Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=3[F:21])[N:11]=[N:10][N:9]=2)=[CH:6][C:5]([Br:22])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:42]1[CH2:46][CH2:45][C@H:44](O)[CH2:43]1>C1COCC1>[O:42]1[CH2:46][CH2:45][C@@H:44]([O:19][C:16]2[CH:17]=[CH:18][C:13]([N:12]3[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:22])[CH:6]=4)=[N:9][N:10]=[N:11]3)=[C:14]([F:21])[C:15]=2[F:20])[CH2:43]1
Reactant: Nc1ncc(Br)cc1-c1nnnn1-c1ccc(O)c(F)c1F
Reactant: O[C@H]1CCOC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1-c1nnnn1-c1ccc(O[C@@H]2CCOC2)c(F)c1F
Yield: 92.5 %

Procedure:
A solution of Compound 1086 (90 mg, 0.2438 mmol), triphenylphosphine (76.74 mg, 0.2926 mmol), diisoproplylazodicarboxylate (59.17 mg, 56.68 μL, 0.2926 mmol), and (S)-tetrahydrofuran-3-ol (25.78 mg, 0.2926 mmol) in THF (90 μL) was heated at 70° C. for 10 minutes under microwave irradiation. The reaction was quenched with ammonium chloride (satd') and extracted with EtOAc. The organics were washed with 1 M NaOH (2×), brine, dried over sodium sulfate, and concentrated under vacuum. The residue was chromatographed over silica gel (0-50% EtOAc/hexanes gradient) to give 3-(1-(4-((R)-tetrahydrofuran-3-yloxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-bromopyridin-2-amine (Compound 1090, 99 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Li+].[OH-]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1-c1ccn[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(F)ccc1-c1ccn[nH]1
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 1.9 mmol) in EtOH (10 mL) was treated with 4.0 eq of LiOH and stirred and monitored for two hours the reaction was complete. Reaction was made to pH=5, and then the solution concentrated under reduced pressure during which time a ppt formed. The reactions was then concentrated to minimum volume and cooled in ice, then filtered and washed with ice water to give 5-fluoro-2-(1H-pyrazol-5-yl)benzoic acid (172 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6): 13.03 (s, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.67 (dd, J=8.3, 5.6 Hz, 1H), 7.37 (td, J=8.6, 2.9 Hz, 2H), 6.44 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CN(C=O)C>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Br:30])[S:16]([C:19]2[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])(=[O:17])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2c3ccccc3nc3ccccc23)c(C)c1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(CCCCCBr)c2c3ccccc3nc3ccccc23)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of 450 mg (1.20 mmol) of N-(9-acridyl)-mesitylenesulfonamide in 20 mL of DMF was placed under an atmosphere of argon and cooled to 0° C. To the cooled solution was added 36 mg (1.42 mmol) of NaH (95%). The reaction mixture was stirred at 0° C for 5 min and at room temperature for 1 hr. Then the reaction mixture was cooled to 0° C., and 1.65 mL (12.1 mmol) of 1,5-dibromopentane were added. The reaction mixture was stirred at 70-80° C. for 23 hr. The reaction mixture was cooled, and quenched with 20 mL of water. The mixture was partitioned between CH2Cl2 and water. The aqueous phase was washed with CH2Cl2 (2×20 mL). The CH2Cl2 washes were combined with the organic phase, dried with MgSO4, and evaporated to dryness. The material was purified by column chromatography on silica gel with CH2Cl2 to afford 382.2 mg (60%) of bromide 542 as an orange oil: 1H NMR (300 MHz, CDCl3, TMS) δ 8.25 (d, J=9 Hz, 2H), 7.94 (d, J=9 Hz, 2H), 7.76 (t, J=8 Hz, 2H), 7.45 (t, J=8 Hz, 2H), 6.87 (s, 2H), 4.0-3.9 (m, 2H), 3.27 (t, J=6.5 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 6H), 1.8-1.6 (m, 4H), 1.4-1.3 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[CH:10](O)=[O:11].S(S([O-])=O)([O-])=O.[Na+].[Na+].C>C(N)=O.O>[CH:10]([NH:1][C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:11]
Reactant: O=CO
Reactant: O=[N+]([O-])c1ncccn1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: NC=O
Product: O=CNc1ncccn1
Reaction time: 0.29 h

