Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C1(N(C)C2CCCCC2)CCCCC1.[CH3:39][Si:40]([CH2:43][CH2:44][O:45][CH2:46]Cl)([CH3:42])[CH3:41]>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:46][O:45][CH2:44][CH2:43][Si:40]([CH3:42])([CH3:41])[CH3:39])[N:9]=2)[CH:5]=[C:4]([CH2:11][CH:12]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([O:15][CH3:16])=[O:14])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)Cc1cc(C)c2[nH]ncc2c1
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1
Reaction time: 8 h

Procedure:
To a solution of 4-tert-butyl 1-methyl 2-((7-methyl-1H-indazol-5-yl)methyl)succinate (0.6053 g, 1.82 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.4686 mL, 2.19 mmol) in tetrahydrofuran (10 mL) was added trimethylsilylethoxymethyl chloride (0.3859 mL, 2.19 mmol) at room temperature under nitrogen. The reaction was stirred overnight and the solvent was removed in vacuo. The crude product was taken up in ethyl acetate (10 mL) and washed with water (3×5 mL). The ethyl acetate layer was dried, filtered and concentrated. The final product was obtained by flash chromatography, eluting with 0% to 20% ethyl acetate/hexane. (0.5873 g, 70%) HPLC tR=1.89 min, MS(ESI)[M+H]+=462.94.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]([OH:25])([C:11]1[CH:16]=[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])[N:14]=[C:13]([O:21][CH3:22])[C:12]=1[CH2:23][OH:24])[CH2:9][CH3:10])(C)(C)C.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[CH2:9]([C:8]1([OH:25])[C:11]2[C:12](=[C:13]([O:21][CH3:22])[N:14]=[C:15]([Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:16]=2)[CH2:23][O:24][C:6](=[O:5])[CH2:7]1)[CH3:10]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1cc([Si](C)(C)C)nc(OC)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CC(=O)OCc2c1cc([Si](C)(C)C)nc2OC
Reaction time: 24 h
Yield: 81.6 %

Procedure:
To a 100 mL flask was added the beta hydroxy ester (6) (0.75 g, 1.9 mmol) followed by trifluoroacetic acid (150 mL). After 24 hours, the mixture was poured into sat. NaHCO3 (pH 8) and extracted with ether (3×100 mL). The organic phase was dried (MgSO4) and chromatographed (hexanes:EtOAc 2:1) to give beta-hydroxy lactone (7) 0.48 g (79%) as a white solid: IR (CHCl3, cm−1) 3020, 2978, 2873, 1742, 1561, 1448, 1384, 1348, 1110, 909, 842; 1H NMR (300 MHz, CDCl3) δ 0.22 (s, 9H), 0.83 (t, J=7 Hz, 3H), 1.81–1.88 (m, J=7 Hz, 2H), 1.37 (br s, 1H), 3.00 (d, J=14 Hz, 1H), 3.32 (d, J=14 Hz, 1H), 3.91 (s, 3H), 5.18.(d, J=15 Hz, 1H), 5.42 (d, J=15 Hz, 1H), 7.26 (s, 1H); 13C NMR (75 MHz, CDCl3) δ −1.9, 8.4, 33.9, 42.9, 53.8, 62.2, 73.8, 114.7, 121.2, 151.6, 159.8, 165.9, 172.3; HRMS (EI) m/z calcd for C15H23NO4Si (M+) 309.1396, found 309.1399 LRMS (EI) m/z 309 (M+), 294, 266, 252, 238, 89.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10]([C:19]([O:21]CC)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10]([C:19]([OH:21])=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Yield: 78.2 %

Procedure:
Part C: To a stirred suspension of ethyl 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (23.0 gram, 0.07 mol) in methanol (200 ml) is added water (15 ml) and concentrated NaOH (10 ml) and the resulting solution is heated at reflux temperature for 2 hours. The methanol is partly removed by evaporation and the residue is dissolved in a mixture of water and ethyl acetate. Ice, concentrated HCl (20 ml) and ethyl acetate are successively added, the ethyl acetate layer collected, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is washed with diethyl ether (100 ml) and diisopropyl ether respectively, to give 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid (16.46 gram, 78% yield). Melting point: 177-179° C.
Reaction SMILES: [OH:1][C:2]1([CH2:17]N)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1>O.C(O)(=O)C>[CH:13]1[C:5]2[O:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:17][C:2](=[O:1])[CH2:3][C:4]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC1(O)Cc2ccccc2Oc2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2ccccc2Oc2ccccc2C1
Yield: 78.5 %

