Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:16]=[CH:15][C:7]2=[CH:8][C:9]3[C:14]([N:6]2[N:5]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=O.[CH2:17]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][O:19][CH2:18]1.CN1CCCC1=O>CO.ClCCl>[N:22]1([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:4]3[N:16]=[CH:15][C:7]4=[CH:8][C:9]5[C:14]([N:6]4[N:5]=3)=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:27][CH:28]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)c1ncc2cc3ccccc3n2n1
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)cc1cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Temperature: 145 °C
Yield: 0 %

Procedure:
Into a 30 ml, vial 2-methanesulfinyl-[1,2,4]triazino[1,6-a]indole (50.00 mg, 0.216 mol), 4-(4-morpholino)aniline (84.8 mg, 0.476 mol), and N-methylpyrrolidinone (0.10 mL) were combined and heated at 145° C. for 2 hours. The reaction was cooled to room temperature and the product was isolated by flash chromatography (ISCO, Silicagel, methanol/dichloromethane 0-10%) to provide (4-morpholin-4-yl-phenyl)-[1,2,4]triazino[1,6-a]indol-2-yl-amine as a brown solid (14 mg, 19%). MP: 205-210° C.; 1H-NMR (CDCl3) δ 9.00 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.42 (m, 1H), 7.31 (m, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.94 (s, 1H), 6.80 (s, 1H), 3.89 (m, 4H), 3.16 (m, 4H); LC/MS (ESI+): 346.7 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Li].C([Li])(C)(C)C.[CH:31](=[O:33])[CH3:32]>C(OCC)C.O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10]([CH:31]([OH:33])[CH3:32])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Reactant: CC=O
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(NC(=O)OC(C)(C)C)ccc1NC(=O)OC(C)(C)C
Temperature: 20 °C
Yield: 85.1 %

Procedure:
3.3 g (0.01 mol) (4-tert.butoxycarbonylamino-3-bromophenyl)carbamic acid-tert.-butyl ester are dissolved in 200 ml diethyl ether under argon. Then first 20 ml of a 1.6 molar methyl lithium solution are added at −25° C. and then 16 ml of a 1.6 molar tert.-butyl lithium solution are added. After one hour 1.2 ml (0.02 mol) of acetaldehyde are added and the reaction mixture is slowly heated to 20° C. After halting the reaction the reaction mixture is hydrolyzed with water, the organic phase is extracted with dilute sodium hydroxide and then dried with magnesium sulfate. The solvent is distilled off in a rotary evaporator and the residue is purified with petroleum ether/acetic acid ethyl ester (8:2). 3.0 g (85% of theoretical) of (4-tert.-butoxycarbonylamino-3-(1-hydroxyethyl)phenyl)carbamic acid-tert.-butyl ester having a melting point of 189° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Mg].Cl[C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13]C=1.C1(=O)CCCC1.Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH2:14][CH2:15][CH2:16][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: Clc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: O=C1CCCC1
Solvent: CCOCC
Product: Clc1ccc(C2=CCCC2)cc1
Reaction time: 8 h

