Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.[I:40]N1C(=O)CCC1=O>CC#N.ClCCl>[CH3:37][Si:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:38])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:40])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
To tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9f, 18.8 g, 32.5 mmol) in CH3CN (130 mL) and dichloromethane (130 mL) was added N-iodosuccinimide (8 g, 35.8 mmol) portionwise and the resulting mixture was stirred at room temperature for 1.5 h, at which time LC/MS confirmed full conversion of starting material to product. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave the desired product, tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9g) (21.7 g, 95%). LC/MS: m/z=704.2 (M+H4).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][N:20]([CH2:28][C@@H:29]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=3)[O:30][Si](C(C)(C)C)(C)C)C(OC(C)(C)C)=O)[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].C(OCC)C>Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][CH2:19][NH:20][CH2:28][C@@H:29]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=3)[OH:30])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(NCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)C(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Reaction time: 0.33 h

Procedure:
A solution of (R)-3′-[[2-[[2-(3-chlorophenyl)-2-[[(tert-butyl)dimethylsilyl]oxy]ethyl][(tert-butoxy)carbonyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester (275 mg) in 4 N hydrochloric acid in dioxane (10 mL) was stirred for 3 days. Diethyl ether was added and the reaction was stirred for 20 minutes. The title compound was collected by suction filtration as a white solid (210 mg);
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]2[CH2:11][CH2:10][C@:9]3([OH:26])[C@H:12]4[C@H:22]([CH2:23][CH2:24][C@:7]23[CH3:8])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([OH:25])[CH2:18][CH2:19]2)[CH2:14][CH2:13]4)=[CH:2]1.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>O1CCCC1>[CH2:31]([O:25][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@:9]3([OH:26])[CH2:10][CH2:11][C@@H:6]2[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH2:16]1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Reaction time: 20 h
Yield: 87 %

Procedure:
To a solution of 0.60 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377) in 50 ml of dry tetrahydrofuran, 0.44 g of sodium hydride (60% dispersion in mineral oil) were added under nitrogen atmosphere at room temperature and the resulting mixture was stirred at reflux temperature for 6 hrs; 1.4 g of allyl bromide were added and the reflux continued for further 20 hrs. The mixture was quenched with water and the organic solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate, the organic solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 0.58 g of 3β-(prop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[Na].[C:10]([C:12](=[N:21][OH:22])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])#[N:11]>C1C=CC=CC=1.ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:22][N:21]=[C:12]([C:10]#[N:11])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: N#CC(=NO)c1c(Cl)cccc1Cl
Agent: [Na]
Solvent: ClCCl
Solvent: c1ccccc1
Product: N#CC(=NOS(=O)(=O)CCCCl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5.0 g (0.0281 mol) sample of 3-chloropropylsulfonyl chloride was added slowly at about 0° C. (ice bath) to a suspension of 6.7 g (0.0281 mol) of the sodium salt of alpha-cyano-2,6-dichlorobenzaldoxime in 60 ml benzene. The reaction was exothermic. The reaction mixture was stirred at 25° C. for 2 hours during which time a solid product formed. The reaction mixture was then diluted with 200 ml dichloromethane, washed with water, dried over magnesium sulfate and silica gel, and evaporated under reduced pressure to give a yellow oil. The oil was crystallized from ether/hexane to give the product as white crystals, m.p. 86°-88° C. This product is tabulated in Table I as compound No. 12.