Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]3[N:24]=[C:25]([C:27]4[C:36]([CH3:37])=[N:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[CH:26]=[C:13]3[N:12]=2)[CH2:7]1)(=O)=O.[F-].[K+]>C(#N)C>[N:8]1([C:11]2[CH:16]=[C:15]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]3[N:24]=[C:25]([C:27]4[C:36]([CH3:37])=[N:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[CH:26]=[C:13]3[N:12]=2)[CH2:7][CH:6]=[CH:10][CH2:9]1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(N3CC[C@H](OS(C)(=O)=O)C3)cc(NC3CCOCC3)n2n1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2ccccc2nc1-c1cc2nc(N3CC=CC3)cc(NC3CCOCC3)n2n1
Temperature: 25 °C

Procedure:
A solution of (35)-1-[2-(3-methylquinoxalin-2-yl)-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidin-3-yl methanesulfonate (50 mg, 0.0955 mmol) 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (108 mg, 0.286 mmol), and potassium fluoride (17 mg, 0.286 mmol) in acetonitrile (2.0 mL) was refluxed for 15 min. After being cooled to ambient temperature, the reaction mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=97:3) to give 5-(2,5-dihydro-1H-pyrrol-1-yl)-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (the compound of Example 1.009 listed in the Table of Examples as described hereinafter). 1H-NMR (400 MHz, CDCl3): δ 1.73-1.82 (2H, m), 2.13-2.16 (2H, m), 3.04 (3H, s), 3.59 (2H, dt, J=11.8, 2.1 Hz), 3.68-3.78 (1H, m), 4.09 (2H, dt, J=11.8, 3.6 Hz), 4.38 (4H, br), 5.17 (1H, s), 5.98 (2H, s), 6.17 (1H, d, J=7.9 Hz), 6.67 (1H, s), 7.69-7.77 (2H, m), 8.03-8.06 (1H, m), 8.17-8.19 (1H, m).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[C:13](N)=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F:27]C1C=CC([C@@H](N)C)=CC=1>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:27])=[CH:12][CH:13]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1N)c1ccc(F)cc1
Reactant: C[C@H](N)c1ccc(F)cc1
Product: C[C@H](Nc1ccc(F)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 185 °C
Yield: 26.8 %

Procedure:
A mixture of N-(5-cyclopropyl-1H-pyrazol-3-yl)-3,6-difluoropyridin-2-amine (Method 31, 0.10 g, 0.42 mmol) and (S)-1-(4-fluorophenyl)ethanamine (0.3 g, 2.2 mmol) were heated to 185° C. under microwave conditions (30 min×3 cycles). The resulting dark oil was purified by column chromatography (DCM-MeOH=80:1) to give the title compound (0.04 g, 26%). 1H NMR (400 MHz, CD3OD) δ 7.08-6.99 (m, 3H), 6.67-6.62 (m, 2H), 6.22 (dd, J=8.9, 2.3 Hz, 1H), 5.04 (s, 1H), 4.64-4.59 (m, 1H), 1.16-1.12 (m, 4H), 0.30-0.14 (m, 3H), 0.04-0.02 (m, 1H). MS: Calcd.: 355. Found: [M+H]+ 356.
Reaction SMILES: [O:1]=[C:2]1[CH:7](OS(C)(=O)=O)[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH:7]3[CH2:6][CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)OC1CCCNC1=O
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)C2CCN(C3CCCNC3=O)CC2)cc1
Temperature: 85 °C
Yield: 31.6 %

Procedure:
To a solution of methanesulfonic acid 2-oxo-piperidin-3-yl ester (250 mg, 1/294 mmol, 1.0 eq) and (4-methoxy-phenyl)-piperidin-4-yl-methanone (312 mg, 1.423 mmol, 1.1 eq) in acetonitrile (2.5 mL) was added diisopropylethylamine (351 mg, 0.475 mL, 2.1 eq) and the reaction was heated at 85° C. for 3 hours. The reaction was cooled to room temperature and the solvent evaporated in vacuo. The resulting oily residue was purified by silica gel column chromatography (MeOH/CH2Cl2) to give the title compound as a clear oil (142 mg, 0.449 mmol, 34.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J=9.09 Hz, 2H) 7.39-7.43 (br. s, 1H) 7.04 (d, J=8.59 Hz, 2H) 3.84 (s, 3H) 3.23-3.33 (m, 2H) 2.97-3.14 (m, 4H) 2.74-2.85 (m, 2H) 1.75-1.91 (m, 2H) 1.57-1.75 (m, 4H) 1.47-1.54 (m, 2H). MS (m/z, MH+): 316.8
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[C:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[O:11][CH2:10]2.I[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[C:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[O:11][CH2:10]2
Reactant: ICCN1CCOCC1
Reactant: COc1ccc(CNc2ccc3c(c2)COC3=C2C(=O)Nc3ccccc32)c(OC)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(CCN2CCOCC2)c2ccc3c(c2)COC3=C2C(=O)Nc3ccccc32)c(OC)c1
Temperature: 85 °C

