Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:33]([CH3:34])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8]([OH:10])=O)=[CH:4][C:3]=1[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:65]1[CH2:70][CH2:69][CH:68]([N:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[OH:1][C:2]1[C:3]([CH3:35])=[CH:4][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)=[O:31])[C:8]([N:74]2[CH2:73][CH2:72][N:71]([CH:68]3[CH2:69][CH2:70][O:65][CH2:66][CH2:67]3)[CH2:76][CH2:75]2)=[O:10])=[CH:32][C:33]=1[CH3:34]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 70 mg (0.15 mmol) (S)-2-(4-hydroxy-3,5-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid, 52 mg (0.15 mmol) TBTU and 25 μL (0.18 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 25 mg (0.15 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added to the reaction mixture, which was then stirred for a further 16 h at RT. The reaction mixture was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [Br:1][CH:2]1[N:6](C(C)C)[C:5]([C:10]([OH:12])=O)=[CH:4][S:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:10]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:12])[N:6]=1
Reactant: CC(C)N
Reactant: CC(C)N1C(C(=O)O)=CSC1Br
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1csc(Br)n1

Procedure:
The product was prepared from 2-bromo-N-(1-methylethyl)-1,3-thiazole-4-carboxylic acid (WO 9848799) (0.77 g), carbonyldiimidazole (0.66 g) and isopropylamine (0.24 g) using the method of example 115 step (i). Yield 0.82 g.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[N:22]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[N:22]1[C:23]2[C:28](=[N:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:17][CH2:18]3)[C:8]2=[O:19])[CH2:4]1
Reactant: Clc1ccc2ncccc2n1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2ccc3ncccc3n2)C1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.133 g, 0.472 mmol), 2-chloro-1,5-naphthyridine (0.100 g, 0.608 mmol) and DMSO (2 mL). N,N-Diisopropylethylamine (0.250 mL, 1.437 mmol) was added and the reaction mixture was sealed under argon and heated at 100° C. for 59 h. The reaction was cooled to room temperature and partitioned between water/DCM. The aqueous layer was extracted with DCM (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (25 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→1:19) to give 67 mg (34%) of a white crystalline solid. ESI-MS 374.0 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (dd, J=4.30, 1.56 Hz, 1 H), 8.00 (d, J=3.33 Hz, 1 H), 7.97 (d, J=3.33 Hz, 1 H), 7.93 (d, J=9.19 Hz, 1 H), 7.81-7.89 (m, 2 H), 7.46 (dd, J=8.41, 4.11 Hz, 1 H), 7.02 (d, J=9.19 Hz, 1 H), 5.21 (m, 1 H), 4.64-4.76 (m, 1 H), 3.25-3.38 (m, 2 H), 2.91-3.02 (m, 1 H), 2.34-2.45 (m, 2 H), 0.94-1.11 (m, 4 H)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([N+:26]([O-])=O)=[CH:18][CH:17]=1>>[CH3:3][C:2]1([CH3:11])[NH:26][C:19]2[C:20]3[C:25]([C:16]([N:15]=[N:1][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[CH:5]=[CH:4][C:3]=4[N+:12]([O-:14])=[O:13])=[CH:17][CH:18]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[NH:1]1
Reactant: Nc1c([N+](=O)[O-])ccc2ccccc12
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Product: CC1(C)Nc2cccc3c(N=Nc4c([N+](=O)[O-])ccc5ccccc45)ccc(c23)N1

Procedure:
In the manner described in Example 8, substituting 9.5 grams of 1-amino-2-nitronaphthalene for the 1-amino-4-nitronaphthalene, the desired compound is obtained.
Reaction SMILES: [Mg].[C:2](Br)([CH3:5])([CH3:4])[CH3:3].[CH:7]([C:10]1[C:18]([CH:19]=[O:20])=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1)([CH3:9])[CH3:8].[Cl-].[NH4+]>CCOCC.C1C=CC=CC=1>[CH:7]([C:10]1[C:18]([CH:19]([OH:20])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1nn2ccccc2c1C=O
Reactant: CC(C)(C)Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)c1nn2ccccc2c1C(O)C(C)(C)C
Yield: 52 %