Procedure:
From 575 g of p-chlorophenyl bromide and 78 g of magnesium turnings in 2.6 liters of anhydrous ether was prepared p-chlorophenyl magnesium bromide to which was added dropwise a solution of 252 g of cyclopentanone in 1 liter of ether. The mixture was stirred overnight and was decomposed by careful addition of dilute hydrochloric acid. The organic phase was separated, washed and dried, and the solvent was evaporated. The resulting solid was recrystallized from ethanol to give 316 g of 1-(p-chlorophenyl)cyclopentene, M.P. 71°-73° C., which was dissolved in 2.9 liters of acetic acid containing 6 ml of concentrated sulfuric acid. To this solution 133 g of 50% hydrogen peroxide was added dropwise during which time the reaction temperature was maintained at 30° to 35° C. The reaction mixture was stirred overnight after which water was added and the product was extracted into ether. The extract was washed, dried and the solvent evaporated leaving crude 2-(p-chlorophenyl)cyclopentanone which was distilled, B.P. 135°-154° C. (0.1 mm) yielding 140 g. The oxime, M.P. 154°-155° C. was reduced using Raney nickel in alcoholic ammonia to give 2-(p-chlorophenyl)cyclopentylamine which was subsequently converted to the hydrochloride salt, M.P. 226°-228° C. Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride, an appropriate amount of 2-(p-chlorophenyl)cyclopentylamine hydrochloride, the desired product was obtained, M.P. 253°-255° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:15])[CH:12]([Cl:14])[CH3:13].[Li+].[OH-].O.Cl>C1COCC1.CCOC(C)=O>[Cl:14][CH:12]([CH3:13])[C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:16])=[O:2])=[O:15]
Reactant: COC(=O)c1ccccc1NC(=O)C(C)Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Cl)C(=O)Nc1ccccc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To the 2-(2-chloro-propionylamino)-benzoic acid methyl ester (7.75 g, 32.1 mmol) stirring in THF (40 mL) was added 1M LiOH/H2O (40 mL). The reaction was allowed to stir at 50° C. for 3 h. After this period the reaction was concentrated under vacuum to afford a crude residue that was acidified with 1N HCl. The resulting suspension was then diluted with EtOAc and washed with water (3×50 mL). The organic layer was then washed with brine (25 mL), dried over MgSO4, and concentrated under vacuum to afford crude acid. The crude material was purified by flash chromatography (silica gel, 80% EtOAc/Hex) to afford the desired product as an off white solid (7.1 g, 97% yield). 1H-NMR (CDCl3): δ 8.6 (d, 1H), 8.12 (d, 1H), 7.61 (t, 1H), 7.57 (t, 1H), 4.89 (br, 1H), 4.65 (t, 1H), 1.78 (d, 3H).
Reaction SMILES: [CH2:1]1[C:6](=O)[CH2:5][CH2:4][N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2]1.Cl.[CH2:16]([NH2:18])[CH3:17].[C-:19]#[N:20].[K+].C(O)(C)C>C(O)C.O>[CH2:8]([N:3]1[CH2:4][CH2:5][C:6]([NH:18][CH2:16][CH3:17])([C:19]#[N:20])[CH2:1][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [C-]#N
Reactant: CCN
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: CCNC1(C#N)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 4-N-benzylpiperidone (5.69 g, 29.5 mmol) in ethanol (4.2 ml) cooled in an ice bath was added ethylamine hydrochloride (2.69 g, 32.3 mmol) in water (3 ml), keeping the internal temperature of the reaction below 10° C. A solution of KCN (2.04 g, 31.3 mmol) in water (7 ml) was added to the reaction solution over 10 minutes while keeping the internal temperature below 10° C. The reaction was then warmed to room temperature and stirred 18 hours. Isopropanol (10 ml) was added to the reaction mixture to give two distinct layers: lower colorless aqueous layer and an orange organic upper layer. The organic layer was separated and stirred with water (30 ml) for 30 minutes. The organic layer was separated (orange organic layer now the bottom layer), the solvent was removed in vacuo, and the resultant oil diluted in methylene chloride (30 ml). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated, in vacuo, to give I-1A-1e as an orange oil (6.05 g, 84%): +APcI MS (M+1) 244.2; 1H NMR (400 MHz, CD2Cl2) δ 7.32 (d, J=4.1 Hz, 4H), 7.29–7.23 (m, 1H), 3.54 (s, 2H), 2.81–2.76 (m, 2H), 2.75 (q, J=7.1 Hz, 2H), 2.35–2.29 (m, 2H), 2.01–1.98 (m, 2H), 1.74–1.68 (m, 2H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:16]=[C:17]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])[N:18]=[CH:19][C:14]=3[N:13]([CH3:32])[C:12](=[O:33])[CH:11]3[CH:7]2[CH2:8][CH2:9][CH2:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[NH2:80][CH:81]1[CH2:86][CH2:85][N:84]([CH3:87])[CH2:83][CH2:82]1>O.CN(C)C=O>[CH:7]1([N:6]2[C:15]3[N:16]=[C:17]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:80][CH:81]5[CH2:86][CH2:85][N:84]([CH3:87])[CH2:83][CH2:82]5)=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])[N:18]=[CH:19][C:14]=3[N:13]([CH3:32])[C:12](=[O:33])[CH:2]3[CH:1]2[CH2:5][CH2:4][CH2:3]3)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C1CCCC1C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)C1CCCC1C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a mixture of 0.277 g (0.00061 mole) of (rac)-4-(4-cyclopentyl-9-methyl-10-oxo-1,2,3,3a,4,9,10,10a-octahydro-4,5,7,9-tetraaza-benzo[f]azulen-6-ylamino)-3-methoxy-benzoic acid, 0.129 g (0.00092 mole) of 1-hydroxy-1H-benzotriazole, 0.505 g (0.00092 mole) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 0.404 g (0.00306 mole) of ethyldiisopropylamine and 40 mL of dimethylformamide was added 0.150 g (0.00092 mole) of 4-amino-1-methyl piperidine. The mixture was stirred overnight at room temperature, then diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed successively with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Waters X-terra column), eluting with a gradient of acetonitrile −0.004 M aqueous ammonium acetate to give 0.070 g of (rac)-4-(4-cyclopentyl-9-methyl-10-oxo-1,2,3,3a,4,9,10,10a-octahydro-4,5,7,9-tetraaza-benzo[f]azulen-6-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-68) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([Mg]Br)=[N:6][CH:7]=1.C1C[O:13][CH2:12]C1.CN(C=O)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc([Mg]Br)nc1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C=O)nc1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To the 0.25 M 5-methyl-2-pyridinylmagnesium bromide of THF solution (20 mL, 5 mmol), DMF (0.773 mL, 10 mmol) was added at room temperature under argon. The reaction mixture was stirred for 10 min. and concentrated in vacuo. The residue was quenched with saturated ammonium chloride and dichloromethane. The organic layer was dried and the product was purified by silica gel column chromatography with 20% ethyl acetate in hexanes to give 379 mg (62.6%) of the title compound. GC-MS (M+): 121.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:34])([F:33])[C:26]1[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:29]4[CH:30]=[N:31][C:26]([C:25]([F:34])([F:24])[F:33])=[CH:27][CH:28]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(C(F)(F)F)nc4)ncnc32)CC1
Yield: 21.5 %