Procedure:
A mixture of 3-[5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (100 mg, 0.24 mmol), 4-(2-iodo-ethyl)-morpholine (90 mg, 0.37 mmol), N,N-diisopropylethylamine (63 mg, 0.49 mmol) and silver triflate (75 mg (0.29 mmol) in 1,4-dioxane (5 ml) was heated at 85° C. under nitrogen for 16 hours. Purification of the mixture by silica gel chromatography, eluted with a gradient of MeOH in CHCl3 led to 3-{5-[(2,4-dimethoxy-benzyl)-(2-morpholin-4-yl-ethyl)-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (40 mg, 31%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[SH:14].[OH:15][C@:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[S:14][C:27]1[CH:28]=[C:23]([C@@:16]2([OH:15])[CH2:21][CH2:20][O:19][C@@H:18]([CH3:22])[CH2:17]2)[CH:24]=[CH:25][CH:26]=1
Reactant: C[C@H]1C[C@@](O)(c2cccc(I)c2)CCO1
Reactant: CN1C(=O)CCc2cc(S)c(F)cc21
Product: C[C@H]1C[C@@](O)(c2cccc(Sc3cc4c(cc3F)N(C)C(=O)CC4)c2)CCO1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 6, 7-fluoro-6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydropyran to give (2S,4R)-4-[3-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-hydroxy-2-methyltetrahydropyran in 55% yield, m.p. 90-92° C. (recrystallised from diethyl ether);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:38]C)=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[Cl-].[Li+].C(OCC)(=O)C.Cl>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:38])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Temperature: 140 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 4.62 g of ethyl [4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate in 40 mL of N,N-dimethylformamide was added 1.03 g of lithium chloride, and the mixture was stirred at 140° C. for 2 hours. After being cooled to room temperature, the reaction mixture was poured into a mixture of 60 mL of ethyl acetate, 6 mL of toluene, and 32 mL of 1 mol/L hydrochloric acid. The organic layer was separated, and washed with 1 mol/L hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: acetic acid-ethyl acetate) to give 3.67 g of ethyl [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate, colorless and amorphous.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[CH2:8])[CH3:7])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([O:4][CH2:5][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:7])[CH3:8])(=[O:3])[CH3:2]
Reactant: C=C(C)COC(C)=O
Reactant: c1ccccc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)OCC(C)(C)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Mix methallyl acetate (228 g, 2.0 mol) and benzene (1L) and cool to 5° C. Add aluminum chloride (266 g, 2.0 mol) over approximately 30 minutes while maintaining the temperature below 10° C. Add, in portions of 50 mL to 80 mL each, to a 5° C. mixture of aluminum chloride (15 g) in benzene (600 mL). After addition is complete, stir at 0-3° C for ½ hour, pour onto ice (2 kg) and separate the organic layer. Wash with water (2×300 mL ), dry (Na2SO4), and distill to give neophyl acetate.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[NH2:24][C@H:25]([C:27]([NH:29][C@H:30]([C:32]([N:34]1[CH2:43][CH2:42][CH2:41][C@H:35]1[C:36]([NH:38][CH2:39][CH3:40])=[O:37])=[O:33])[CH3:31])=[O:28])[CH3:26].N=C=N>>[NH:1]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:2]([C:14]([NH:24][C@H:25]([C:27]([NH:29][C@H:30]([C:32]([N:34]1[CH2:43][CH2:42][CH2:41][C@H:35]1[C:36]([NH:38][CH2:39][CH3:40])=[O:37])=[O:33])[CH3:31])=[O:28])[CH3:26])=[O:16])[CH2:3][C:4](=[O:13])[OH:5]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: N=C=N
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Yield: 68 %

