Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.N1C=CC=CC=1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)(Cl)Cl>[Cl:14][CH2:15][C:16]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(N)no1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC(=O)CCl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To 800 ml of chloroform is added 118 grams (1.12 moles) of 3-amino-5-methylisoxazole followed by 118 grams (1.5 moles) of pyridine. To this solution is added 147 grams (1.3 moles) of chloroacetylchloride with the addition temperature maintained at 0°-10° C. The reaction is then stirred at room temperature for 1 hour, filtered and dried in a vacuum desiccator to give 116 grams (56%) of 3-(chloroacetamido)-5-methylisoxazole, mp 192°-195° C. This material is slightly irritating to the skin and due caution should be exercised.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[C:10]([N:17]4[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][CH2:18]4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:4][O:3]1.Cl>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[OH:6][CH:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([N:17]3[CH2:18][CH2:19][CH:20]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:21][CH2:22]3)[CH:11]=[CH:12][CH:13]=2)[N:8]=1)[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C4COC(C)(C)O4)nc23)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C(O)CO)nc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl (1-(2-(2,2-dimethyl-1,3-dioxo lan-4-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (81 mg, 0.18 mmol) in THF (3 mL) was added HCl (20 mg, 0.55 mmol) (6M). The reaction was stirred for 3 hours at ambient temperature and then diluted with EtOAc (10 mL) and saturated NaHCO3 (5 mL). The phases were separated, and the organic layer was dried and concentrated to give crude product.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[CH2:25]O)([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[OH:9].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:17]2[C:18](=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[CH2:25][O:9]1
Reactant: N#Cc1ccc(C(O)(CCC2OCCO2)c2ccc(F)cc2)c(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)COC2(CCC1OCCO1)c1ccc(F)cc1
Temperature: 7.5 °C
Reaction time: 0.08 h
Yield: 134.8 %

Procedure:
4-[3-[1, 3]-Dioxolan-2-yl-1-(4-fluorophenyl)-1-hydroxypropyl-]3-hydroxymethylbenzonitrile (15 g) was dissolved in dichloromethane (150 mL) at room temperature, followed by addition of triethylamine (25 mL). The reaction mixture was cooled to 5-10° C. and stirred for 5 min, followed by addition of methane sulfonylchloride (8.4 g). The reaction mixture was warmed to room temperature and stirred for 10 min. It was quenched with 2% NaOH (100 mL) while maintained to 10-20° C. The organic phase was separated and was dissolved in water and concentrated to give 19.2 g crude product. 1H NMR (CDCl3, δ): 1.42-1.57 (m, 1H), 1.63-1.76 (m, 1H), 2.20-2.38 (m, 2H), 3.78-3.96 (m, 4H), 4.84 (t, J=3 Hz, 1H), 5.18 (m, 2H), 7.00 (m, 2H), 7.38-7.50 (m, 4H), 7.60 (m, 1H). The product was separated into its enantiomers by CHIRALCEL OD=column using Methanol as eluent. Enantiomer 6a, 6.67 min; Enantiomer 6b, 8.30 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:24](O)[CH2:25][OH:26].CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[C:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:5]3([C:8]#[N:9])[CH2:6][CH2:7][C:2]4([O:26][CH2:25][CH2:24][O:1]4)[CH2:3][CH2:4]3)=[CH:11][CH:12]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCO
Reactant: N#CC1(c2ccc(OCc3ccccc3)cc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccc(OCc3ccccc3)cc2)CCC2(CC1)OCCO2
Yield: 47 %

