Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14]C(C)([O-])C.[K+].CI>CN(C=O)C>[CH3:14][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]=[CH:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C(=Nc1ncc[nH]1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccnc1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
N-(2-imidazolyl)benzylideneamine (0.2 g) was dissolved in DMF (4 ml), and potassium t-butoxide (0.15 g) and methyl iodide (0.18 g) were added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform). The resulting crude crystals were recrystallized from diethyl ether--hexane to give the title compound (0.1 g, 49.9%) as pale yellow needles.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:15]1([O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[O:13][CH3:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC2CCCC2)c(OC)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-hydroxy-3-methoxybenzoate (7.17 g), cyclopentyl bromide (4.7 ml) and potassium carbonate (7.6 g) in N,N-dimethylformamide (70 ml) was stirred at 80° C. for 3 hours. Then the mixture was poured into water and extracted with ethyl acetate twice. The combined organic solution was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (hexane-ethyl acetate, 4:1) to give ethyl 4-cyclopentyloxy-3-methoxybenzoate (8.58 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>C1COCC1>[Cl:11][CH2:12][CH2:13][C:14]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:15]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: O=C(CCCl)Nc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 3-nitroaniline (37a, 6.9 g, 50 mmol) in THF (50 mL) was added dropwise 3-chloropropionyl chloride (10 mL, 100 mmol) over 30 min under argon atmosphere. The reaction was stirred at 50° C. for 10 h. After cooling, the reaction mixture was evaporated to dryness under vacuo and the residue was neutralized with saturated aqueous solution of NaHCO3 and the solid product was collected by filtration, washed with water followed by hexane, and dried to afford 3-chloro-N-(3-nitrophenyl)propanamide, 10.61 g (92%), mp 86-88° C. (Lit. 100-102° C.57). 1H NMR (DMSO-d6) δ: 2.87-2.90 (2H, t, J=9.9 Hz, CH2), 3.90-3.92 (2H, t, J=9.9 Hz, CH2), 7.61-7.64 (1H, t, J=6.6 and 6.6 Hz, Ar—H), 7.90-7.94 (2H, m, Ar—H), 8.65-8.66 (1H, t, J=3.4 and 1.7 Hz, Ar—H), 10.59 (1H, brs, NH).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:41]([O:40][C:38](=[O:39])[CH2:37][O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:6][CH2:7]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (21.1 g) and tetrabutylammonium hydrogen sulfate (1.5 g) in toluene (160 mL) −50% sodium hydroxide (160 mL) was added dropwise tert-butyl bromoacetate (20 mL) at 50° C., and the mixture was stirred at 50° C. for 1.5 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate and then neutralized with 6M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as an amorphous pale-yellow solid (24.4 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH2:14].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CCCCCCC>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH:14][C:16](=[O:18])[CH3:17]
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1cc(OC)c(OC)cc1NC(C)=O

Procedure:
Commercially available 2-amino-4,5-dimethoxy-benzoic acid methyl ester (3 g, 0.014 mol) and acetic anhydride (4.03 mL, 0.0426 mol) were heated in heptane at 100° C. for 3 hours. After removal of heptane in vaccuo, the crude product of 2-acetylamino-4,5-dimethoxy-benzoic acid methyl ester was obtained and used without further purification. LC/MS: m/z 254 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.CCN=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O.C1(N)CC1>CN(C=O)C>[CH:18]1([NH:19][C:8](=[O:10])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:16][CH2:17]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(O)cc1

Procedure:
4-Hydroxybenzenecarboxylic acid was stirred with WSC hydrochloride, HOBt hydrate and cyclopropylamine in DMF at room temperature to obtain N-cyclopropyl-4-hydroxybenzamide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=[O:8].I[CH:10]([CH3:12])[CH3:11].O>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH:10]([CH3:12])[CH3:11])[C:6]=1[CH:7]=[O:8]
Reactant: CC(C)I
Reactant: Cc1nc[nH]c1C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncn(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 4-methyl-1H-imidazole-5-carbaldehyde (5.0 g, 45.4 mmol) in anhydrous THF (50 mL) was added diaza(1,3)bicyclo[5.4.0]undecane (DBU, 6.8 mL, 45.4 mmol) and 2-iodopropane (4.5 mL, 45.4 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added. The mixture was extracted with EtOAc (1×50 mL) and 2-butanol (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-2% MeOH/DCM), affording 4-methyl-1-(propan-2-yl)-1H-imidazole-5-carbaldehyde (691 mg, 10% yield).
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[CH:11]([OH:13])[CH3:12].CC(C1C=CC2C(=CC=CC=2)C=1)=O.C1C2C(=CC=CC=2)C=CC=1[C@H](O)C>>[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@@H:11]([OH:13])[CH3:12]
Reactant: CC(O)c1ccc2ccccc2c1
Agent: CC(=O)c1ccc2ccccc2c1
Agent: C[C@@H](O)c1ccc2ccccc2c1
Product: C[C@H](O)c1ccc2ccccc2c1
Yield: 50 %