Procedure:
4-[4-(6-Trifluoromethyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 22%) was prepared using the procedure described for the preparation of Example 96, by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol) with 6-trifluoromethyl-pyridin-3-ol (Matrix Scientific, Columbia, S.C., USA; 31 mg, 0.19 mmol) in the presence of potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL). Mass spectrum (ES) MH+=465. HRMS Calcd. for C21H24F3N6O3 (MH+): 465.1857. Found: 465.1857.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1C2C=NC(C(OC)=O)=CC=2C2C1=CC=CC=2)C1C=CC=CC=1>C1COCC1.CN(C=O)C>[CH2:21]([N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: COC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Ethyl β-carboline-3-carboxylate 10 (4.8 g, 20 mmol), DMF (100 ml) and THF (100 ml) were respectively added in a 100 ml round-bottom flask, and were stirred at room temperature for 15 minutes, then 60% NaH (2.4 g, 60 mmol) was added and stirred until there were no bubbles formed. Benzyl bromide (15 ml) was added, and the mixture was refluxed for 12 h. Later the mixture was treated in a manner similar to that described for compound 29 to afford white crystals (4.6 g, 70%), mp 126-127° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][O:27][CH:28]=1)CCC>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:23]3[O:24][CH2:25][CH2:26][O:27][CH:28]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=COCCO1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Product: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)OCCO1