Procedure:
To a suspension of 1.6 g of magnesium in 10 ml of dry ether was added a solution of 9.3 g of tert. butylbromide in 15 ml of dry ether under stirring. After the addition was completed, the stirring was continued for an hour at room temperature. To the Grignard reagent were added 2.5 g of 2-isopropyl-3-formylpyrazolo[1,5-a]pyridine in 5 ml of dry benzene under stirring. The mixture was stirred for an hour at room temperature and 11 hours at reflux temperature. The reaction mixture was treated with 100 ml of aqueous 20% ammonium chloride solution and extracted with ether. The ether layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography, eluted with dichloromethane, to give 1.7 g (52%) of pale yellow crystals, mp 95° C.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].CS(C)=O.[C-:15]#[N:16].[K+]>O>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:15]#[N:16])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: [C-]#N
Reactant: C=Cc1ccc(CCl)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 22.2 g 4-vinyl benzylchloride (0.131 mol), 60 mL dimethylsulfoxide, and 12.8 g potassium cyanide (0.196 mol) was stirred at room temperature for 17 hours. The mixture was poured into 500 mL water and extracted several times with ethyl acetate. The combined organic layers were washed with brine and concentrated under vacuum. The crude red oil was purified by column chromatography on silica gel using 7/93 ethyl acetate/hexane to give 4-vinylbenzylcyanide, a yellow oil (18.03 g, 96%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[F:9][C:10]1[C:15]([N:16]([CH3:36])[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[C:20]=2[C:32]([F:35])([F:34])[F:33])=[O:18])=[CH:14][CH:13]=[C:12]([F:37])[C:11]=1[CH2:38][NH3+:39].N1C=CC=CC=1>C1COCC1>[C:1]([NH:39][CH2:38][C:11]1[C:10]([F:9])=[C:15]([N:16]([CH3:36])[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]([F:31])([F:30])[C:26]([F:29])([F:27])[F:28])[C:20]=2[C:32]([F:33])([F:34])[F:35])=[O:18])[CH:14]=[CH:13][C:12]=1[F:37])(=[O:3])[CH3:2]
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1C)c1ccc(F)c(C[NH3+])c1F
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NCc1c(F)ccc(N(C)C(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)c1F
Reaction time: 20 h
Yield: 99.1 %