Procedure:
In Example 3, the biochemical conversion reaction of immobilized buckwheat protein for the substrate (±)-1-(2-naphthyl)ethanol (200 mg) required 4 days by going through bioconversion to 2-acetonaphthone accompanying sterically selective oxidation of (R)-1-(2-naphthyl)ethanol to obtain 100 mg of (S)-1-(2-naphthyl)ethanol at a yield of 50% and optical purity of 99% e.e. or higher. In Example 4, as a result of reacting with the substrate (±)-1-(2-naphthyl)ethanol by continuously recycling immobilized buckwheat protein used in this fourth step from the third step, optically active (S)-1-(2-naphthyl)ethanol was obtained at an optical purity of 99% e.e. or higher by going through a conversion mechanism which sterically selectively converts (R)-1-(2-naphthyl)ethanol to 2-acetonaphthone in the same manner as the first round. Continuous recycling of immobilized buckwheat protein maintained effectiveness for at least three rounds, and there were no changes observed in reaction time, chemical yield or optical purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]([CH3:14])([CH3:13])[CH3:12].CN(C)CCN(C)C.C([Li])CCC.[I:28]I>CCOCC.O1CCCC1>[CH3:10][O:9][C:6]1[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[I:28]
Reactant: II
Reactant: COc1ccc(OC)c(C(C)(C)C)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C)c(OC)cc1I
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3.00 g (15.5 mmol) of 1,4-dimethoxy-2-t-butyl-benzene (obtained by methylation of t-butyl hydroquinone with sodium hydride and methyl iodide in tetrahydrofuran) and 2.52 g (21.7 mmol) of tetramethylethylenediamine in 50 mL of anhydrous ether under nitrogen is cooled to 0° C. and 8.66 mL (21.7 mmol) of n-butyllithium (2.5 M in hexane) is added over a 5 minute period. The mixture is warmed to 22° C., stirred for 18 hours and then cooled back to 0° C. The reaction is quenched with 7.86 g (30.9 mmol) of iodine in 30 mL of tetrahydrofuran and partitioned between ethyl acetate (200 mL) and 10% NaHSO3 (300 mL). The organic layer is washed with water (50 mL), brine (50 mL), dried (MgSO4) and evaporated to give a brown, partially crystalline oil which is chromatographed on silica gel (eluting with 98:2 hexane/ethyl acetate) to give crude product which is recrystallized from hexane to obtain 2,5-dimethoxy-4-t-butylphenyl iodide m p 80.5-82.5° C.)
Reaction SMILES: [CH:1]1([N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)=[O:20].C(NC(C)C)(C)C>CN(C)C=O>[F:37][C:35]([F:36])([F:38])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:19]([N:15]3[CH2:16][CH2:17][CH:12]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH2:5][C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:13][CH2:14]3)=[O:20])=[CH:23][CH:24]=2)=[N:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: c1cncc(CN(C2CCNCC2)C2CC2)c1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2cccnc2)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-piperidin-4-yl-pyridin-3-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (26%, light brown solid). HPLC-MS m/z=(M+1) 513.3, Rt: 2.64 min.
Reaction SMILES: [CH2:1]([C@H:8]([NH2:23])[CH2:9][N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([C@H:8]([NH:23][C:37]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:38])[CH2:9][N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccsc1C1=CCN(C[C@@H](N)Cc2ccccc2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccsc1C1=CCN(C[C@H](Cc2ccccc2)NC(=O)C2CCCCC2)CC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A magnetically stirred solution of 0.5 g (1.52 mmol) of (1S)-1-Benzyl-2-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethylamine and 0.42 ml (3.04 mmol) of triethylamine in 30 ml of dry dichloromethane was cooled in an ice bath under a dry nitrogen atmosphere. A solution of 0.25 g (1.67 mmol) of cyclohexane carbonyl chloride in 6 ml of dry dichloromethane was added dropwise over 10 minutes. The resulting solution was stirred at 4° C. for 1 hour and then the ice bath was removed and stirring was continued overnight (app. 18 hours), during which time the reaction came up to room temperature. TLC on silica gel (4% methanol/dichloromethane) revealed the absence of starting material and a new product (Rf=0.5). The reaction was concentrated on a rotary evaporator and partitioned between 75 ml of ethyl acetate and 50 ml of 1N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The resulting oil was purified by flash chromatography on silica gel (4% methanol/dichloromethane) to give 0.34 g of the desired (S)-cyclohexanecarboxylic acid {1-benzyl-2-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-amide as oil which hardened upon exposure to vacuum. The compound was converted to its monofumerate·1.25 hydrate salt, yield=0.35 g (41%); mp=194-196° C.; [a]D25 =+5.86 (EtOH, c=0.5).
Reaction SMILES: [Br:1][CH:2]([Br:16])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH3:17][Si:18]([CH3:22])([CH3:21])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OC)(C)(C)C>[Br:1][CH:2]([Br:16])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:20][CH2:19][Si:18]([CH3:22])([CH3:21])[CH3:17])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: C[Si](C)(C)CN
Reactant: O=C(O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CNC(=O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
4-(dibromomethyl)-3-(trifluoromethyl)benzoic acid (18.0 g, 49.7 mmol) was suspended in CH2Cl2. 1-(Trimethylsilyl)methanamine (5.1 g, 49.7 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.5 g, 54.7 mmol) were added to the solution at 0° C. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with t-BuOMe and washed with 2M HCl, H2O, and brine. After drying over MgSO4 and evaporation, the product was found to be 22.0 g (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][C:13]1[NH:14][O:15][C:16](=[O:18])[CH:17]=1>C(=O)(O)[O-].[Na+]>[CH3:12][C:13]1[N:14]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[O:15][C:16](=[O:18])[CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1cc(=O)o[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(=O)on1C(=O)c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 237.4 %

