Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>C(OCC)(=O)C>[CH3:8][S:9]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:23][CH:22]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)Oc1ccc(CCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Oc1ccc(CCCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (32.9 ml) and methanesulfonyl chloride (14.6 ml) were added to a solution of 4-(4-tert-butoxyphenyl)butan-1-ol (35.0 g) in ethyl acetate (360 ml) at 0° C., and the mixture was stirred at 0° C. for 1.5 hr. By adding water, the reaction mixture was separated. The organic layer was washed successively with 5% sodium hydrogen carbonate solution and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 4-(4-tert-butoxyphenyl)butyl methanesulfonate (50.2 g). A suspension of the product (50.2 g) and sodium iodide (46.1 g) in acetone (500 ml) was stirred for 4.5 hr. By adding water and diisopropyl ether, the reaction mixture was separated. The organic layer was successively washed with 10% hypo-water and water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the titled compound (52.1 g) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][S:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][C:21]4[CH:20]=[CH:19][C:18]([NH:17][S:14]([CH3:13])(=[O:15])=[O:16])=[CH:23][CH:22]=4)[CH2:27][CH2:28]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)Nc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(C(=O)c3ccc4[nH]ccc4c3)CC2)cc1

Procedure:
In the manner described in Example 24, indole-5-carboxylic acid (100 mg, 0.62 mmol) and 1-[2-(4-methanesulfonamidophenyl)ethyl]piperazine (180 mg, 0.64 mmol) gave, after purification by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 ; 95:5:0.5 and trituration with hexane/EtOAc, the piperazine (68 mg, 26%), mp 94°-97° C. Elemental analysis for C22H26N4O3S.0.5H2O: Calculated: C, 60.66; H, 6.26; N, 12.86%. Found: C, 61.02; H, 6.19; N, 12.51%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.O>[C:10]([O:14][C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:22][C:21]3[CH:20]=[CH:19][C:18]([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[CH:24][CH:23]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ncc(F)c(Nc3ccc(NC(=O)OC(C)(C)C)cc3)n2)cc1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in a mixture of MeOH (2 ml) and H2O (0.2 ml). 4-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and the mixture was refluxed for 24 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 7.96 (d, 1H, J=3.5 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.37 (d, 2H, J=8.8 Hz), 7.24 (d, 2H, J=8.8 Hz), 1.45 (s, 9H), 1.43 (s, 9H); LCMS: purity: 97.9%; MS (m/e): 511.04 (M+, 100).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](N)[N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:17]([OH:38])[C@@H:18]([NH:26][C:27](=[O:37])[C@H:28]([CH:34]([CH3:36])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C[N:48](C=O)C>O1CCOCC1>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([NH2:48])[CH2:16][C@H:17]([OH:38])[C@@H:18]([NH:26][C:27](=[O:37])[C@H:28]([CH:34]([CH3:36])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(C(=O)OC(C)(C)C)C(N)c1ccc(-c2ccccn2)cc1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2ccccn2)cc1)C(C)C
Reaction time: 3.5 h

Procedure:
Analogously to Example 37f, 30 ml of 4M HCl in dioxane are, added to 3.5 g (5.65 mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-Boc-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and the mixture is diluted with 5 ml of DMF. After 3.5 hours, the mixture is worked up. The title compound is obtained: TLC: Rf =0.53 (methylene chloride/methanol: 9/1); HPLC20-100 : tRet =8.00; FAB MS (M+H)+ =520.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[C:20]=2[CH2:34][CH3:35])=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O1CCCC1.Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:20]=2[CH2:34][CH3:35])=[CH:36][CH:37]=1)=[O:12]
Reactant: CCOC(=O)Cn1c(CC)c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Into a dry reaction vessel, ethyl 2-[3-[4-(2-naphthamido)benzyl]-2-ethyl-1H-indol-1-yl]acetate (340 mg, 0.69 mmol), lithium hydroxide monohydrate (117 mg, 2.79 mmol), 5 mL tetrahydrofuran, 5 mL water were weighed, and stirred at room temperature for 2 h. The reaction was monitored to be complete by TLC, the system was added 10 mL water, and adjusted to pH=5 with 2 N HCl solution. A solid precipitated, it was pumping filtered, washed with dichloromethane to obtain the product as a light yellow solid 240 mg, at a yield of 75.2%.
Reaction SMILES: [C:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([CH3:3])=[CH2:2].[H][H]>O1CCOCC1.[Pd]>[CH:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1cc2c(s1)Oc1ccccc1NC2=O
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 40 °C
Reaction time: 7.5 h
Yield: 76.3 %