Procedure:
Prepared in analogy to Example A49(a) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and tributyl-(5,6-dihydro-[1,4]dioxin-2-yl)-stannane. Light brown solid. MS (m/e): 294.4 ([M+H]+, 100%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4]Br.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][N:17]=[N+:18]=[N-:19]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A mixture of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienyl bromide (1.5 g, 5.26 mmol) and sodium azide (0.68 g, 10.5 mmol) in DMF (20 mL) was stirred at room temperature for 0.5 hours, then poured into cold water and extracted with ether. The ethereal extract was washed with brine, dried, filtered and evaporated to yield a residue. Purification of the residue by flash chromatography on a silica gel column, using hexane as the eluant, afforded the title compound as an oil (1.2 g, 4.85 mmol, 92%) NMR (CDCl3): δ5.35 (H, t, J=7Hz), 5.10 (2H, m), 3.78 (2H, d, J=7Hz), 1.9-2.2 (8H, m), 1.72 (3H, s), 1.68 (3H, s) 1.60 (6H, s).
Reaction SMILES: [Se].[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[O:14]1CCOCC1>>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: C1COCCO1
Agent: [Se]
Product: O=Cc1ccc2cc(Br)ccc2n1
Temperature: 25 °C

Procedure:
Selenium dioxyde (1.3 g, 12 mmol, 1.3 eq) in suspension in dioxane (50 mL) was heated at 60° C. 6-bromoquinaldine (2 g, 9 mmol) was then introduced and the mixture was left to react at 80° C. for 3 hours. After cooling to room temperature, the mixture was filtered on celite, eluted with dioxane and concentrated under reduced pressure. The product obtained is a pure white solid (3.3 g, >98%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:17]=[C:16]([CH2:18][CH3:19])[NH:15][N:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[CH2:20]([NH:22][C:23]([N:15]1[C:16]([CH2:18][CH3:19])=[CH:17][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][N:4]=2)=[N:14]1)=[O:24])[CH3:21]
Reactant: CCN=C=O
Reactant: CCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1CC
Yield: 23 %

Procedure:
Reaction of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole with ethyl isocyanate was carried out in the same manner as in Example 164, to give a white solid of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole-1-carboxamide (0.25 g, yield: 23.0%). mp: 85-86° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 1.30 (t, J=7.5 Hz, 3H), 3.13 (q, J=7.5 Hz, 2H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 6.08 (s, 1H), 6.90-7.15 (m, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.37 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8]C[CH2:10][CH2:11][O:12][C:13]2[CH:20]=CC(C=O)=C[CH:14]=2)ON=1.NCCS.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1>C1(C)C=CC=CC=1>[C:11]([O:12][CH:13]([CH3:20])[CH3:14])(=[O:32])[CH3:10].[CH3:8][CH2:7][CH2:5][CH2:6][CH2:2][CH3:1]
Reactant: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: NCCS
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)C
Product: CCCCCC