Procedure:
20.9 gm of 2,4-dichlorobenzoyl chloride was added to 5 gm of 3-methyl-3-isoxazolin-5-one. The reaction mixture was heated at 150° C. for 3 hours. The reaction was neutralized with 100 ml of saturated sodium bicarbonate solution and extracted with methylene chloride. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was stripped to yield 32.6 gm of the crude product. The product was recrystallized from methylene chloride-hexane yielding 6.4 gm, m.p. 137°-139° C.
Reaction SMILES: COC(=O)C([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)NC(=O)CN(S(C1C=CC(C)=CC=1)(=O)=O)C.[Na].[C:30]([NH:33][CH:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])[CH3:31].Cl.N1C=CC(CCl)=CC=1>CCO>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:34]([NH:33][C:30](=[O:32])[CH3:31])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:23][CH:24]=1
Reactant: COC(=O)C(Cc1ccncc1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: ClCc1ccncc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccncc1)(NC(C)=O)C(=O)OCC

Procedure:
N-(Toluene-4-sulfonyl)sarcosyl-β-(pyrid-4-yl)-D,L-alanine methyl ester was employed in this reaction and was prepared as follows. Sodium metal (2 eq.) was dissolved in EtOH containing diethyl acetamidomalonate (1 eq.) and 4-picolylchloride hydrochloride (1 eq.). The mixture was heated to reflux for 6 hr, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up into saturated aq NaHCO3 and extracted with EtOAc. The solvent was removed and the residue purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to give diethyl 2-(4-pyridylmethyl)-2-acetamidomalonate.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:22])[CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.Cl[CH2:31][C:32]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[O:34][N:33]=1>C(O)(C)(C)C>[CH3:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:22])[CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:31][C:32]4[CH:36]=[C:35]([C:37]5[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:41][CH:42]=5)[O:34][N:33]=4)[CH2:20][CH2:21]3)=[CH:8][C:6]=2[N:7]=1
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Cc1nc2cc(OCC(O)CN3CCN(Cc4cc(-c5ccc(C(F)(F)F)cc5)on4)CC3)ccc2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol hydrochloride (50 mg) in t-butanol at room temperature was added triethylamine (60 μl), and the mixture was stirred at room temperature for 5 minutes. To this mixture was added 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazole (26 mg), and the mixture was stirred at 100° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of methanol, and purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to afford 1-(2-methylbenzothiazol-5-yloxy)-3-[4-({5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methyl)piperazinyl]propan-2-ol, a compound of Formula I.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:39]=[CH:40][CH:41]=1)[C:15]([NH:17][CH2:18][C:19]1[C:20]([NH:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:21]2[CH:29]=[N:28][N:27]([CH2:30][CH3:31])[C:22]2=[N:23][C:24]=1[CH2:25][CH3:26])=[O:16])=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:30]([N:27]1[C:22]2=[N:23][C:24]([CH2:25][CH3:26])=[C:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]3[CH:39]=[CH:40][CH:41]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])[CH:13]=3)[C:20]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:21]2[CH:29]=[N:28]1)[CH3:31]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(NC(=O)CCCCCCCBr)c1
Reactant: CNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(NC(=O)CCCCCCCN(C)CCO)c1
Temperature: 60 °C