Procedure:
Acetic anhydride (34 mg, 0.34 mmol, 1.3 eq) in THF (1 ml) was added to a solution of [2,6-difluoro-3-(methyl{[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]methanaminium chloride (130 mg, 0.26 mmol) and pyridine (43 mg, 0.54 mmol, 2.1 eq.) in THF (2.5 ml), and the mixture was left at room temperature for 20 h. After concentration under reduced pressure, the product was purified by column chromatography (hexane/ethyl acetate) to give N-[3-(acetamidomethyl)-2,4-difluorophenyl]-N,1-dimethyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (131 mg, 99%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[C:14]2[CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30]>N1C=CC=CC=1>[C:1]([N:34]1[CH2:35][CH2:36][N:31]([C:29](=[O:30])[CH2:28][CH2:27][C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([Cl:10])[CH:12]=3)[NH:16][C:15]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:32][CH2:33]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
Benzoyl chloride (0.011 mL) was added to a stirred solution of 1-{3-[5-chloro-2-(4-chlorophenyl)-1H -indol-3-yl]-1-oxopropyl}piperazine (Description 30, 35 mg) in pyridine (0.5 mL) and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure, hydrochloric acid (2M, 5 mL) and ethyl acetate (5 mL) were added and the layers were separated. The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was crystallized from dichloromethane/ethyl acetate (4:1) to give the title compound as a colorless solid (25 mg, 58%). 1H NMR (360 MHz, CDCl3) δ2.56-2.68 (2H, m), 3.02-3.67 (10H, m), 7.17 (1H, dd, J 8.6, 1.8 Hz), 7.28 (1H, d, J 8.6 Hz), 7.33-7.50 (9H, m), 7.56 (1H, s), and 8.13 (1H, s). m/z (ES+) 506, 508 (M+1).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C@H:14]([C:16]3O[CH:18]=[CH:19][CH:20]=3)[CH3:15])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH:23]=[CH:22]1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:24](=[O:25])[C:23]4[C:22]([C:21]([OH:26])=[O:27])=[CH:18][CH:19]=[CH:20][C:16]=4[C@@H:14]3[CH3:15])[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](NC1CCN(C2CCCCC2)CC1)c1ccco1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: C[C@H]1c2cccc(C(=O)O)c2C(=O)N1C1CCN(C2CCCCC2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-Cyclohexyl-N-[(1S)-1-(furan-2-yl)ethyl]piperidin-4-amine (0.3 gr, 1.08 mmol) and maleic anhydride (0.13 gr, 1.3 mmol) in toluene (10 mL) were stirred at reflux for 16 hours. Solvent was evaporated and the residue was dissolved in aqueous 37% hydrochloric acid (5 mL) and stirred at 100° C. for 2 hours. Volatiles were evaporated affording crude title product that was used for the next step without further purification
Reaction SMILES: [C-:1]#[N:2].[Na+].CS([C:8]1[N:13]=[C:12]([CH2:14][CH2:15][CH3:16])[CH:11]=[C:10]([Sn:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1)(=O)=O>CS(C)=O>[CH2:14]([C:12]1[CH:11]=[C:10]([Sn:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=[C:8]([C:1]#[N:2])[N:13]=1)[CH2:15][CH3:16]
Reactant: CCCc1cc([Sn](C)(C)C)nc(S(C)(=O)=O)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Sodium cyanide (0.63 g, 12.9 mmol) was added at room temperature to 2-methanesulfonyl-4-propyl-6-trimethylstannanyl-pyrimidine (2.34 g, 6.5 mmol) in DMSO (23 mL). The mixture was stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 9/1) to give 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (1.53 g, 76%) as an off white solid (mp=62° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)(O[C:14]([CH3:18])([CH3:17])[C:15]#[CH:16])OC.C1CCN2C(=NCCC2)CC1>C(#N)C.[Cu]>[CH3:17][C:14]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:18])[C:15]#[CH:16]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)OC(=O)OC
Agent: [Cu]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 23 h

Procedure:
To a solution of 4-cyanophenol (3.0 g, 25.18 mmol) and methyl 1,1-dimethyl-2-propynyl carbonate (3.93 g, 27.64 mmol) in acetonitrile (24 mL) at 0° C. under argon was added DBU (5.0 mL, 33.43 mmol). To the resulting solution at 0° C. was added cuprous chloride (7.47 mg, 0.003 eq., 0.3 mol %) and copper bronze (83 mg). After stirring at 0° C. for 23 hours, the reaction mixture was filtered and the filtrate was diluted with toluene (~400 mL). The resulting solution was washed with 1N HCl (×2), 1N NaOH (×2), and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil (4.18 g). Distillation of the crude material (bulb-to-bulb) afforded the title compound as a colorless, low melting (mp 28°-29° C.) solid (4.02 g).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: CN1CCNCC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)N1CCN(C)CC1
Yield: 100 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.354 g) obtained in Example 9 and N-methylpiperazine (0.119 ml) to give (±)-4-[(3,5-Dichloro-4-pyridyl)aminocarbonyl]-7-methoxy-3-[(4-methylpiperazin-1-yl)carbonylmethyl]-2,3-dihydrobenzofuran (0.427 g, 100%) as an oily substance. The obtained free base was dissolved in ethyl acetate (50 ml), and a saturated solution of hydrochloric acid in ethyl acetate (2 ml) was added thereto followed by stirring. The precipitated hydrochloride was collected by filtration and washed with ethyl acetate to give Compound 17 as a white solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27]Br)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)Oc1cccc(C(=O)N2CCC(CCBr)(c3ccc(C(F)(F)F)cc3)C2)c1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(C(F)(F)F)cc3)C2)c1