Procedure:
2-Isopropenylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (780 mg) was suspended in dioxane (40 ml) and 10% palladium-activated charcoal (100 mg) was added. Hydrogen was sealed in and the mixture was stirred at 40° C., 50 atm for 7.5 hours. The catalyst was filtered off and the solvent was evaporated under reduced pressure to give 2-isopropylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH3:22])[C:14](=[O:20])[CH2:15]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-one (550 mg, 1.75 mmol) in THF (2 mL) at −78° C. was added LiHMDS in THF (2.62 mL, 1.0 M in THF, 2.62 mmol) dropwise over 15 min. The resulting mixture was allowed to stir at −78° C. for 30 min before the addition of MeI (1.24 g, 8.75 mmol). The reaction mixture was stirred at −78° C. for 2.5 h before it was allowed to warm up to room temperature for 15 min. The reaction mixture was quenched by the addition of a saturated aqueous NH4Cl solution (25 mL) and EtOAc (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified via silica gel chromatography to give 9-(4-chloro-benzenesulfonyl)-2-methyl-9-aza-bicyclo[3.3.1]nonan-3-one as a white solid. Retention time (min) 2.13 min, Method [1], MS (ESI) 350 (M+Na).
Reaction SMILES: [Br:1]Br.[BrH:3].[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH2:13][C:14]([O:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:5]1>C(O)(=O)C>[BrH:1].[Br:3][CH:13]([C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:4][N:5]=1)[C:14]([O:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)=[O:15]
Reactant: CN1CCC(OC(=O)Cc2noc3ccccc23)CC1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CN1CCC(OC(=O)C(Br)c2noc3ccccc23)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of bromine (1.12 g) in glacial acetic acid (2 ml) was added dropwise at 60° C. with stirring to a solution of 1-methyl-4-piperidyl 1,2-benzisoxazole-3-acetate hydrobromide (2.0 g) in glacial acetic acid (8 ml). The reaction mixture was stirred for 3 hours at 60° C. and then concentrated in vacuo to about a half volume. The residue was dissolved in acetone and thereto was added diethyl ether until it became turbid. After cooling, the resulting crystals were collected by filtration to give 1-methyl-4-piperidyl 2-bromo-2-(1,2-benzisoxazol-3-yl)acetate hydrobromide (1.9 g). An analytical sample was obtained by recrystallization from ethanol, m.p. 169°-171° C.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:19].C1C[O:23]CC1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[C:43](O)(=O)[C:44]([OH:46])=[O:45]>CCOCC.O.CO>[C:44]([O:46][C@H:1]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:16]([CH2:17][CH2:18][C@:2]12[CH2:3][OH:19])[C:15]1[CH:14]=[CH:13][C:12]([OH:23])=[CH:11][C:10]=1[CH2:9][CH2:8]3)(=[O:45])[CH3:43]
Reactant: C[C@]12CC[C@@H]3c4ccccc4CC[C@H]3[C@@H]1CCC2=O
Reactant: C1CCOC1
Reactant: O=C(O)C(=O)O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12CO
Reaction time: 0.75 h