Procedure:
A solution of 3-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (42 mg, 0.067 mmol, e.g. which can be as prepared in Intermediate 47) in N,N-dimethylformamide (3 ml) was treated with 2-(methylamino)ethanol (0.011 ml, 0.13 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.0235 ml, 0.13 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (33 mg). LCMS showed MH+=622; TRET=2.21 min.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[C:13]12([CH2:23][NH2:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(C(CC)CN)C>>[C:13]12([CH2:23][NH:24][C:2]3[N:12]=[CH:11][CH:10]=[CH:9][C:3]=3[C:4]([OH:6])=[O:5])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CCC(CC)CN
Product: O=C(O)c1cccnc1NCC12CC3CC(CC(C3)C1)C2

Procedure:
The title compound was prepared according to the procedure of Example 3A substituting 2-chloronicotinic acid for ethyl 2-chloronicotinate and 1-adamantanemethylamine for 2-ethylbutylamine (0.185 g, 79%). MS (ESI+) m/z 287.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.74 (m, 12H), 2.00 (s, 3H), 3.31 (m, 2H), 6.60 (dd, J=7.35, 5.52 Hz, 1H), 7.96 (dd, J=5.33, 2.02 Hz, 1H), 8.26 (dd, J=7.35, 1.84 Hz, 1H).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([F:34])=[C:10]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29]C)=[O:28])[CH:25]=4)[C:20]([CH:31]([OH:33])[CH3:32])=[CH:19]3)=[N:16][CH:17]=2)[CH:11]=1)[CH3:5]>C1COCC1.O>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([F:34])=[C:10]([C:12]2[CH:17]=[N:16][C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=4)[C:20]([CH:31]([OH:33])[CH3:32])=[CH:19]3)=[N:14][CH:13]=2)[CH:11]=1)[CH3:5]
Reactant: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)OC)cc43)nc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)O)cc43)nc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Lithium hydroxide monohydrate (33 mg, 0.786 mmol) was added to an ice-cooled suspension of 331d) (0.22 g, 0.524 mmol) in THF/water (1:1, 10 mL) and the resulting mixture was stirred at room temperature for 48 h. The THF was distilled off and the residue was diluted with water (5 mL) and acidified with saturated sodium hydrogen sulfate solution. A precipitating solid was filtered off and washed with water. Remaining humidity was removed by repeated azeotropic distillation of toluene. White solid. Yield: 0.17 g (80% of theory)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>C(#N)C>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:11]2[S:10][CH2:16][C:14](=[O:15])[N:13]=2)=[N:4][CH:5]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1cnc(CN)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cnc(CNC2=NC(=O)CS2)cn1
Temperature: 0 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
To a solution of 2-(aminomethyl)-5-methyl-pyrazine (3.69 g, 30 mmol) and Rhodanine (3.59 g, 27 mmol) in acetonitrile (100 mL) was added DIPEA (10.45 mL, 60 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (8.15 g, 30 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in acetonitrile (25 mL) at hot condition. After cooling in the refrigerator overnight, the solids were collected by filtration and washed with acetonitrile. After drying in air, 1.5 g (25% yield) of 2-[(5-methyl-pyrazin-2-ylmethyl)-amino]-thiazol-4-one was isolated as a white solid: HRES(+) m/e calcd for C9H10N4OS (M+H)+223.0648, found 223.0648.