Procedure:
Condensation of BOC-Asp(OBzl) with Ala-Ala-Pro-NH-Et is achieved by the carbodiimide method as described in Example 1. Subsequent debenzylation by the procedure in Example 1 gives BOC-Asp-Ala-Ala-Pro-NH-Et in a yield of 68%; Rf =0.75(S)1. Acylation with undecanolylchloride, by the procedure in Example 3, produces the title product, Nα -Undecanoylaspartyl-alanyl-alanyl-proline ethylamide; m.p. 184°-189° C. (from water). Amino acid composition analysis yields; Asp 1.02, Pro 1.04, Ala 1.97.
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[I-:14].[Na+]>C(#N)C>[C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3]([I:14])[CH3:4]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)OC1CCCCC1

Procedure:
A solution of 1.65 g of 1-chloroethyl cyclohexyl carbonate and 5.0 g of sodium iodide in 50 ml of acetonitrile is stirred at 70° C. for 45 minutes and then concentrated under reduced pressure. The residue is extracted with ether. The extracts are combined and evaporated under reduced pressure to remove the solvent to give the title compound as pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.C(OCC)(=O)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction was carried out under argon. (4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (5.0 g, 10.1 mmol; 90% pure) was initially charged in dry THF (135 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 3.85 g, 16.17 mmol; 1.6 eq.) was added and the mixture was then stirred at RT for 2 h. Ethyl acetate (300 ml) was then added to the reaction mixture. The organic phase was washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from cyclohexane/ethyl acetate. The crystals obtained were dried under high vacuum. The title compound was obtained as a solid (2.8 g, 65% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (119 mg, 48%). MS (ISN) 495.2 [(M−H)−]; mp 216° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(-c2ccc3cc[nH]c3c2)c1
Reactant: Brc1ccncc1
Agent: Cl
Product: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4ccncc4)c3c2)c1

Procedure:
The target compound was prepared as in Example 1 using 6-(3-nitrophenyl)-1H-indole (98 mg, 0.412 mmol) and 4-bromopyridine hydrochloride (88 mg, 0.453 mmol).
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[CH:9](=[N:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCOC1=O
Agent: Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCCC1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3.84 g of α-amino-γ-butyrolactone hydrogenbromide in 40 ml of dichloromethane is added 2.15 ml of benzaldehyde, followed by5.9 ml of triethylamine and excess magnesium sulfate. After stirring at room temperature for 20 hours, the mixture is filtered and the filtrate concentrated. A 200 ml portion of ether is added and the resulting suspension filtered. The filtrate is washed with 50 ml of saturated aqueous sodium chloride. The aqueous phase is extracted with two 100 ml portions of ether. The combined organic phase is dried (magnesium sulfate), filtered, and then concentrated. The residue is evaporatively distilled at 0.05 mmHg (Krugelrohr oven 200°-250° C.) to give 3.5 g of N-benzylidene-α-amino-γ-butyrolactone as an oil which solidifies on storage in a freezer:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)[OH:6].[H-].[Na+].[F:15][C:16]([S:19](O)(=[O:21])=[O:20])([F:18])[F:17]>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=1[O:6][S:19]([C:16]([F:18])([F:17])[F:15])(=[O:21])=[O:20]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)c1cccc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(C)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an inert atmosphere, a stirred solution of 3-methylsalicylic acid methyl ester (9.96 g) in dichloromethane (150 mL) cooled in an ice bath, was treated portionwise with 55% sodium hydride dispersion in mineral oil (3.0 g). The mixture was stirred at 0° C. for 15 minutes, then trifluoromethyl sulfonic acid (18.65 mL) was added dropwise over 20 minutes. The cooling bath was removed and the reaction was allowed to proceed for an additional hour. Water (75 mL) was added and the phases were separated. The organic layer was washed in turn with 10% potassium carbonate (75 mL) and with brine. The dried (Na2SO4) organic layer was evaporated and the resulting amber oil was purified by HPLC (diethyl ether-hexane; 1:4) to yield 14.3 g of 3-methyl-2-(trifluoromethylsulfonyloxy)benzoic acid methyl ester as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[C:9]([OH:12])[NH:10][N:11]=1.[CH2:23](O)[CH2:24]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[C:9]2[O:12][CH2:23][CH2:24][N:10]2[N:11]=1
Reactant: OCCO
Reactant: Oc1[nH]nc(-c2ccccn2)c1-c1ccnc2ccccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: c1ccc(-c2nn3c(c2-c2ccnc4ccccc24)OCC3)nc1
Yield: 74.9 %