Procedure:
The crude nitropyrimidine (25.32 g) from above was suspended in formamide (150 ml) and 90% formic acid (50 ml) and the suspension was warmed to 70° C. in a water bath. Sodium dithionite was carefully added to the warm suspension and then boiled for 15-20 minutes. The reaction mixture was diluted with hot water (300 ml), treated with charcoal and then boiled for an additional 20-25 minutes, filtered through celite, cooled and concentrated under reduced pressure to give formamido-pyrimidine which was collected by filtration, washed with acetone, and dried under vacuum at 56° C.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC(OC)=O.C(N(CC)CC)C.[CH:26]([C:29]([CH3:38])([N:33]1CC=CC1)[C:30]([NH2:32])=[O:31])([CH3:28])[CH3:27]>O1CCCC1.O>[C:30]([C:29]([NH:33][C:1](=[O:13])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:38])[CH:26]([CH3:28])[CH3:27])(=[O:31])[NH2:32]
Reactant: CC(C)C(C)(C(N)=O)N1CC=CC1
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C(C)(NC(=O)c1ccc2ccccc2n1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of quinaldic acid (20 g, 0.116 mol) in tetrahydrofuran (500 ml) cooled to -9° C. is added methyl chloroformate (8.92 ml, 0.116 mol) followed by triethylamine (18.4 ml, 0.139 mol). After 20 minutes α-isopropyl-α-methyl-3-pyrroline-1-acetamide (15.1 g, 0.116 mol) is added and the mixture stirred overnight at room temperature. Water is added and the solution is reduced to 200 ml on a rotorvap. A white solid separates and is filtered off, water washed and dried. Recrystallization from absolute ethanol gives the product mp 179°-180° C., 26.86 g (87%). Anal. calcd. for C16H19N3O2 : C, 67.34; H, 6.73; N, 14.72. Found: C, 67.14; H, 6.17; N, 14.72.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]([C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]([C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A solution of 167.4 g of ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate (13, 0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in 685 mL of dichloromethane was added to a 2 L reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. To this solution, 63.8 g of triethylamine (0.629 mol, 1.2 equiv.) was added and the mixture was cooled to less than 5° C. temperature. 66 g (0.576 mol, 1.1 equiv.) of methanesulfonyl chloride was added dropwise while maintaining the temperature below 10° C. and after the addition was complete, the mixture was stirred for an additional 30 min and then warmed to approximately 20° C. temperature under nitrogen atmosphere. The reaction mixture was stirred for NLT 1 h and quenched with 261 mL of ice-water at below 25° C. temperature and mixed for NLT 15 min. The lower organic layer was separated and the upper aqueous layer was extracted with 2×135 mL of dichloromethane. The combined organic layers were washed with 3×327 mL of water, dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated on a rotary evaporator under vacuum at NMT 60° C. temperature. The resulting crude product (viscous oil) was dried over night using a high vacuum pump to afford 204.7 g of ethyl 2-(((1S,2S)-2-((methylsulfonyloxy)methyl)cyclohexyl) ((S)-1-phenylethyl)amino) acetate (14) as a viscous oil, which was carried to the next step without further purification. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150×4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8): Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55° C., Rt: 17.23 min; LC-MS (m/z): 398.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:17][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:21][N:20]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1Cl
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccc(Oc3ccccc3)cc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of 0.09 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.45 g of 2-chloro-4-phenoxyphenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.34 g of 2-chloro-5-chloromethylpyridine in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.50 g of 2-chloro-5-(2-chloro-4-phenoxyphenoxy)methylpyridine. Yield, 71%. nD22 : 1.6173
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1>C(O)(=O)C>[F:15][C:10]1[CH:9]=[C:5]2[C:4]([CH:3]=[C:1]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:2]=[C:6]2[OH:7])=[CH:12][C:11]=1[O:13][CH3:14]
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1F
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(O)c2cc1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
2-Cyanomethyl-5-fluoro-4-methoxy-benzoic acid (1.75 g), 3-amino-5-methylpyrazol (1.63 g), acetic acid (15 ml), were sealed in a process vial. The mixture was heated at 130° C. for 30 minutes under microwave irradiation. The mixture was concentrated, and the residue was dissolved in 5 ml MeOH. The resulting solution was added dropwise to 200 ml water. After stirred for 1 hour, the solid was collected, and dried to give product (1.85 g, 77% yield). LC-MS: m/e 289 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[CH3:15].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[CH3:15])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(-n2ccccc2=O)ccc1N
Product: Cc1cc(-n2ccccc2=O)ccc1NC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
70.1 Using general method G, 1-(4-amino-3-methyl-phenyl)-1H-pyridin-2-one (prepared according to WO 2003045912) was activated with 4-nitrophenyl chloroformate to give [2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester. Pale grey solid.
Reaction SMILES: [NH3:1].[H][H].[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[C:6]1=[O:12]>[Pd].[Zn]>[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[C:6]1=[O:12].[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH2:1]
Reactant: N
Reactant: [H][H]
Agent: [Pd]
Agent: CC1CCCC(C)C1=O
Agent: [Zn]
Product: Cc1cccc(C)c1N