Procedure:
A mixture of 65 parts of 4-oxo-1-[4-(phenylmethoxy)phenyl]-1-cyclohexanecarbonitrile, 15.7 parts of 1,2-ethanediol, 0.2 parts of 4-methylbenzenesulfonic acid and 360 parts of methylbenzene is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, washed successively with water, with a sodium hydroxide solution 5% and again with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 33.5 parts (47%) of 8-[4-(phenylmethoxy)phenyl]-1,4-dioxaspiro[4,5]decane-8-carbonitrile.
Reaction SMILES: I[CH2:2][C@H:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[CH2:5][CH2:4]1.[Cl-].[Li+].[CH:18]([Mg]Cl)=[CH2:19].Cl>O1CCCC1>[C:9]1([CH2:8][N:7]2[C@H:3]([CH2:2][CH:18]=[CH2:19])[CH2:4][CH2:5][C:6]2=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C[Mg]Cl
Reactant: O=C1CC[C@@H](CI)N1Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-iodomethyl-1-(phenylmethyl)-2-pyrrolidinone (31.5 g, 0.1 mol) in 250 mL of anhydrous tetrahydrofuran was added a solution of Li2CuCl4 (7.5 mL of a 0.1M solution in tetrahydrofuran; prepared from anhydrous lithium chloride (85 mg) and anhydrous cupric chloride (134.5 mg) in 10 mL of tetrahydrofuran). The solution was cooled to -78° C. and vinyl magnesium chloride (200 mL of 1M solution in tetrahydrofuran) was added over a 25 min period. After stirring for 1 h at -78° C., a second portion of vinyl magnesium chloride (200 mL of 1M solution) was added as before. After stirring for another 1 h, a third portion (200 mL of 1M solution) was added as before, and the mixture was stirred at -78° C. overnight. The cold solution was then poured onto 1.5 kg of ice and was acidified with 100 mL of 6N hydrochloric acid (HCl). The mixture was extracted with methylene chloride, washed with saturated sodium bicarbonate and brine, and dried over MgSO4. The solution was concentrated on a rotary evaporator to give 23.8 g of crude (S)-1-(phenylmethyl)-5-(2-propenyl)-2-pyrrolidinone as a brown oil. The crude product was chromatographed on 700 g of silica gel, eluting with 50% ethyl acetate in hexanes to give 14.2 g (66% yield) of the pure (S)-1-(phenylmethyl)-5-(2-propenyl)-2-pyrrolidinone as a colorless oil. 1H NMR (CDCl3) δ 1.7-2.75 (m, 6 H, CH2 's), 3.51 (m, 1 H, NCH), 4.99 and 5.02 (AB, Jgem =15 Hz, 2 H, CH2Ph), 5.0-5.2 (m, 2 H, vinyl H), 5.4-5.9 (m, 1 H, vinyl H), 7.25-7.40 (m, 5 H, phenyl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=S)[CH:5]=[C:6]([Br:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:16][CH3:17])([CH3:14])[CH3:15])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCC(C)(C)NC(=S)Nc1cc(Br)cc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)(C)N=C=Nc1cc(Br)cc(Br)c1

Procedure:
To a solution of 2.4 g of N-(3,5-dibromophenyl)-N'-t-pentylthiourea produced in Example A-10 in 55 ml of dichloromethane were added 3.3 g of triphenylphosphine, 2.0 g of carbon tetrachloride and 1.3 g of triethylamine. The mixture was refluxed for 4 hours and evaporated in vacuo. The residue was extracted with petroleum ether and the extract evaporated in vacuo to give N-(3,5-dibromophenyl)-N'-t-pentylcarbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 1.2 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 3 hours, cooled to room temperature and poured into 600 ml of water. The resulting crystals were collected, washed with a small amount of cyclohexane and recrystallized from ethanol to give 0.9 g of the title compound as colorless needles melting at 168.0°-170.0° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:30])[C:17]([CH3:29])([CH3:28])[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:30])[C:17]([CH3:28])([CH3:29])[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)C(=O)C(C)(C)O2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 107.2 %

Procedure:
5% Palladium on carbon (7.0 g) was added to a solution 4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (19 g, 42.1 mmol) in methanol (25 ml) at RT under an atmosphere of nitrogen. The nitrogen atmosphere was changed to an atmosphere of hydrogen. The reaction mixture was stirred under an atmosphere of hydrogen at RT for 4 h (the reaction was monitored by TLC). The reaction mixtures was filtered over through a pad of Celite®, washed with methanol, concentrated in vacuo and the resultant residue was slurried with heptane. The solid was filtered & dried under vacuum to afford 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (14.0 g, 95%) as light yellow solid. 1H NMR, 500 MHz, DMSO-d6: δ 9.5 (bs, 1H), 7.55 (d, 2H), 7.05 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]: m/z=311.2. HPLC: (98.8%, Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:26]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].CC(S)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(c3ccc(O)cc3)=C1c1ccc(OC)cc1C2
Agent: CC(C)S
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCC12CCC(=O)C(c3ccc(O)cc3)=C1c1ccc(O)cc1C2
Temperature: 0 °C