Procedure:
A solution of 4.00 g of 4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde (part a above), 1.22 g of 2-aminoethanethiol and a trace of p-toluenesulfonic acid in 30 ml of toluene was heated at reflux for 2 hours using a Dean-Stark trap. The product was isolated and recrystallizedfrom isopropyl acetate-hexane to give 1.93 g of the above-indicated product, m.p. 82°-84° C.
Reaction SMILES: [C:1]([O:5][CH:6](Cl)[CH3:7])(=[O:4])[CH2:2][CH3:3].[CH:9]([O:22][C:23]([CH2:25][O:26][N:27]=[C:28]([C:44]1[N:45]=[CH:46][S:47][CH:48]=1)[C:29]([NH:31][CH:32]1[C:42](=[O:43])[N:34]2[C:35]([C:39]([OH:41])=[O:40])=[CH:36][CH2:37][S:38][C@H:33]12)=[O:30])=[O:24])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH:9]([O:22][C:23]([CH2:25][O:26][N:27]=[C:28]([C:44]1[N:45]=[CH:46][S:47][CH:48]=1)[C:29]([NH:31][CH:32]1[C:42](=[O:43])[N:34]2[C:35]([C:39]([O:41][CH:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH3:7])=[O:40])=[CH:36][CH2:37][S:38][C@H:33]12)=[O:30])=[O:24])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1cscn1)OC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3cscn3)C(=O)N12
Temperature: 40 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
1-Chloroethyl propionate (0.6 g) was added to the mixture of 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) in dimethyl sulfoxide (13 ml) and potassium carbonate (0.3 g) and the mixture was stirred for 2 hours at 40° C. The reaction mixture was added to the mixture of ice-water and ethyl acetate and the mixture was adjusted to pH 7.5 with 20% aqueous solution of potassium carbonate. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated to give 1-propionyloxyethyl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylate (syn isomer) (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22]=[O:23])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][CH:12]=2.O1CCC[CH2:25]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22]([OH:23])[CH3:25])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:13][CH:12]=2
Reactant: C1CCOC1
Reactant: O=Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring heterogeneous mixture of 3-(2-chlorophenyl)-5-(trifluoromethyl)-quinoxaline-2-carbaldehyde (0.2129 g, 0.632 mmol) in tetrahydrofuran (6.32 mL, 0.632 mmol) was added methylmagnesium bromide 3 M in diethyl ether (0.632 mL, 1.90 mmol) dropwise at 0° C. (started at 11:20 am), and the mixture was then stirred at room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown syrup. The brown syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (1 H, d, J=8.6 Hz), 8.31 (1 H, d, J=7.0 Hz), 8.05 (1 H, t, J=8.0 Hz), 7.48-7.71 (4 H, m), 5.33 (1 H, br. s.), 4.84 (1 H, br. s.), 1.28-1.55 (3 H, m); LC-MS (ESI) m/z 353.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][NH2:11].Cl[C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][NH:11][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCC#Cc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C(#Cc1ccccn1)CCNc1nc2ccccc2s1
Temperature: 120 °C
Yield: 94.7 %

Procedure:
4-(pyridin-2-yl)but-3-yn-1-amine (640 mg, 4.40 mmol), 2-chlorobenzo[d]thiazole (373 mg, 2.2 mmol) and DIEA (452 μL, 2.64 mmol) were poured into DMF (2.2 mL) and the resulting solution was heated two days at 120° C. The solvent was removed under reduce pressure and the crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 70/30 as eluent) to afford 582 mg of N-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazol-2-amine (Yield: 95%) as a brownish oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>ClCCl>[S:13]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: OCCCCCOc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCOc2ccccn2)cc1
Reaction time: 4 h
Yield: 54.6 %

Procedure:
5 ml of pyridine and 7 g of p-toluenesulfonyl chloride were added to a solution of 6.5 g of the compound obtained in Example 3a in 20 ml of dichloromethane and then the mixture was stirred for 4 hours. The organic layer was washed with 10% aqueous citric acid and then with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 6.57 g of the title compound (yield: 53%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][NH2:17]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:17][CH2:16][CH2:15][O:14][CH3:13])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:17][CH2:16][CH2:15][O:14][CH3:13])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: COCCN
Product: COCCNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added in portions to 180 ml of 2-methoxyethylamine heated to 80° C., with stirring. Heating is continued for 2 hours 30 minutes after the addition is complete. The reaction medium is diluted with 180 ml of ice-cold water. The product expected precipitates. It is drained, washed with water and dried under vacuum at 60° C. in the presence of phosphorous pentoxide. Recrystallized from 96° ethanol, it melts at 90° C.