Procedure:
A catalyst in extrudate form, containing 0.5% by weight of Pd, 0.11% by weight of Zn and 0.1% by weight of Cd on Al2O3 as the carrier is introduced into a tubular reactor having a capacity of one liter, corresponding to 1,000 parts by volume, and is brought to 210° C. Per hour, a gaseous mixture of 400,000 parts by volume of ammonia and 10,000 parts by volume of hydrogen, and, in co-current therewith, 100 parts of 2,6-dimethylcyclohexan-1-one in gaseous form, is passed over the catalyst bed at atmospheric pressure. The reaction product is cooled sufficiently to liquefy the high-boiling constituents, which can then be distilled, whilst the gaseous constituents are recycled. In this way, 100 parts of 2,6-dimethylcyclohexan-1-one give 92 parts of 2,6-dimethylaniline (xylidine) (boiling point 216° C. at atmospheric pressure), corresponding to a yield of 96% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=[C:11]([N:21](C)[C:22](=O)C)[N:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:28][NH2:29]>CCO>[CH3:22][NH:21][C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH2:2])=[N:28][NH:29]3)=[CH:8][CH:7]=2)[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:12]=1
Reactant: CC(=O)N(C)c1nc(-c2ccc(C#N)c(F)c2)cc(N2CCCCC2)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCCC2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
In a 25 mL sealable tube were combined N-[4-(4-cyano-3-fluorophenyl)-6-(1-piperidinyl)-2-pyrimidinyl]-N-methylacetamide (0.04 g, 0.11 mmol) and hydrazine monohydrate (0.11 mL, 2.21 mmol) in EtOH (10 mL). The tube was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting oil was dissolved in EtOH (3 mL) followed by the addition of water (6 mL). Since no solid was observed (a yellow oil was formed), the mixture was concentrated to dryness. The resulting oil was diluted with CH3CN (2 mL) and sonicated. The resulting yellow solid was filtered, washed with CH3CN (1 mL) and dried to afford the title compound (18 mg, 48%). LC-MS (ES) m/z=324 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.60 (m, 4H), 1.68 (m, 2H), 2.92 (d, J=4.3 Hz, 3H), 3.84 (bs, 4H), 5.54 (bs, 2H), 6.81 (bs, 1H), 7.21 (bs, 1H), 7.40 (bs, 1H), 7.76 (bs, 1H), 7.85 (d, J=8.3 Hz, 1H), 11.83 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10]Cl)[CH:3]=1.[C-:12]#[N:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][C:12]#[N:13])[CH:3]=1
Reactant: [C-]#N
Reactant: COc1ccc(Cl)cc1CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(Cl)cc1CC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.2 %

Procedure:
To a solution of (5-chloro-2-methoxy-phenyl)-methanol (17.1 g, 99.1 mmol) in methylene chloride (100 mL) was added thionyl chloride (14.5 mL, 198 mmol). The reaction was stirred at reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The crude product was dissolved in methylene chloride and washed with saturated aqueous sodium hydrogen carbonate then dried over magnesium sulfate. Concentration in vacuo gave 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g). To a solution of 4-chloro-2-chloromethyl-1-methoxy-benzene (18.4 g, 96.4 mmol) in acetonitrile (100 mL) was added potassium cyanide (12.5 g, 193 mmol) and 18-crown-6 (2.54 g, 9.64 mmol). The reaction was stirred 12 hours at ambient temperature, diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by passing it through a pad of silica gel, eluting with methylene chloride to give the title compound (17.2 g).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][NH2:24]>>[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][NH:24][C:14]([C:3]1[N:4]=[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]2[C:7](=[O:8])[C:2]=1[OH:1])=[O:16]
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Reactant: Cc1ccc(CN)cc1C
Product: Cc1ccc(CNC(=O)c2nc3n(c(=O)c2O)CC(=O)N3C)cc1C
Yield: 43.8 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.070 g, 0.28 mmol) with 3,4-dimethylbenzylamine (0.15 g, 1.12 mmol) as described in the preparation of example 1 gave 0.042 g (58% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.18 (3H, s, CH3), 2.20 (3H, s, CH3), 3.14 (3H, s, NCH3), 4.42 (2H, d, J=6.3 Hz, NCH2), 4.47 (2H, s, CH2), 7.0–7.1 (3H, m, aromatics), 9.40 (1H, broad t, NH), 12.35 (1H, s, OH). MS (ESI+) m/z 343 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1ccccc1Br
Product: Clc1ccc(-c2ccccc2Br)cc1
Yield: 86.4 %