Procedure:
10,11-Dihydro-10-hydroxy-dibenz[b,f]oxepine-10-methanamine (46.6 g - as prepared in example A) was dissolved in a mixture of water (940 ml) and acetic acid (23 ml), and the solution was filtered and cooled below 5° C. To this cooled solution was quickly added a solution of sodium nitrite (20.5 g) in the minimum of water, the cooling was then removed, and the mixture was allowed to stand at ambient temperature for eighteen hours. The product was filtered, dissolved in dichloromethane, and the solution was filtered through silica, then evaporated. The residue was crystallised from 1,1'-oxybisethane/n-hexane to give pure 5H-dibenz[b,g]oxocin-6(7H)-one (34 g). M.P. 86° C. (Lit. 84.5° C. J.Org.Chem.34.1165(1969).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[I-].[K+]>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Yield: 102.1 %

Procedure:
A solution of 4-methyl-2'-nitro-1,1'-biphenyl (Step J) (6.0 g, 28.2 mmol), N-bromosuccinimide (4.99 g, 28.2 mmol) and AIBN (653 mg) in 75 mL of carbon tetrachloride was heated at reflux until a negative potassium iodide test was obtained (1.5 h). The reaction mixture was cooled and filtered. The filtrate was evaporated under vacuum to yield 8.41 g of crude product. 1H NMR revealed the product composition was approximatly 75% monobromo and 10% dibromo, in addition to 15% of unreacted starting material. 1H NMR (200MHz, CDCl3): δ 4.53 (s, 2H), 7.2-7.7 (m, 7H), 7.85 (m, 1H). EI-MS: calculated for C14H10BrN 272; found 272,274 (M+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:29][CH2:30][N:26]([CH3:25])[C:27]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)nc3)CC2)c(C)c1
Yield: 76.7 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (389 mg) described in Preparation Example 145 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (313 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>C1COCC1>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[O:10][C:11](=[O:12])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C)c(O)c(N)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c2oc(=O)[nH]c2c1

Procedure:
A mixture of 2-amino-4,6-dimethylphenol (412 mg, 3.00 mmol) and 1,1′-carbonyldiimidazole (730 mg, 4.50 mmol) in THF (15 mL) was heated at reflux for 3 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with 1.0 N aqueous HCl (2×), then brine, then the EtOAc was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=164 (M+1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([S:30][CH3:31])=[N:28]2)=[CH:23][CH:22]=1>>[CH3:31][S:30][C:27]1[N:26]=[CH:25][C:24]2=[CH:23][CH:22]=[C:21]([C:6]3[CH:11]=[N:10][CH:9]=[CH:8][N:7]=3)[N:29]2[N:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CSc1ncc2ccc(Br)n2n1
Product: CSc1ncc2ccc(-c3cnccn3)n2n1
Yield: 44.9 %

Procedure:
Analogous to Example 1562a, 2-Tributylstannanyl-pyrazine (0.650 mL, 2.06 mmol) and 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.224 g, 0.916 mmol) were reacted to afford 2-Methylsulfanyl-7-pyrazin-2-yl-pyrrolo[2,1-f][1,2,4]triazine (0.100 g, 44%). 1H-NMR (DMSO-d6): 9.87 (s, 1H), 9.50 (s, 2H), 9.15 (s, 1H), 8.80 (m, 6H), 8.62 (s, 1H), 7.64 (d, 1H, J=4.96 Hz), 7.17 (d, 1H, J=4.96 Hz), 2.66 (s, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[OH-].[Na+].Cl>CO.C1COCC1.C(OCC)(=O)C.O>[C:3]([C:5]1[C:6]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[N:7][O:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1ccccc1
Temperature: 55 °C
Yield: 100.4 %

Procedure:
To a solution of 4-methoxycarbonyl-5-phenyl-3-(2-chloro-6-fluorophenyl)isoxazole (0.70 g, 2.1 mmol) in methanol (5 ml) and THF (2 ml) was added a solution of 2N NaOH (4 ml) at room temperature. The mixture was heated to 55° C. for 1.5 h. Upon cooling to room temperature, aqueous HCl was added until the pH was below 4. The mixture was diluted with ethyl acetate and water and the fractions separated. The organic fraction was washed (brine) and dried (MgSO4). Filtration and concentration gave the title compound (0.67 g, 100%), which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[C:23]([CH3:24])=[N:22][S:21][N:20]=1>CN(C)C=O>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH:5][CH2:18][C:19]1[C:23]([CH3:24])=[N:22][S:21][N:20]=1)[CH3:2]
Reactant: Cc1nsnc1CBr
Reactant: CCc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NCc1nsnc1C
Temperature: 100 °C
Yield: 73.7 %

