactant: COc1cc(CCl)ccc1Sc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 30 °C
Reaction time: 14 h

Procedure:
The 1-chloromethyl-3-methoxy-4-phenylthiobenzene obtained above is dissolved in N,N-dimethylformamide (200 ml), and thereto is added finely divided sodium cyanide (7.34 g), and the mixture is stirred at 30° C. for 14 hours. To the reaction mixture are added saturated aqueous sodium chloride solution (300 ml) and ice water (300 ml), and the mixture is extracted with ethyl acetate (300 ml×3). The combined extracts are washed with saturated aqueous sodium chloride solution (200 ml×3) and dried over anhydrous sodium sulfate to give 1-cyanomethyl-3-methoxy-4-phenylthiobenzene. benzene.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Br:18])=[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2]>[OH-].[Na+]>[CH:1]([NH:3][C:4]1[S:5][C:6]([Br:18])=[C:7]([C:9](=[N:15][O:16][CH3:17])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=NOC)c1nc(NC=O)sc1Br
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Yield: 73.5 %

Procedure:
1N-Aqueous sodium hydroxide (290 ml.) was added dropwise to an aqueous suspension (325 ml.) of ethyl 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetate (syn isomer, 32.5 g.) under ice-cooling, and the mixture was treated in a similar manner to that of Preparation 2-(2) to give 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 21.9 g.), m.p. 165° to 167° C.