Procedure:
Following the general procedure outlined in Synthetic Scheme III, 9.0 g (38 mmol) of 1,2-dibromobenzene was reacted with 3.0 g (19 mmol) of 4-chlorophenylboronic acid (Lancaster). Purification by silica gel chromatography (Waters Prep-500A) with hexane gave 4.39 g (84%) of 1-bromo-2-(4-chlorophenyl)benzene as a colorless oil: NMR (CDCl3) δ 7.18-7.26 (m, 1H), 7.28-7.44 (m, 6H), 7.68 (dd, J=1.5, 8 Hz, 1H).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[C:32]=1[OH:33])[CH:28]=O)[CH3:23].[NH2:37][C:38]([NH2:40])=[O:39].Cl>CCO>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:40][C:38](=[O:39])[NH:37][CH:28]([C:27]3[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[C:32]([OH:33])=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)[C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(-c4ccccc4)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 14.3 %

Procedure:
A mixture of 1-(biphenyl-4-yl)-2-phenylethanone (Intermediate 14) (100 mg, 0.37 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (65 mg, 0.31 mmol), urea (66 mg, 1.1 mmol), and concentrated HCl solution (0.03 mL, 0.37 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and purified by preparative HPLC to give Compound 34 (22.52 mg, yield 14%). 1H NMR (DMSO-d6 300 MHz): δ 10.33 (s, 1H), 8.79 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.61-7.58 (m, 3H), 7.47-7.43 (m, 3H), 7.37 (d, J=6.9 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.22 (s, 1H), 7.09-7.02 (m, 3H), 6.89 (d, J=7.8 Hz, 2H), 5.21 (d, J=2.7 Hz, 1H), 4.06 (q, J=3.6 Hz, 2H), 1.34 (t, J=6.9 Hz, 3H); MS (ESI): m/z 508.1 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:38](=[O:53])[NH:39][C@H:40]([C:45](=[O:52])[NH:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-]>O1CCOCC1.O>[CH:47]1([NH:46][C:45]([C@@H:40]([NH:39][C:38]([C@@H:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@:6]2([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]2[CH:9]=[CH2:10])=[O:13])=[O:53])[C:41]([CH3:44])([CH3:42])[CH3:43])=[O:52])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)NC1CCCC1)C(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)NC1CCCC1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a solution of 52 (14 mg, 0.019 mmol) in dioxane/H2O 1:1: (4 mL) was added 1 M LiOH (115 μL, 0.115 mmol). The solution was stirred for 24 h at room temperature. Thereafter an additional portion of LiOH (75 μL, 0.075 mmol) was added and the solution was stirred for another 24 h. After acidification to approximately pH 3 with 1 M HCl and co-evaporation with toluene the residue was purified by HPLC (MeOH/H2O 70:30 with 0.2% TFA) yielding 53 (8 mg, 60%) as a colorless solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Br:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:13])[CH3:14])=[CH:10][CH:9]=[C:8]([N+:18]([O-:20])=[O:19])[C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc([N+](=O)[O-])c(C(C)C)c1NC(=O)CBr
Reaction time: 0.17 h
Yield: 95 %

Procedure:
2-Bromo-N-(2,6-diisopropylphenyl)acetamide (5.96 g, 20 mmol) was dissolved in concentrated sulfuric acid (100 ml) with ice-cooling, a solution of fuming nitric acid (1.51 g, 24 mmol) dissolved in concentrated sulfuric acid (10 ml) was dropped thereinto and the mixture was stirred for 10 minutes. The reaction solution was poured onto ice water, the separated matters were filtered off and the extraction with ethyl acetate was conducted. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was recrystallized from acetone-hexane to provide 6.52 g (yield 95%) of 2-bromo-N-(2,6-diisopropyl-3-nitrophenyl)acetamide as pale yellow needles.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[CH:33](N=C=O)([CH3:35])[CH3:34].C[N:40]([CH:42]=[O:43])C>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][N:1]([CH:33]([CH3:35])[CH3:34])[C:42]([NH2:40])=[O:43])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: CC(C)N=C=O
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Product: CC(C)N(CCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a solution of 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (0.06 g, 0.15 mmol, obtained in example 90) in DMF (1 mL), isopropylisocyanate (0.02 g, 0.18 mmol) was added under argon atmosphere. This was stirred at room temperature for 2 days. The solvent was concentrated again and diethyl ether was added to the residue obtained. The solvent was concentrated, to afford 38 mg of title compound in solid form (yield: 50%).