Procedure:
An ice-cold solution of 9a-butyl-4-(4-hydroxy-phenyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (29 mg, 0.08 mmol) in anhydrous CH2Cl2 (1 mL) was added to AlCl3 (96 mg, 0.72 mmol) contained in an ice cooled flask. The mixture was stirred at 0° C. under a nitrogen atmosphere and treated with 2-propanethiol (0.056 mL, 0.6 mmol). The resulting mixture was stirred at 0° C. for 5 minutes and at room temperature for 3.25 hours, then treated with ice (approx. 2 mL), 2N HCl (2 mL) and EtOAc (4 mL) and stirred for 15 minutes at room temperature. The EtOAc layer was separated, washed with 1N HCl and brine, dried over MgSO4, filtered, and evaporated under vacuum to give a yellow gum. This material was triturated with benzene to give, after filtration and drying under vacuum, 9a-butyl-7-hydroxy-4-(4-hydroxyphenyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an off-white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>CCOCC>[C:4]1([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:23](=[O:26])[CH2:24][CH3:25])=[CH:13][CH:14]=2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CCC(=O)Cl
Reactant: Oc1ccc(N=Nc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)Oc1ccc(N=Nc2ccccc2)cc1
Yield: 71.8 %

Procedure:
4-Phenylazophenol (0.25 g, 1.26 mmoles) was dissolved in ether (5-10 mL) and triethylamine (0.26 mL) was added. Then propanoyl chloride (0.14 g 1.5 mmoles) in ether (1 mL) was added dropwise at room temperature. The mixture was stirred and reaction was rapidly completed. The reaction mixture was washed with water, dilute acid and brine and dried with magnesium sulfate. The solvent was evaporated to give 0.23 g (72%) of product. 1H NMR (CDCl3) δ=1.16 (3H, t, J=7.7), 2.40 (2H, q J=7.7), 7.25 (2H, m), 7.40-7.58 (3H, m), 7.88-8.0 (4H, m) ppm.
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.ClCCl.Br[Si](C)(C)C.C(OCC)(=O)C>CCOCC.O>[OH:5][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][C:21]2([S:22][CH2:23][CH2:24][S:25]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC)SCCS2
Agent: C[Si](C)(C)Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1CC2(CN1C(=O)CP(=O)(O)CCCCc1ccccc1)SCCS2
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
(S)-7-[[Ethoxy(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, methyl ester (3.44 g) and dry dichloromethane (15 ml) are added to a flask under an argon atmosphere. Using a gas-tight syringe, bromotrimethylsilane (1.5 ml) is added to the flask, which is stirred for about 16 hours at room temperature. Ethyl acetate (50 ml) and water (10 ml) are added to the flask and stirred for 30 minutes. The mixture is diluted with ether and transferred to a separatory funnel. The organic layer is extracted with saturated sodium bicarbonate (two 25 ml portions) and the extract is acidified to pH 1.0 to precipitate product which is extracted into ethyl acetate. The ethyl acetate extract is washed with brine, run through sodium sulfate to dry, and the solvent is stripped leaving the title compound as an oil (2.99 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13]
Reactant: OB(O)c1cccnc1
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Yield: 35.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]piperidine (0.150 g, 0.350 mmol) was dissolved in methylene chloride (3.5 ml) and after adding thereto in sequence copper acetate (0.064 g, 0.350 mmol), 3-pyridylboronic acid (0.114 g, 0.700 mmol), Molecular Sieves 4A (0.150 g), triethylamine (0.088 g, 0.874 mmol) and pyridine (0.069 g, 0.874 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.063 g, 0.125 mmol, 36%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC#N.Cl[CH2:27][C:28]([N:30]1[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH2:27][C:28]([N:30]3[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]3)=[O:29])[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Reactant: COC1CN(C(=O)CCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC1CN(C(=O)CN2CCN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)CC2)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine and MeCN was added to 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg) and potassium carbonate (219 mg), followed by stirring at 80° C. for 3 hours. CHCl3 was added to the reaction mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 2-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}-1-(3-met hoxyazetidin-1-yl)ethanone (354 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[CH3:16][N:17]([CH3:32])[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[C:23]2[S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:28]([C:23]3[C:24]4[C:19](=[C:18]([N:17]([CH3:32])[CH3:16])[CH:27]=[CH:26][CH:25]=4)[CH:20]=[CH:21][CH:22]=3)(=[O:30])=[O:29])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3cccc4c(N(C)C)cccc34)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 5-dimethylamino-naphthalene-1-sulfonyl chloride (356 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12k as a solid (233 mg, 57.50%). HPLC: 99.04% (Rt=12.33 min).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.[C:18]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=O)[CH3:19]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:18]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[CH:19]2
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)C1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Clc1ccc2[nH]c(C3CCNCC3)cc2c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A mixture of 0.60 gm (3.4 mMol) 4-chlorophenylhydrazine hydrochloride and 0.54 mL (6.7 mMol) pyridine in 20 mL ethanol were stirred at 60° C. for 15 minutes. To this mixture was then added 4-acetylpiperidine hydrochloride and the reaction mixture was stirred for 2 hours at 70° C. The reaction mixture was concentrated under reduced pressure and the residue was treated with polyphosphoric acid. This mixture was heated at 90°-100° C. for 48 hours. The reaction mixture was quenched with a slurry of ice in 5N sodium hydroxide. The aqueous mixture was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a dichloromethane gradient containing 4-20% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.26 gm (36%) of the title compound as a tan solid.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH:11]=[CH:10]1.CN(C1CCCCC1)C1CCCCC1>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:8][C:3]1[C:2]([C:11]2[CH2:12][CH2:13][C:9](=[O:14])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: O=C1C=CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1C=C(c2cccnc2F)CC1
Temperature: 23 °C
Reaction time: 21 h