Procedure:
To a solution of 5-pyridin-2-yl-4-quinolin-4-yl 2H-pyrazol-3-ol (50 mg, 0.17 mmol), ethylene glycol (15 mg, 0.24 mmol) and tri-n-butylphosphine (100 mg, 0.50 mmol) in tetrahydrofuran (15 mL) is added 1,1′-(azodicarbonyl)dipiperidine (120 mg, 0.48 mmol). The solution is heated at reflux for 5 h, cooled, and filtered through an SCX cartridge. The residue is chromatographed on SiO2 (15:1 dichloromethane:methanol). The product residue is converted to the disoxylate salt to give the title compound 40 mg (46%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:19][C:20]#[N:21])[N:7]([CH3:18])[C:8]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[CH3:22]I.O>COCCOC>[Cl:3][C:4]1[CH:5]=[C:6]([CH:19]([CH3:22])[C:20]#[N:21])[N:7]([CH3:18])[C:8]=1[C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CI
Reactant: Cn1c(CC#N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C#N)c1cc(Cl)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 1 h

Procedure:
To a suspension of 12.2g. of 50% sodium hydride (mineral oil) in 1,2-dimethoxyethane is added 70 g. (0.24 mole) of 4-chloro-5-(p-chlorobenzoyl)-1-methylpyrrole-2- acetonitrile in 1,2-dimethoxyethane over a period of one half hour at room temperature. After the addition is complete, the whole is stirred for one hour and then 35 g. (0.25 mole) of methyl iodide is added. The reaction mixture is stirred for an additional 3 hours and is concentrated in vacuo; the residue is diluted with water and extracted with chloroform. After the extract is dried the chloroform is removed, leaving a brown solid residue which, upon trituration with cold water, yields 4-chloro-5- (p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1Cl)=[CH:22][CH:21]=[CH:20][C:19]=2[O:26][CH3:27])(=[O:14])[CH2:11][CH2:12][CH3:13]>O1CCOCC1>[C:10]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[O:26][CH3:27])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccc(O)c(F)c1
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)c(F)c1

Procedure:
2-Fluoro-4-aminophenol (0.8 g, 6 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.5 g, 5.7 mmol) were heated together under reflux in 1,4-dioxan (50 ml) for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane, washed with water, sodium hydrogen oarbonate solution and brine then dried and evaporated. The residue was recrystallised from methanol-water to afford 3-butyryl-4-(3-fluoro-4-hydroxyphenylamino)-8-methoxyquinoline, m.p. 266°-268°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[C:17]1([NH2:24])[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>C(O)(C)C>[CH3:16][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:23][C:20]2[CH:21]=[CH:22][C:17]([NH2:24])=[CH:18][CH:19]=2)[CH:8]=1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: Nc1ccc(N)cc1
Solvent: CC(C)O
Product: Cn1ccnc1-c1cc2nccc(Nc3ccc(N)cc3)c2s1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A mixture of 214 (500 mg, 2.0 mmol, scheme 46) and benzene-1,4-diamine (500 mg, 4.62 mmol) in iso-PrOH (15 mL) was refluxed overnight, cooled to room temperature and filtered. The solid was collected, washed with iso-PrOH/H2O mixture, to afford the title compound 301 (300 mg, 44% yield) as a yellowish solid. MS (m/z): 322.1 (M+H) (found).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>CN(C)C1C=CN=CC=1.ClCCCl>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:24]([N:5]2[CH2:6][CH2:7][CH2:8][C:2]([CH3:16])([CH3:1])[C:3]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]2=3)=[O:25])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC1(C)CCCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 41 h
Yield: 46 %

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.797 g, 3.62 mmol), Pyridine (0.310 mL, 3.83 mmol) and 4-Dimethylaminopyridine (21 mg, 0.17 mmol) were dissolved in anhydrous 1,2-Dichloroethane (5.0 mL) before adding p-Nitrophenyl Chloroformate (0.541 g, 2.68 mmol). The reaction was stirred at room temperature for 41 hours and then concentrated under reduced pressure. The residue was purified by normal phase chromatography to yield an off-white solid, 5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 4-nitro-phenyl ester (0.475 g, 46%). LCMS: m/z=386.07 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.21 (m, 4H), 7.65 (d, 1H, J=8.8 Hz), 7.42 (m, 1H), 7.23 (m, 1H), 4.53 (m, 1H), 2.87 (m, 1H), 2.32 (m, 1H), 1.69 (m, 5H), 1.34 (m, 4H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[C:11]([CH3:22])=[N:12][O:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:18]3[CH:19]=[CH:20][C:15]([C:14]4[O:13][N:12]=[C:11]([CH3:22])[C:10]=4[CH2:9][NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:16][CH:17]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using benzyl-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.