Procedure:
400 mg. of 3,18-bis)tetrahydropyranyloxy)-1,3,5(10)-estratrien-17-one is mixed, in 4 ml. of absolute THF, at 0° C. with 400 mg. of lithium tri-tert.-butoxyaluminum hydride and stirred for 30 minutes at room temperature. After the mixture has been poured into water, it is extracted with ether. The ether phase is washed neutral with water, dried, and evaporated. The residue of crude 3,18-bis(tetrahydropyranyloxy)-1,3,5(10)-estratrien-17β-ol is heated in 1 ml. of pyridine with 1 ml. of acetic anhydride for 30 minutes to 100° C. The mixture is then introduced into water, stirred for 45 minutes, extracted with ether, and washed neutral with water. After drying and evaporation, crude 3,18-bis(tetrahydropyranyloxy)-17β-acetoxy-1,3,5(10)-estratriene is obtained, which is heated to the boiling point in 4 ml. of methanol with 4 ml. of water and 0.4 g. of oxalic acid. After 1 hour, the mixture is taken up in ether, washed neutral with water, dried, and evaporated. After purification by chromatography over silica gel, 17β-acetoxy-1,3,5(10)-estratriene-3,18-diol is obtained.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:12][C:13]([Br:18])([Br:17])[C:14](Cl)=[O:15]>C(#N)C>[C:1]([N:4]([C:14](=[O:15])[C:13]([Br:18])([Br:17])[Br:12])[NH2:5])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(Br)(Br)Br
Reactant: CC(=O)NN
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)N(N)C(=O)C(Br)(Br)Br
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
4.68 g (0.063 mol) of acetohydrazide (2-a) and 5 g (0.063 mol) of pyridine were dissolved in 50 ml of acetonitrile, and stirred with cooling in an ice-bath. Thereto, a solution of 20 g (0.064 mol) of tribromoacetic acid chloride (which was prepared from tribromoacetic acid and thionyl chloride, and had b.p. of 800°-81° C./17 mm Hg) dissolved in 20 ml of acetonitrile was added dropwise. After the conclusion of the dropwise addition, the stirring ring was further continued for 30 min. Thereupon, a white precipitate was deposited. It was filtered off, and washed with successive, acetonitrile and water. Thus, 10.7 g (0.030 mol) of N-acetyl-N-tribromoacetylhydrazine (3-a) was obtained. Yield 48%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=O)N2)=C[CH:6]=1.[CH3:15]I.[CH3:17][N:18]([CH:20]=[O:21])[CH3:19]>>[CH3:3][O:4][C:5]1[CH:6]=[C:17]2[C:8]([C:9]([CH3:10])([CH3:15])[C:20](=[O:21])[N:18]2[CH3:19])=[CH:12][CH:13]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
To a stirred ice cold suspension of sodium hydride (60% in mineral oil, 3.9 g, 98.1 mmol) in 50 mL of dry DMF was added solid 6-methoxy-1,3-dihydro-indol-2-one (4.00 g, 24.5 mmol) portionwise over 10 minutes. To the resultant gray mixture was added dropwise MeI (2.68 g, 98.1 mmol). The mixture was warmed to room temperature and stirred for 45 minutes, and then was cooled back to 0° C. and quenched with 90 mL of water. The mixture was extracted with an ethyl acetate (EtOAc)/toluene mixture (2:1), and the extracts were dried with magnesium sulfate (MgSO4), treated with activated charcoal, filtered and concentrated to give a red syrup. Silica gel chromatography (1:10 EtOAc/hexanes) gave 4.16 g (83%) of the title compound as a white solid (mp 67–69° C.). Mass spectrum m/e calcd for M+H=234.1. Found 234.2.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:11])[C:5](=[CH2:10])[C:6]([O:8]C)=[O:7].COC1C=C(OC)C=CC=1C[NH2:18]>C1(C)C=CC=CC=1>[CH3:11][CH:4]1[C:3](=[O:2])[NH:18][CH2:10][CH:5]1[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=C(C(=O)OC)C(C)C(=O)OC
Solvent: Cc1ccccc1
Product: CC1C(=O)NCC1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 174.1 %

Procedure:
To a solution of 2-methyl-3-methylenesuccinic acid dimethyl ester (9.81 g) in toluene (100 ml) was added 2,4-dimethoxybenzylamine (9.72 g) and the mixture was stirred for 3 days at reflux. This reaction solution was cooled to room temperature and then purified by silica gel column chromatography (eluent: n-hexane/chloroform=1/1 to 0/1) to give the titled compound (14.2 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([O:18]CC)=[O:17])[CH:7]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[N:9]=[C:8]([C:16]([OH:18])=[O:17])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(COC(C)=O)nc(C(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1cc(C(=O)O)nc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 6-[(acetyloxy)methyl]-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.95 g, 3.2 mmol, from Step B) in tetrahydrofuran (8.7 mL) at 0° C. was treated with lithium hydroxide, monohydrate (140 mg, 3.2 mmol) in water (1.3 mL). The reaction was stirred for 15 minutes, then was treated with 1N HCl to pH4 while still in the ice bath. THF was removed from the mixture in vacuo. The product was extracted first with ethyl acetate, then with several portions of 10% iPrOH in CHCl3, including periodic adjustment of pH as necessary. The extracts were combined and dried over sodium sulfate, filtered and concentrated to afford a yellow oil, which was used without further purification (0.86 g, 100%). 1H NMR (300 MHz, CDCl3): δ 8.25 (s, 1H), 5.35 (s, 2H), 2.23 (s, 3H); LCMS (M+H)+: 265.0.
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][C:19]([NH:21][C:22]1[C:39]([OH:40])=[C:38]2[C:25]([CH2:26][CH:27]3[C:36]([C:37]2=[O:41])=[C:35]([OH:42])[C:34]2([OH:43])[CH:29]([CH:30]([N:49]([CH3:51])[CH3:50])[C:31]([OH:48])=[C:32]([C:45]([NH2:47])=[O:46])[C:33]2=[O:44])[CH2:28]3)=[C:24]([N:52]([CH3:54])[CH3:53])[CH:23]=1)=[O:20]>CN1C(=O)N(C)CCC1.C(#N)C>[CH2:2]([N:9]([OH:10])[CH2:18][C:19]([NH:21][C:22]1[C:39]([OH:40])=[C:38]2[C:25]([CH2:26][C@@H:27]3[C:36]([C:37]2=[O:41])=[C:35]([OH:42])[C@@:34]2([OH:43])[C@H:29]([C@H:30]([N:49]([CH3:51])[CH3:50])[C:31]([OH:48])=[C:32]([C:45]([NH2:47])=[O:46])[C:33]2=[O:44])[CH2:28]3)=[C:24]([N:52]([CH3:53])[CH3:54])[CH:23]=1)=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ONCc1ccccc1
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CC#N
Product: CN(C)c1cc(NC(=O)CN(O)Cc2ccccc2)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Yield: 36.8 %

