Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH2:9]([C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:21]=1)[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)=[N:3][CH:4]=1
Reactant: C#CCCc1cn2ccccc2n1
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1ccc(C#CCCc2cn3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (6.5 mg, 0.03 mmol) and triethylamine (2.3 mL), were added 2-bromo-5-fluoropyridine (120 mg, 0.68 mmol) and Pd(PPh3)2Cl2 (39 mg, 0.03 mmol) under N2. A yellow suspension was obtained after 5 min of stiffing at room temperature. A solution of 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (120 mg, 0.68 mmol) in triethylamine (0.5 mL) was then added under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and heated at 80° C. overnight. The reaction mixture was concentrated and the crude product was purified by Flash chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 97/3 as eluent) to afford 15 mg of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 8%) as a brown semi-solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][Br:31]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(Br)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Br)cc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
In a 250 ml round bottom flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (5.85 g, 28.5 mmol) was dissolved in diethy ether (125 ml). To this solution triphenylphosphine (9.73 g, 37.1 mmol) and carbon tetrabromide (12.30 g, 37.1 mmol) were added. The resulting mixture was stirred at ambient temperature for about three hours. The progress of the reaction was monitored by thin layer chromatography. The mixture was then stirred at ambient temperature for about 19 additional hours. The reaction mixture was filtered and washed with cold diethyl ether. The filtrate was evaporated, yielding a light yellow oil. The oil was further purified by chromatography on a silica gel with hexanes. The desired fractions were purified by evaporation to yield 5.8 grams of the desired title intermediate. The material slowly crystallized upon standing.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(Br)cc1
Product: O=C(O)Cc1ccccc1Nc1ccc(Br)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-bromoaniline to yield 2-[(4-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH:18]([NH:22][CH:23]([CH2:25][CH3:26])[CH3:24])([CH2:20][CH3:21])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.CCOCC>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[CH2:2][N:22]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH:18]([CH2:20][CH3:21])[CH3:19]
Reactant: O=C(CCl)c1cccn1Cc1ccccc1F
Reactant: CCC(C)NC(C)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: CCC(C)N(CC(=O)c1cccn1Cc1ccccc1F)C(C)CC
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 16.0 g of 2-chloroacetyl-1-(o-fluorobenzyl)pyrrole, Example 1a, 8.3 g of di-sec-butylamine and 20.0 g of potassium carbonate in 250 ml xylene is stirred at 120° C for 72 hours. The mixture is cooled, washed with water, dried and filtered and the xylene is evaporated leaving a brown oil. The oil is dissolved in ether and extracted into a 2N hydrogen chloride solution. The aqueous acidic solution is basified with a sodium carbonate solution and extracted with ether. The ether solution is washed, dried and filtered and the ether removed leaving a brown oil of 1-(o-fluorobenzyl)-2[(di-sec-butylamino)acetyl]pyrrole. Infrared and nuclear magnetic resonance spectra confirm this structure.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H-].[Na+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.CCOC(C)=O.Cl>[Br:1][C:2]1[N:6]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution (0.2 M) of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (from Step 1) in dry DMF was treated with sodium hydride (2 eq., 60% suspension in mineral oil) at 0° C. The reaction mixture was stirred at RT for 30 min then tert-butyl bromoacetate (3 eq.) was added. The reaction was heated to 50° C. for 1 h. After cooling, the solution was diluted with EtOAc and 1 N hydrochloric acid was added. The organic phase was washed with 1 N hydrochloric acid, saturated NaHCO3 solution and brine, dried over sodium sulfate and evaporated in vacuo to give a residue that was purified by flash chromatography (PE:EtOAc, 9:1) to afford the title compound (80%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 7.99 (s, 1H), 4.99 (s, 2H), 3.82 (s, 3H), 2.66-2.52 (m, 1H), 1.82-1.21 (m, 101H), 1.42 (s, 9H). MS (ES+) m/z: 456, 458 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([F:26])=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[CH3:29][NH:30][CH2:31][C:32]#[CH:33]>CN(C=O)C>[F:26][C:17]1[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:30]([CH3:29])[CH2:31][C:32]#[CH:33])=[C:6]([O:27][CH3:28])[CH:7]=3)[N:12]=[CH:11][N:10]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:25])[NH:21]2
Reactant: C#CCNC
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCBr
Solvent: CN(C)C=O
Product: C#CCN(C)CCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (250 mg, 0.56 mmol), (prepared as described for the starting material in Example 17), in DMF (2.5 ml) was treated with N-methylpropargylamine (116 mg, 1.68 mmol) and stirred at ambient temperature overnight. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8). The relevant fractions were combined and evaporated under vacuum to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{2-[N-methyl-N-(2-propynyl)amino]ethoxy}quinazoline as a white solid. (165 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)=[N:6][CH:7]=1.[C:25](OCC)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[N:22]=[CH:25][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH:10]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(CN2CCOCC2)c1
Reactant: CCOC(C)=O
Product: Brc1cnc2c(c1)ncn2-c1cccc(CN2CCOCC2)c1

Procedure:
6-Bromo-3-[3-(morpholin-4-ylmethyl)phenyl]-3H-imidazo[4,5-b]pyridine was prepared from N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(morpholin-4-ylmethyl)phenyl]amine as described in Example 1. Maleate salt, cream-coloured powder, m.p. 176-178° C. (from ethyl acetate); δH (400 MHz, d6-DMSO @ 340K) 2.64-2.68 (4H, m), 3.68-3.72 (4H, m), 4.00 (2H, s), 6.13 (2H, s), 7.51 (1H, d, J 8), 7.64 (1H, t, J 8), 7.89 (1H, d, J 8), 7.94 (1H, s), 8.47 (1H, d, J 2), 8.52 (1H, d, J 2), 8.89 (1H, s); m/z (ES+) 373 and 375 (M++H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:22][C:23](=[O:25])[CH3:24])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[P:26]([O:33]CC)([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>>[CH2:28]([O:27][P:26]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:22][C:23](=[O:25])[CH3:24])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:30][CH2:31][CH3:32])=[O:33])[CH3:29]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C(Cc1ccccc1CCBr)(NC(C)=O)C(=O)OCC
Product: CCOC(=O)C(Cc1ccccc1CCP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Yield: 86 %

Procedure:
A solution of 5 g (1.2 mmol) of ethyl 3-[2-(2-bromoethyl)phenyl]-2-acetamido-2-carboethoxypropanoate in 10 mL of P(OEt)3 was stirred at reflux for 4 h. The excess P(OEt)3 and the volatile by-products were removed from the mixture by distillation under vacuum. The remaining viscous oil was initially purified by column chromatography (C-18, MeOH:H2O; 4:1), then by preparative HPLC (C-18, MeOH:H2O, 7:3) giving 0.48 g (86%) of the product as a clear viscous oil. IR(Nujol) 1745.9, 1676.5 cm-1 (C=O); 1H NMR(CDCl3) δ 1.1-1.5 (m, 12H); 1.8-3.1 (complex, m, 7H); 3.7 (s, 2H); 3.8-4.4 (m, 8H); 6.6 (s, 1H), 7.0-7.3 (m, 4H) Anal. Calcd. for C22H34NO8P: C, 56.04; H, 7.27; N, 2.97. Found: C, 55.91; H, 7.31, N, 2.84.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[OH:25][C:26]1[CH:36]=[CH:35][C:29](/[CH:30]=[CH:31]/[C:32](O)=[O:33])=[CH:28][CH:27]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:32](=[O:33])/[CH:31]=[CH:30]/[C:29]1[CH:35]=[CH:36][C:26]([OH:25])=[CH:27][CH:28]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)/C=C/c2ccc(O)cc2)C(=O)O)cc1
Yield: 45 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine was reacted with trans-4-hydroxycinnamic acid under the conditions described in example 86 to yield 45% of the desired product.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]2[N:25]([CH3:26])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:22]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:11][CH:10]=1>CN(C)C=O>[CH3:40][C:39]1([CH3:44])[N:22]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:21]3[N:25]([CH3:26])[N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:22]3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:11][CH:10]=2)[C:21]([CH2:16][CH2:15][CH3:12])=[N:25][C:1]1=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CN1C(c2ccccc2-c2ccc(CBr)cc2)N(c2ccccc2)N(c2ccccc2)N1c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1=NC(=O)C(C)(C)N1Cc1ccc(-c2ccccc2C2N(C)N(c3ccccc3)N(c3ccccc3)N2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
A mixture of potassium carbonate (500 mg, 3.7 mmol), 2-propyl-4-4-dimethyl-1H-imidazol-5(4H)-one (0.6 g, 3.9 mmol), and 4'-bromomethyl-2-(triphenyl methyl tetrazol-5-yl)biphenyl (1.08 g, 1.9 mmol) in dimethyl formamide (5 mL) was allowed to stir at room temperature overnight. The mixture was chromatographed over silica gel eluting with ethyl acetate-hexane to give 1,5-dihydro-5,5-dimethyl-2-propyl-1-[(2'-(triphenyl methyl tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl]-4H-imidazol-4-one (70 mg, 14% ) M.S. m/e 631.5 (M+ +H) NMR (CDCl3 /TMS) δ0.88 (t, 3H, J=7 Hz, CH3), 1.38 (s, 6H, 2 CH3), 1.67 (m, 2H, CH2), 2.21 (t, 2H, J=7Hz, CH2), 4.56 (s, 2H, CH2), 6.92 (d, J= 7 Hz, 8H, Harom), 7.11 (d, J=7 Hz, 2H, Harom), 7.24-7.38 (m, 10H, Harom), 7.47 (m, 2H, Harom), 7.92 (m, 1H, Harom).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.C1C=C[NH+]=CC=1.[Br:21][Br-]Br.C([O-])([O-])=O.[Na+].[Na+]>CC#N.O>[Br:21][C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13][C:12]=1[CH3:14]
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2nc(C)c(Br)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
2-(p-Methoxyphenyl)-4-methylimidazole, (5.0 g, 0.0265 mole), was dissolved in CH3CN (250 ml) at the boiling point. The solution was cooled to room temperature and stirred while a solution of pyridinium bromide perbromide (7.0 g) in CH3CN (70 ml) was added dropwise. A precipitate separated as the addition was completed (30 min) and stirring was continued for 30 minutes. The mixture was poured into water (1.5 L) and the precipitated hydrobromide salt was collected. The filtrate was made basic with saturated Na2CO3 solution and the product was collected, washed with water, and dried to afford 2.45 g, m.p. 183°-187° C. The hydrobromide salt was dissolved in hot CH3CN (75 ml)-H2O (25 ml) and the solution was made basic with saturated Na2CO3 solution. A second crop of product was collected, washed with water, and dried to yield 2.2 g of 35; m.p. 179°-184° C.; 65 % combined yield. A sample of the first crop recrystallized from 50% CH3CN melted at 184°-187° C.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:24][CH3:25])=[C:5]([C:10](=[O:23])[CH2:11][NH:12][C:13]([CH3:22])([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][C:8]=1[OH:9]>CO.[Pt](=O)=O>[CH3:22][C:13]([NH:12][CH2:11][CH:10]([C:5]1[C:4]([O:24][CH3:25])=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1)[OH:23])([CH3:21])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1c(C(=O)CNC(C)(C)Cc2ccccc2)ccc(O)c1O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COc1c(C(O)CNC(C)(C)Cc2ccccc2)ccc(O)c1O
Yield: 64.5 %

Procedure:
10 g of 1-(3,4-dihydroxy-2-methoxyphenyl)-2-(1,1-dimethyl-2-phenylethylamino)ethanone hydrochloride is hydrogenated with 0.5 g of platinum(IV) oxide in 200 mL methanol. The catalyst is suction filtered and the solvent is distilled off under reduced pressure. The residue remaining is dissolved in 200 mL acetonitrile, combined with 5 g of sodium benzoate and refluxed for 15 minutes. After the excess sodium benzoate has been filtered off, the product which crystallizes out of the filtrate is filtered off and washed with acetonitrile and diethyl ether. Yield: 64.5% (benzoate); melting point: 149° C.-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([NH2:9])[N:5]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:36](N1C=CN=C1)(N1C=CN=C1)=[O:37]>CN(C)C=O>[NH2:9][C:6]1[C:7]2[O:8][C:36](=[O:37])[NH:1][C:2]=2[N:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
159 mg (0.453 mmol) of the compound prepared in example 58A in dimethylformamide (10 ml) were admixed with 94 μl (0.543 mmol) of N,N-diisopropylethylamine and 88 mg (0.543 mmol) of carbonyldiimidazole, and the mixture was stirred at RT overnight. The mixture was filtered, the filtrate was concentrated and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 90 mg of the title compound were obtained (52% of theory).
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[CH2:34][CH2:33]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 87 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][CH:26]=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1C(F)(F)F
Yield: 85.1 %

Procedure:
A mixture of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (2.17 g, 7.28 mmol) and commercially available 3-aminopyrazole (0.73 g, 8.78 mmol) in acetic acid (15 ml) was refluxed for 4 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/heptane) to yield 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (2.14 g, 85%) as a yellow solid. MS (EI) 345.1 [(M)+]; mp 87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9](OC)=[O:10])=[C:4]([N+:17]([O-:19])=O)[CH:3]=1.O>[Pt].C(O)(=O)C>[OH:19][N:17]1[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]1=[O:10]
Reactant: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1C(=O)N(O)c2cc(Cl)ccc21
Temperature: 60 °C

Procedure:
A mixture of dimethyl 4-chloro-2-nitrophenylmalonate (30 g, 0.10 mol), 5% Pt/C (0.15 g), water (3 mL), and acetic acid (95 mL) were charged to an autoclave reactor. The sealed autoclave was flushed with nitrogen, then charged with hydrogen (75 psig). The reaction mixture was mixed with the hydrogen, kept at constant pressure, by rapid stirring. Hydrogen was consumed over 1 hour at 30-40° C. The reaction mixture was then heated to 60° C. for 10 minutes to complete the hydrogenation with in situ cylization forming methyl N-hydroxy-6-chloro-2-oxindole-3-carboxylate. The hydrogen was then vented and replaced with nitrogen. The mixture was then heated at 105° C. for 1 hour to effect the in situ hydrolysis and decarboxylation of N-hydroxy-6-chloro-2-oxindole-3-carboxylate to N-hydroxy-6-chloro-2-oxindole. The reaction mixture was cooled to 80° C. and emptied under nitrogen pressure from the reactor as a slurry. This slurry was stirred under nitrogen until it cooled to 45° C. Filtration afforded a crude product contaminated with the catalyst. This solid was dissolved in hot tetrahydrofuran (450 mL) and filtered through a Celite pad with vacuum. Concentration to 100 mL followed by the addition of hexane (100 mL) afforded a slurry which was filtered. The solid was dried in vacuo to yield 9.85 g of N-hydroxy-6-chloro-2-oxindole (1H-NMR). Isolated yield: 54% on dimethyl 4-chloro-2-nitrophenylmalonate.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:15]1[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:30]#[N:31])[CH:29]=[CH:28][C:5]=43)[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccc(F)cc2F)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C#N)cc2OCC3)n(-c2ccc(F)cc2F)n1

Procedure:
8-Bromo-2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with zinc cyanide, and Tetrakis(triphenylphosphine)palladium(0) in DMF under microwave irradiation at 60 W for 30 minutes (Tmax=175° C.) to give 2-[2-(2,4-difluoro-phenyl)-5-methyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbonitrile. MS (ESI+) 405.1
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8](O)=[O:9])[CH2:3]1>O1CCCC1.CCOCC>[OH:9][CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1
Reactant: CC1CCCC(C(=O)O)C1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1CCCC(CO)C1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a boran-methyl sulfide complex (1.7 ml, 0.028 mole) in 7 ml tetrahydrofuran, at 0° C., was added dropwise 2 g of 3-methylcyclohexanecarboxylic acid (0.014 mole) in 7 ml tetrahydrofuran. Stirring was continued for one hour. The reaction mixture was diluted with ether and washed with 1N aqueous sodium hydroxide and then with brine. Concentration and distillation gave 1.34 g of the title compound The NMR spectrum showed absorption at 0.54-0.74 (m, 1H), 0.90, 0.93 (s, 3H), 1.17-1.53 (m, 3H), 1.65-1.77 (m, 3H) and 3.39-3.52 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH2:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23](N(CC)CC)[CH3:24].ClC(OCC)=O.C(O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:23][CH3:24])=[O:9])=[C:6]([O:11][CH2:12][C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(COc2cccc(Cl)c2C(=O)O)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)cccc1OCc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.0 g of 6-chloro-2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoic acid was dissolved in 20 ml of tetrahydrofuran and cooled with ice. 0.35 g of triethylamine dissolved in 1 ml of tetrahydrofuran and 0.40 g of ethyl chloroformate dissolved in 1 ml of tetrahydrofuran were added thereto, and the mixture was stirred under ice cooling for about 30 minutes. Then, a solution of 1 g of ethanol and 0.35 g of triethylamine in 2 ml of tetrahydrofuran was added, and the temperature was raised up to room temperature in about one hour. After the removal of the solvent, the residue was purified using column chromatography to obtain 1.0 g of ethyl 6-chloro-2-[(4,6-dimethoxy-2-pyrmidyl)methyloxy]benzoate (yield 92%).