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[CH2:33][OH:34].O>CN(C=O)C>[OH:34][CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][N:27]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OCC1CCCCN1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4CO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the mixture was added 2-piperidinemethanol (19lmg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[2-(hydroxy-methyl)piperidinomethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 68) (120 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].[C:31]([O:34][CH2:35][CH2:36]Br)(=[O:33])[CH3:32].Cl.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O:22][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH3:36])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cscn1
Reactant: CC(=O)OCCBr
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (100 mg) in dimethylformamide (1 ml) was added 2-bromoethyl acetate (54 mg). After stirring for 2 hours at room temperature, the reaction mixture was added to a mixture of dil. HCl (10 ml) and ethyl acetate (20 ml). The resulting ethyl acetate layer was separated, washed successively with dil. HCl (10 ml), phosphate buffer (pH 7, 10 ml×2), and saturated aqueous NaCl (10 ml), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (2 ml), and the solution was added dropwise to a petroleum ether-diethyl ether mixture (100 ml) with stirring. Resulting crystals were filtered, and dried under reduced pressure to give the title compound (50 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of (4-bromophenyl)methanamine (2.5 g, 13 mmol) in dichloromethane (45 mL) was added N,N-diisopropylethylamine (3.5 mL, 20 mmol), followed by phenylmethanesulfonyl chloride (3.1 g, 16 mmol) and the reaction was stirred at ambient temperature for 1 hour. The precipitate was then collected by filtration, washed with dichloromethane and dried under reduced pressure to give N-[(4-bromophenyl)methyl]-1-phenyl-methanesulfonamide (2.79 g, 61% yield). LCMS (m/z) ES+ 340.0 [M+1]+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](S(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+]>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([O:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:20][CH3:21])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(S(C)(=O)=O)nc(=O)c1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Oc3ccccc3)nc(=O)c1-2
Temperature: 172.5 °C
Yield: 67.4 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(methylsulfonyl) pyrazolo[3,4-d]pyrimidin-4-one (3 g, 9.6 mmol), phenol (6 g, 64 mmol) and NaH (0.5 g, 12.8 mmol, 60% dispersion in mineral oil) was heated at 170-175° C. for 5 hours. The reaction mixture was poured into water (50 mL) and extracted with CHCl3 (100 mL). The CHCl3 layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with 10% ether/hexane to afford 2.1 g (68%) of 1-cyclopentyl-3-ethyl-6-(phenyloxy) pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 175-177° C.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10].Cl.C(OCC)(=O)C>C1COCC1>[OH:11][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(O)c1ccccc1
Yield: 96 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 3.96 g (6.50 mmol, 0.65 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.20 g (10 mmol) of acetophenone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.99 g of the desired product (yield 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[C:32]([F:38])[CH:31]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][C:32]=3[F:38])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Reactant: C#Cc1ccc(Cl)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4ccc(Cl)cc4F)cc3F)[nH]c2=O)c1)C1CC1
Yield: 47.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.050 g, 0.097 mmol), 4-chloro-1-ethynyl-2-fluorobenzene (Intermediate-49, 0.022 g, 0.14 mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.025 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.65-0.68 (m, 4H), 1.60 (m, 1H), 4.32 (d, J=6.0 Hz, 2H), 7.33-7.52 (m, 3H), 7.55-7.74 (m, 5H), 7.90 (m, 1H), 8.68 (m, 1H), 12.0 (br s, 1H).; MS (m/z): 539.0 (M+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([S:26][C:23]2[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(Br)cc2)CC1
Yield: 95.9 %