Procedure:
The compound of the example is prepared by the procedure of Example 1 using 3 g of N-benzylhydroxylamine hydrochloride, 2 g of sodium carbonate, and 0.8 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 10 ml DMPU and 3 ml acetonitrile to give 0.315 g of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([CH3:23])=[C:15]([O:19]C(=O)C)[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=3[CH3:23])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Oc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(O)cccc1C(=O)c1c[nH]c2ncc(Br)cc12

Procedure:
A solution of acetic acid 3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl ester (84, 25.0 mg, 0.067 mmol) in 6 N HCl (4.0 mL) was heated with a CEM Discover microwave instrument at 110° C. for 10 min. The reaction mixture was poured into water, neutralized with 1 M aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give a colorless oil (P-0055, 4.7 mg, 21%). MS(ESI) [M−H+]−=329.0, 331.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.C(N(CC)CC)C>CC(O)C>[C:31]([O:30][C:28]([N:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:27][CH2:26]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.79 mmol) in 2-propanol (40 mL) was added tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (613 mg, 1.97 mmol) followed by triethylamine (200 mg, 1.98 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-{2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester. (Yield 600 mg, crude).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:5][OH:6])[CH3:4].S(=O)(=O)(O)O.[CH2:12]=[C:13]([CH3:15])[CH3:14].C(=O)([O-])[OH:17].[Na+]>C(OCC)C>[C:13]([O:17][O:6][N:5]=[C:3]([CH2:2][Cl:1])[CH3:4])([CH3:15])([CH3:14])[CH3:12]
Reactant: C=C(C)C
Reactant: CC(CCl)=NO
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CC(CCl)=NOOC(C)(C)C

Procedure:
Then, 0.54 g of chloroacetone oxime, 0.1 ml of concentrated sulfuric acid, and 10 ml of diethyl ether are placed in a reaction vessel, into which isobutene gas is blown with stirring under ice cooling, and the reaction mixture is further stirred at room temperature. After completion of the reaction, the reaction mixture is slowly poured into saturated aqueous sodium hydrogencarbonate solution, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with 10% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium hydroxide, and concentrated, which affords chloroacetone O-tert-butyloxyoxime.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[NH:8][C:9]2[C:13]([C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[N:8]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[C:9]2[C:13]([C:14]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Reactant: Fc1ccc(CBr)cc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(Cc2ccc(F)cc2)c1=O
Yield: 54 %

Procedure:
The compound was prepared from 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (40) and 4-fluorobenzylbromide by applying general procedure A. Yield 54%; MP 227° C. 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 3.30 (m, 4H), 3.83 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 5.18 (s, 2H), 7.14-7.17 (m, 3H), 7.20 (d, J=3.2 Hz, 1H), 7.33 (m, 2H), 7.46 (dd, J=1.2, 4.8 Hz, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 8.13 (d, J=3.2 Hz, 1H) ppm; MS m/z=526 amu (M++1). Anal. (C26H24FN3O4S2) C, H, N.
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][NH:8][CH:7]=1)=O)C.[OH-].[Na+].O.C(Cl)Cl>C(O)CO>[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[CH:6]=[CH:7][NH:8][CH:9]=2)=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(-c2cc[nH]c2)cc1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 26.9 %

Procedure:
A solution of 55 (2.44 g, 9.92 mmol) in ethylene glycol (25 mL) was flushed with argon for 20 min. The mixture was immersed in an oil bath pre-heated to 160° C., and powdered NaOH (4.22 g, 105 mmol) was added. Stirring was continued for 1.5 h. The reaction mixture was allowed to cool to room temperature, and water and CH2Cl2 were added. The aqueous layer was extracted with CH2Cl2. The organic extract was washed with water and brine. The organic layer was dried (Na2SO4). The solvent was removed at reduced pressure to yield a pale brown oil (502 mg, 25%): 1H NMR δ 6.36-6.48 (m, 1H), 6.69-6.73 (m, 2H), 6.79-6.81 (m, 1H), 6.96-6.98 (m, 1H), 7.33-7.38 (m, 1H), 8.21 (br, 1H).