Procedure:
Combine 2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-bromide (8 mmol), 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol), K2CO3 (36 mmol), KI (0.8 mmol), and THF/H2O (3/1, 80 mL). Heat at reflux for 72 h. Concentrate in vacuo to remove THF and extract with dichloromethane (2×50 mL). Extract the combined organic layers using water (50 mL). Dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph on silica gel to obtain the title compound.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].Cl.[C:9]([C:17](O)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:2]([NH:6][N:7]=[C:17]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:18])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: O=C(O)C(=O)c1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)(C)NN=C(O)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 296 grams (g) (2.37 mol) of t-butyl hydrazine hydrochloride, 20 milliliters (mL) of concentrated hydrochloric acid (HCl) and 2 liters (L) of water was stirred at room temperature to give a clear solution. Benzoylformic acid (400 g, 2.61 mol) was added in four equal portions at 3 minute intervals. The mixture was stirred overnight at room temperature and filtered. The solid collected was washed with water and dried in vacuo to furnish 520 g (99%) of the compound, mp 138°-139° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[N:4]=1)#[N:2].[CH3:14][CH2:15][O:16][P:17](Cl)([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[P:17]([O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]2)([O:19][CH2:20][CH3:21])([O:16][CH2:15][CH3:14])=[O:18]
Reactant: N#Cc1ccc2cc(O)ccc2n1
Reactant: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)Oc1ccc2nc(C#N)ccc2c1
Yield: 91 %

Procedure:
To the mixture of 2-cyano-6-hydroxyquinoline (0.50 g, 2.94 mmol) and diethyl phosphorochloride (0.67 g, 3.53 mmol) in 15 ml of anhydrous methylene chloride was added triethylamine (0.59 g, 5.88 mmol). The resultant mixture was stirred for 5 hours at room temperature. After removal of the solvent, the product was purified by flash chromatography using heptane/ethyl acetate as eluent in a yield of 91%.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>C(OCC)(=O)C>[Cl:17][S:18]([NH:21][C:22]([N:14]1[CH2:15][C@H:12]([NH:11][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[C:13]1=[O:16])=[O:23])(=[O:20])=[O:19]
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)Cl)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 13.8 g of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 500 ml of ethyl acetate was added 5.63 ml (0.0626 mol) of chlorosulfonyl isocyanate. The mixture was stirred for 1 hour at room temperature to form a solution of (S)-1-[[(chlorosulfonyl)amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The solution was cooled to 0° C., at which temperature a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)2-pyridinecarboxamide (prepared from a suspension of 14.9 g (0.0626 mol) of 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)-2-pyridinecarboxamide in 500 ml of ethyl acetate by the addition of 46.4 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.25 mol) and stirring for 30 minutes) was added slowly. Then 150 ml of dichloromethane was added, and the mixture was stirred at room temperature overnight. To the clear solution was added 26.2 ml of triethylamine (0.188 mol), followed by 300 g of ice and 200 ml of water. The pH was 6.5. After stirring for 11/2hours, the two phases were separated and the aqueous phase was washed with three 200 ml portions of ethyl acetate. After removal of residual ethyl acetate in vacuo, the pH of the aqueous phase was adjusted to 2 by the slow addition of 2N hydrochloric acid (47 ml) with cooling. The crystals were filtered off, suspended in 200 ml of ethyl acetate and stirred for one hour. Then the crystals were filtered off, washed twice with 30 ml of ethyl acetate and twice with 50 ml of petroleum ether and dried in vacuo, to yield 28.6 g of the title compound, melting point 190°-200° C., dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)#[N:22]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:21]#[N:22])[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: N#Cc1ccccc1N1CCNCC1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccc4C#N)CC3)nc2c1
Yield: 94 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 94%). 1H NMR (200 MHz, CDCl3): δ 3.30 (s, 4H), 3.88-3.90 (m, 6H), 4.07-4.20 (m, 4H), 6.94-7.07 (m, 3H), 7.27-7.34 (m, 2H), 7.53-7.63 (m, 3H).
Reaction SMILES: [C:1](Cl)(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])[NH2:24])=[C:14]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:13]=1[OH:38])(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([NH:24][C:1](=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])=[C:14]([CH2:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:13]=1[OH:38])(=[O:11])[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(=O)c1ccc(OCCCOc2cc(N)c(C)cc2Br)c(CCC(F)(F)F)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 12.3 ml of ethyl chlorooxalate in 30 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 43.6 g of 3-{3-[4-acetyl-3-hydroxy-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-aniline and 15.3 ml of triethylamine in 400 ml of methylene chloride in the course of about 5 minutes and the mixture is then stirred at room temperature for a further 90 minutes. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether gives ethyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate.