Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[O:34]1[CH:38]=[CH:37][C:36]([CH2:39][N:11]2[CH2:12][CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[CH:35]1
Reactant: O=Cc1ccoc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(Cc2ccoc2)CCC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 3.4 mg of 3-furaldehyde, 0.050 mL of acetic acid, and 0.5 mL of DMF was added 75 mg of MP-Triacetoxyborohydride (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of PS-Isocyanate (Argonaut Technologies, USA) at room temperature, followed by stirring for 2 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl {[1-(3-furylmethyl)-4-phenylpiperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. To 0.5 mL of a methanol solution of the obtained crude product was added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 4.9 mg of (1R)—N-{[1-(3-furylmethyl)-4-phenylpiperidin-3-yl]methyl}-1-(1-naphthyl)ethaneamine.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(OC([NH:37][C:38]1([C:41]([OH:43])=O)[CH2:40][CH2:39]1)=O)(C)(C)C.[CH3:44][O:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=2)=[C:48]([C:61]([F:64])([F:63])[F:62])[CH:47]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH:56][C:41]([C:38]3([NH2:37])[CH2:39][CH2:40]3)=[O:43])=[CH:53][CH:52]=2)=[C:48]([C:61]([F:62])([F:63])[F:64])[CH:47]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: COc1ccc(Oc2ccc(CN)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
540 μL (3.85 mmol) of triethylamine and 864 mg (2.69 mmol) of TBTU were added to a solution of 541.5 mg (2.69 mmol) of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid in 45 mL DMF and the mixture was stirred for 5 min at RT. Then 800 mg (2.69 mmol) of 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamine (from 84a) was added and the mixture was stirred for 2 h at ambient temperature. The reaction mixture was filtered through Alox B, washed with DMF/MeOH=9/1 and the filtrate was evaporated down. 20 ml dichloromethane/trifluoroacetic acid/water=50/45/5 were added to the residue and the mixture was stirred for 1 h at RT. The reaction mixture was evaporated down, the residue was dissolved in dichloromethane and extracted with 10 mL of 1 M sodium hydroxide solution. The dichloromethane phase was separated off and evaporated down.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[OH:16].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][CH:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[OH:16]
Reactant: CC(O)C(N)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(O)C(NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The starting materials were D-glucose and DL-threonine. The reductive amination was carried out using Raney nickel or palladium/activated carbon (10%) and yielded a product having a melting point of 219° C. (decomposition) and a RF -value of 0.67 (determined on DC-finished plates of silica gel G (Merck) with a transporting fluid made up of 75 parts by volume of methanol and 25 parts by volume of water).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A 12 L 3-necked round-bottomed flask was charged with DMF (2L), 5-nitroindazole (200 g, 1.22 mol.) and potassium carbonate (186 g, 1.35 mol). Benzyl bromide (230 g, 1.35 mol) was then added to the stirred suspension at a rate as to maintain the temperature below 40° C. Once the addition was complete the mixture was heated to 75° C. for a further 8 hours, the reaction being monitored by TLC (SiO2, 1:1 ethyl acetate:hexanes). The reaction was then cooled to room temperature, water (2L) added and the resulting slurry stirred at room temperature for 0.5 h. The resulting yellow solids were filtered off and dried at 45° C. and 5 mm Hg vacuum for 48 h. This afforded 424 g of a 1.25:1 mixture of 1- and 2-benzyl-5-nitroindazoles as determined by HPLC analysis (Rt 1-benzyl=14.9 min, Rt 2-benzyl=14.1 min). This material was then split into four approximately 100 g batches and each batch dissolved in acetone (470 mL). Water (156 mL) was then added slowly as a steady stream. After stirring for an additional 1 hour at room temperature the resulting solids were filtered off and vacuum dried. This process afforded a combined total of 126 g (41%) of 1-benzyl-5-nitroindazole, which was 92.1% pure by HPLC analysis, the major contaminant being the 2-benzyl derivative.
Reaction SMILES: [CH3:1][C:2]1([CH2:21][CH2:22][CH2:23][OH:24])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:8]=2)[O:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH2:21][CH2:22][CH:23]=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:8]=2)[O:3]1
Reactant: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCCO)CC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCC=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A mixture of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propan-1-ol (200 mg), pyridinium chlorochromate (PCC)(350 mg), and 4 A° molecular sieves (100 mg) in dichloromethane (15 mL) was stirred at RT for overnight. The mixture was passed through a silica gel column chromatography eluting with 30% EtOAc in hexane to give 40 mg of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propionaldehyde as an oily product. 1H-NMR (300 MHz, CDCl3) δ (ppm): 9.79 (s, 1H, CHO), 6.67 (s, 1H), 5.23 (d, J=2.2 MHz, 1H), 3.90 (m, 1H), 3.58 (m, 1H), 2.75-2.60 (m, 4H), 2.15, 2.08 (2s, 6H), 2.00-1.58 (m, 10H), 1.23 (s, 3H). 13C-NMR (CDCl3, 75 MHz) δ (ppm): 202.64, 148.26, 145.87, 125.57, 125.41, 117.39, 112.93, 112.87, 97.34, 97.22, 74.33, 62.11, 62.05, 38.58, 32.34, 32.09, 31.60, 31.53, 30.76, 25.41, 23.85, 23.64, 22.36, 19.11, 19.08, 12.11, 11.96. MS (m/z): 333 (MH+), 355 (M+Na+).
Reaction SMILES: [C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.OS(O)(=O)=O.[N+:23]([O-])([O-:25])=[O:24].[K+]>>[C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[C:7]([N+:23]([O-:25])=[O:24])[C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)Oc1ccc(F)cc1C1CCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
2-Cyclopentyl-4-fluorophenyl methyl carbonate (2.246 g, 9.43 mmol) was added portion-wise to H2SO4 (6.9 mL, 130.0 mmol) to generate a colorless homogeneous solution. This solution was then cooled to 0° C. and KNO3 (1.143 g, 11.31 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes) provided 2-cyclopentyl-4-fluoro-5-nitrophenyl methyl carbonate (2.063 g, 77% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.19 (d, J=6.9 Hz, 1H), 7.63 (d, J=12.5 Hz, 1H), 3.89 (t, J=5.9 Hz, 3H), 3.18-3.12 (m, 1H), 1.99-1.92 (m, 2H), 1.82-1.74 (m, 2H), 1.69-1.51 (m, 4H). MS (ESI) m/z (M+H+): 284.3.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1c(-c2ccc(O)cc2)ccnc1Cl
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)ccnc1Cl
Yield: 90 %

Procedure:
Following conditions described in Step 1 of Example 3, 2-chloro-4-(4-hydroxyphenyl)nicotinonitrile was reacted with phenylboronic acid to give 2-chloro-4-(4-phenoxyphenyl)nicotinonitrile (60 mg, 90% yield). 1H NMR (500 MHz, CDCl3) 8 ppm 8.56 (1H, δ, J=5.22 Hz), 7.53-7.67 (2H, m), 7.37-7.49 (3H, m), 7.22 (1H, t, J=7.42 Hz), 7.09-7.16 (4H, m); MS (ES+) m/z: 307 (M+H); LC retention time: 3.863 min (analytical HPLC Method A).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](O)(=[O:14])=[O:13])=[CH:4][C:3]=1[N:16]=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][S:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([N:16]=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:4]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(O)c1cc(N=Nc2ccccn2)c(O)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cc(N=Nc2ccccn2)c(O)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture consisting of 10 g of 4-hydroxy-3-(2-pyridylazo)-1-naphthalenesulfonic acid prepared by the process of Japanese patent application (OPI) No. 35533/78 (the term "OPI" as used herein means "unexamined published patent application"), 100 ml of sulforan, and 15 ml of phosphorous oxychloride was heated at an inner temperature of from 55° to 65° C. for 3 hours while stirring. The reaction mixture was cooled to room temperature and poured into 1 l of ice-water. The precipitated crystals were collected by filtration, washed with water, and air-dried to obtain 10.1 g of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:39](=[O:56])[C:40]2[C:41]([O:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:39](=[O:56])[C:40]4[C:41]([O:48][C:49]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2n1
Yield: 76 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-methoxy-2-phenyl-pyrano[2,3-b]pyridin-4-one was reacted to give the title compound (57 mg, 76%) as a colourless gum. LCMS (Method A): RT=4.88 min, [M+H]+=499.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C>[CH3:36][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([C:25]([NH2:27])=[O:26])=[CH:24][C:18]=4[N:17]=3)=[CH:14][CH:15]=2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCCCC2CCOc2ccc(-c3nc4cc(C(N)=O)ccc4[nH]3)cc2)cc1
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (0.10 g, 0.27 mmol) in DMF (1 mL) was added p-tolualdehyde (70 μL, 0.59 mmol), activated 4 Å molecular sieves, and NaB(OAc)3H (0.175 g, 0.82 mmol). The solution was stirred for 16 h and additional portions of aldehyde (1 equiv.) and NaB(OAc)3H (3 equiv.) were added. When HPLC monitoring indicated reaction completion, the solution was quenched with 1 N NaOH and purified by reverse phase HPLC (C18; H2O/CH3CN/0.01% TFA), providing 60 mg (48%) of product. HPLC (Method C): Rt=4.60. MS (ESI+): mass calcd. for C29H32N4O2, 468.25; m/z found, 469.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.18 (s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.34-7.32 (m, 2H), 7.23-7.20 (m, 2H), 7.15-7.13 (m, 2H), 4.33-4.10 (m, 3H), 3.45-3.39 (m, 1H), 3.15-3.07 (m, 1H), 2.90-2.85 (m, 1H), 2.72-2.67 (m, 1H), 2.42-2.37 (m, 1H), 2.20-2.10 (m, 1H), 1.93 (br s, 1H), 1.88-1.73 (m, 2H), 1.73-1.45(m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18]C)=[O:17])[C:8]2=[O:24])#[N:2].[OH-].[Na+]>>[C:1]([C:3]1[CH:4]=[C:5]([N:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH2:30]2)[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([OH:18])=[O:17])[C:8]2=[O:24])#[N:2]
Reactant: CCN1CCN(c2cc(C#N)c3ncn(-c4cc(C(=O)OC)ccc4C)c(=O)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CCN1CCN(c2cc(C#N)c3ncn(-c4cc(C(=O)O)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 1 which is concerned with the preparation of starting material methyl 3-[8-cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate was hydrolysed with 1N NaOH to give 3-[8-cyano-6-(4-ethylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid; Mass Spectrum: M+H+ 418.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:12])[N+:18]([O-:20])=[O:19]
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 54.3 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-phenoxypropionic acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.49 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:10]=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:9][C:5]1[N:4]=[C:3]([CH:10]=[N:19][NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([NH2:1])=[N:7][C:6]=1[Cl:8]
Reactant: NNc1ccccc1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Solvent: CCO
Product: Nc1nc(Cl)c(Cl)nc1C=NNc1ccccc1

Procedure:
0.96 gram (0.005 mole) of 3-amino-5,6-dichloropyrazinaldehyde, 0.54 gram (0.005 mole) of phenylhydrazine and 20 milliliters of ethanol were heated with stirring and refluxed for 10 minutes to obtain a 5,6-dichloro-3-[(2-phenylhydrazono)methyl]pyrazinamine product as a solid. The reaction mixture was allowed to cool and the solid product recovered by filtration and recrystallized from ethanol to obtain 0.71 gram (50 percent yield) of purified product as yellow flakes, m.p. 277°-278° C. (dec.). Elemental analyses were as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.[N:17]1([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]3[C:29](=[O:32])[O:30][CH2:31][C:27]=3[CH:26]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([N:20]2[CH2:21][CH2:22][N:17]([CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:28]4[C:29](=[O:32])[O:30][CH2:31][C:27]=4[CH:26]=3)[CH2:18][CH2:19]2)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)c(F)c1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)c(F)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-fluoro-4-(1H-tetrazol-1-yl)phenyl]acetic acid (0.68 mmol) in 10 mL of anhydrous DCM was added 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (191 mg, 0.68 mmol), EDC (200 mg, 1.01 mmol), HOBt (136 mg, 1.01 mmol), TEA (341 mg, 3.38 mmol) was stirred at ambient temperature overnight. The mixture was added DCM, washed with brine, the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified via prep-TLC to give the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.84 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.31˜737 (m, 3H), 7.11˜7.19 (m, 2H), 5.29 (s, 2H), 3.59 (s, 2H), 3.49˜3.52 (m, 2H), 3.37˜3.4 (m, 2H), 2.89˜2.93 (m, 2H), 2.64˜2.68 (m, 2H), 2.4˜2.45 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH3:33].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[N:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:24]=2[CH3:33])[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (207 mg, 0.75 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (285 mg, 1.125 mmol) and Na2CO3 (239 mg, 2.25 mmol) in DMF (10 mL) was stirred at 80° C. for 3 h. TLC showed no methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate left. It was cooled to room temperature and poured into water (50 mL) and filtered. The solid was dissolved with DCM (150 mL) and it was washed with brine (100 mL×3) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product as a brown solid (320 mg, 95%); LC/MS: MS (ES+) m/e 449 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.40 (s, 3H), 2.51 (s, 3H), 3.41 (t, J=4.8 Hz, 4H), 3.68 (t, J=4.8 Hz, 4H), 3.92 (s, 3H), 5.50 (s, 2H), 6.90 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H).
Reaction SMILES: [N:1]([CH:4]([CH3:28])[CH2:5][O:6][CH:7]1[CH2:27][C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)=[C:17]([F:26])[CH:16]=3)[O:14][C:10]=2[CH2:9][CH2:8]1)=[N+]=[N-].C1C[O:32][CH2:31][CH2:30]1>[C].[Pd]>[CH:23]1([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[O:14][C:10]4[CH2:9][CH2:8][CH:7]([O:6][CH2:5][CH:4]([NH:1][C:31](=[O:32])[CH3:30])[CH3:28])[CH2:27][C:11]=4[N:12]=3)=[CH:16][C:17]=2[F:26])[CH2:25][CH2:24]1
Reactant: C1CCOC1
Reactant: CC(COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1)N=[N+]=[N-]
Agent: [Pd]
Product: CC(=O)NC(C)COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(2-azidopropoxy)-2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazole (3.08 g), 10% palladium-carbon (containing water (50%), 500 mg) and THF (10 mL) was stirred at room temperature for 10 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. To the obtained residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (2.80 g).
Reaction SMILES: N([O-])=O.[Na+].N[C@@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9].[BrH:14]>O.C(OCC)C>[Br:14][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:11]([OH:13])=[O:12]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)CC(Br)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of sodium nitrite (31.55 g) in water (70 ml) was added dropwise to a stirred solution of D-leucine (20 g) in 47% aqueous hydrobromic acid (140 ml)/water (211 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then diluted with diethyl ether (600 ml). The organic layer was separated and washed with aqueous sodium metabisulphite (200 ml), dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give 2-bromo-4-methyl-pentanoic acid as a yellow oil (27.6 g) [1H NMR (CDCl3): δ0.93 (d, 3H), 0.98 (d, 3H), 1.75-1.85 (m, 1H), 1.91-1.95 (m, 2H), 4.30 (t, 1H)]. Oxalyl chloride (9.56 ml) was added dropwise to a stirred solution of the 2-bromo-4-methylpentanoic acid (10.7 g) and pyridine (0.1 ml) in dichloromethane (60 ml). The reaction mixture was stirred for 20 hours and the solvent was removed under reduced pressure to give 2-bromo-4-methylpentanoyl chloride (12 g) [1H NMR (CDCl3); δ0.95 (d, 3H), 1.01 (d, 3H), 1.80-2.07 (m, 3H), 4.52 (t, 1H)]. A solution of this 2-bromo-4-methylpentanoyl chloride (12 g) in dichloromethane (40 ml) was added dropwise to a stirred solution of 2,6-dimethoxy-4-methylphenol (9.41 g) and triethylamine (15.6 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 20 hours and was then chromatographed on silica gel, eluting with dichloromethane, to give the title compound as a viscous yellow oil (14.7 g).