Procedure:
N-BOC 4-mesyloxypiperidine (40 g, 0.14 mol), 4-bromothiophenol (32 g, 0.17 mol) and potassium carbonate (30 g, 0.22 mol) were mixed at room temperature in CH3CN (300 ml) and heated at reflux for 18 h. Work-up by partitioning between water and EtOAc afforded 50 g of material as a yellow oil. δH (360 MHz, CDCl3) 1.44 (9H, s), 1.45-1.55 (2H, m), 1.85-1.95 (2H, m), 2.85-2.95 (2H, m), 3.10-3.20 (1H, m), 3.95-4.05 (2H, m), 7.25-7.30 (2H, m), 7.40-7.45 (2H, m).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[C:18]([N:17]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:16][C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[O:15])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)NNC(=O)c1ccco1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)N(Cc1ccccc1)NC(=O)c1ccco1
Temperature: 25 °C

Procedure:
Benzyl bromide (1.8 g), 1-furoyl-2-t-butyl hydrazine (2 g) and excess powdered potassium carbonate were stirred in dimethylformamide (50 ml) at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed several times with water. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The white solid product was chromatographed on silica gel (G:70-230 mesh) using methylene chloride as eluent to afford the product in good yield: m.p. 152-153.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].Cl.[NH2:13]O.Cl>C(O)C.O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:13]=1
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
In a 100 ml. round bottom flask there was placed 2 g. of pivalyl acetonitrile, 0.64 g. of sodium hydroxide, 17.5 ml. of water and 12.5 ml. of ethanol. This mixture was heated to refluxing and a aqueous solution of 1.1 g. of hydroxylamine hydrochloride was added dropwise. When addition was complete the pH of the mixture was about 7.2. This was adjusted to pH about 6.3 using 10% aqueous hydrochloric acid. After 1 hour the pH was about 7.0 and was adjusted with 10% HCl to pH about 6.5. At the end of 2 hours the pH was about 6.8. At the end of 3 hours the pH was about 6.9. At 31/2 hours the pH was about 6.5. The reaction mixture was refluxed overnight and the following morning the pH was about 6.8. The reaction mixture was concentrated using the rotovapor and the solid material which precipitated was filtered off and dried. It weighed 1.3 g., had a melting point of about 103°-104° C., and was determined by vpc to contain 90.68% of 3-amino-5-(t-butyl)-isoxazole and 6.68% of 5-amino-3-(t-butyl)isoxazole. Yield: 65.9% of desired isomer.
Reaction SMILES: C([O:8][C:9](=[O:18])[NH:10][C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1.[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:16][N:14]([CH3:15])[C:12](=[O:13])[C@@H:11]([N:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:9](=[O:18])[OH:8])[CH3:17]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Reactant: BrCc1ccccn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N(C)C)N(Cc1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
Under nitrogen atmosphere, to a solution of 2.00 g of benzyl[(1S)-2-(dimethylamino)-1-methyl-2-oxo ethyl]carbamate in DMF was added 0.33 g of NaH under ice cooling and the reaction mixture was stirred at room temperature for 10 minutes. Therein, a solution of 3.25 g of 2-(bromo methyl)pyridine in DMF (15 ml) was added, and the solution was stirred at room temperature for 3 hours. A saturated aqueous solution of NaHCO3 was added to the reaction solution, and the resulting mixture was extracted with EtOAc. The combined organic layer was washed with water and with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N, moving bed: CHCl3/EtOAc=1/1; v/v) to obtain 1.04 g of the title compound (colorless oil).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].O.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(CO)cc1
Yield: 51.1 %

Procedure:
p-Cyanobenzylamine (13.2 g), water (54 g), and toluene (20 g) were mixed, and the mixture was stirred with cooling with ice. Concentrated sulfuric acid (14.7 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (44.9 g) of sodium nitrite was added dropwise to the mixture over one hour. The mixture was stirred at the same temperature for four hours. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.8 g of p-cyanobenzyl alcohol (yield 51%). The purity of the product was 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1Br)[C:45]#[N:46]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:49]5[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=5[CH3:41])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C#N)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C#N)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (300 mg) and 3-methyl-4-bromobenzonitrile (120 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-benzonitrile was obtained, and then the PMB groups were removed according to the above Deprotection method 3 using 54 mg of the crude product, to obtain the desired compound (D-234) as an ivory powder (32 mg, 94%).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][C:15]1[O:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][CH:26]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[C:24]=3[CH:36]=2)=[N:18][N:19]=1.[Sb](Cl)(Cl)Cl>ClCCl.C(OCC)(=O)C>[F:11][CH2:35][S:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[C:24]3[CH:36]=[C:20]([C:17]4[O:16][C:15]([CH3:14])=[N:19][N:18]=4)[CH:21]=[CH:22][C:23]=3[O:27][CH:26]=2)=[CH:33][CH:32]=1
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: Cl[Sb](Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(SCF)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To a solution of [bis(2-methoxyethyl)amino]sulfur trifluoride (1.38 mL, 7.50 mmol) in dichloromethane (10 mL) was added dropwise a solution of 2-methyl-5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (1.61 g, 5.00 mmol) in dichloromethane (15 mL) at room temperature. Antimony (III) chloride (0.0570 g, 0.250 mmol) was added to the solution, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/tetrahydrofuran=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (517 mg, yield 30%) as pale-yellow crystals.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Cl)=[N:8][S:9](=[O:11])(=[O:10])[C:4]2=[CH:3][CH:2]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:13]([N:15]([CH2:16][CH3:17])[C:7]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH3:14]
Reactant: CCNCC
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCN(CC)C1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
10.0 g of pseudosaccharine chloride are initially introduced in 150 ml of toluene. 3.7 g of diethylamine diluted with 25 ml of toluene are added dropwise at room temperature over the course of 30 minutes. After a further 30 minutes, 50 ml of pyridine in 25 ml of toluene are added and the mixture is subsequently stirred at room temperature for 2.5 hours. The solvent is then removed in vacuo and the residue is stirred up with 350 ml of water. The colorless precipitate is filtered off to give 10.1 g (84%) of 3-diethylaminobenzoisothiazole 1,1-dioxide.