Procedure:
A solution of 3-bromo-2-fluoropyridine (4 g, 22.73 mmol), 2-cyclopenten-1-one (7.35 mL, 91 mmol), n-methyldicyclohexylamine (12.05 mL, 56.8 mmol) and bis(tri-tert-butylphosphine)palladium (0) (0.581 g, 1.136 mmol) in 1,4-dioxane (50 mL) was heated to 105° C. in a capped vessel. After 21 h, the reaction was cooled to 23° C., diluted with EtOAc (400 mL) and washed with water (150 mL) and brine (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 15-50% EtOAc/hexane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 178.0 (M+1).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(C(F)(F)F)ccc1Cl
Yield: 77.7 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 2-chloro-5-trifluoromethylaniline (4.25 g, 21.7 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (6.49 g, 70%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[C:18]([NH:26][NH2:27])(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C=O)C.C>CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:16]1[NH:17][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][N:27]=1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Reactant: NNC(=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cccc(CO)c2)nc1-c1nnc(-c2ccccc2)[nH]1
Temperature: 190 °C
Yield: 29 %

Procedure:
A mixture of 3-amino-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carbonitrile (0.11 g, 0.5 mmol) and benzoic hydrazide (0.15 g, 1 mmol) were heated at 180-200° C. for 30 min. After cooling, the reaction mass was taken up with 5 mL DMF and the obtained solution was diluted with EtOAc and water, clarified with charcoal and filtered on Celite. The organic layer was separated. After drying over sodium sulfate, the ethyl acetate was evaporated under reduced pressure. Purification of the residue by preparative HPLC (Acetonitrile/water) gave desired product (50 mg): 1H NMR (400 MHz; DMSO-d6): 8.3 (s, 1H); 8.1 (m, 2H); 7.6-7.3 (m, 7H); 5.45 (t, 1H); 4.6 (d, 2H); MS (EI) for C23H22N5OF3 HCl: 442 (MH+).