Procedure:
A mixture of 68 g (0.652 mol) of 2-ethyl-6-methylaniline, 45 g (0.326 mol) of powdered potassium carbonate and 30 ml of dimethylformamide was heated to 100° C. and 63 g (0.326 mol) of 3-bromomethyl-4-methyl-1,2,5-thiadiazole were added dropwise, while stirring. The mixture was stirred at 100° C. for a further 5 hours, the inorganic precipitate was filtered off and the filtrate was distilled. 59.4 g (77.4% of theory) of 2-ethyl-6-methyl-N-(4-methyl-1,2,5-thiadiazol-3-yl-methyl)-aniline of boiling point 160°-163° C./0.3 mm Hg were obtained. ##STR18##
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:13]1)[CH:6]=[CH:5]2.C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][C:20]3[N:36]=[N:37][NH:38][N:21]=3)[CH2:13]1)[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCN[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](NCCc4nn[nH]n4)C3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[6-Chloro-2-[(3S)-3-[(2-cyanoethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (example 87 (b)) (0.15 g), trimethylsilylazide (0.091 ml), dibutyltin oxide (0.009 g) and toluene (5 ml) were heated within a single mode microwave in a sealed 10 ml vial at 100° C. for 30 minutes and then at 120° C. for 120 minutes. The reaction was cooled to room temperature, filtered and washed with toluene. The solid was then triturated with methanol and filtered before being dissolved in hot methanol and purified by Varian SCX cartridge (methanol (50 ml) and then ammonia in methanol (0.7M, 50 ml) as eluant). to afford the title compound (0.025 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([CH:16]=[C:17](O)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9].[N:25]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)=[N+:26]=[N-:27].C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:42])([F:40])[F:41])[CH:32]=1)[CH2:28][N:25]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:16]([C:11]2[C:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:27]=[N:26]1
Reactant: O=C(c1ccccc1Cl)c1cccnc1C=C(O)c1ccncc1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The reaction can also be carried out using (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone (30.0 g; 72.3 mmol; 1.0 equiv) in isopropanol (225 mL). 1-azidomethyl-3,5-bistrifluoromethylbenzene (20.43 g; 76 mmol; 1.05 equiv) and potassium carbonate (5.0 g; 36.2 mmol; 0.5 equiv) are added, and the reaction mixture is heated to reflux for 21-24 hours. Cool the reaction mixture to 20° C., add water (120 mL), and stir for approximately 16 hours. Filter, wash with 120 mL isopropanol/water (1:1 v/v), and dry under reduced pressure at 50° C. to yield the title compound, which may be recrystallized as described above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:36])[CH2:31][CH2:32][C:33](O)=[O:34])=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[CH3:22][S:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([CH2:31][CH2:32][C:33]([NH:20][CH2:19][C@@H:17]2[O:16][C:15](=[O:21])[N:14]([C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:9][CH2:10][O:11][CH2:12][CH2:13]4)=[C:2]([F:1])[CH:3]=3)[CH2:18]2)=[O:34])=[O:36])=[CH:28][CH:29]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: CSc1ccc(C(=O)CCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(=O)CCC(=O)NC[C@H]2CN(c3ccc(N4CCOCC4)c(F)c3)C(=O)O2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
(S)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl amine (0.200 gm, 0.00068 moles) was taken up in 1:1 THF-water mixture (20 ml). To this was added 4-(4-methlythiophenyl)-4-oxobutanoic acid (0.152 g, 0.00068 moles and HOBt (0.091 gm, 0.00068 moles) and the resulting mixture was cooled to 0° C., and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.142 g, 0.00074 moles) was added. The resulting mixture was allowed to warm to room temperature and then stirred for 24 hr. The reaction mixture was concentrated, 15 ml of saturated aqueous sodium bicarbonate was added to, stirred for 15 min and then extracted with ethyl acetate. The ethyl acetate layer was separated and evaporated off. The residue was chromatographed over silica gel (100-200 mesh, 20 g). The column was eluted with mixture of ethyl acetate:hexane, and finally with ethyl acetate. The combined fractions were concentrated to give the title compound (0.270 gm, 79%) as a white solid.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH2:21][CH2:22]N>C(O)C>[CH3:19][N:20]1[CH2:21][CH2:22][NH:18][C:4]1=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CNCCN
Agent: I
Solvent: CCO
Product: CN1CCNC1=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3 g prepared as described in Example 166), N-methylethylenediamine (2 ml) and absolute ethanol (35 ml) was heated under reflux for 8 hours to give a solid which was recrystallised from ethyl acetate to give 4-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 156° C.).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19](B(O)O)=[CH:18][N:17]=1>>[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:2]2[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:18][N:17]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: COc1ncc(-c2cc(C=O)c(OC)cc2OC)c(OC)n1
Yield: 75 %

Procedure:
Ex-38A: 5-(2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and 2,4-Dimethoxy-pyrimidin-5-boronic acid in a similar manner as described in Ex-3A, 75% yield. 1H-NMR (CDCl3) δ 10.34 (s, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 6.51 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:15]=2)=[N:8][C:9](Cl)=[N:10][CH:11]=1)=[O:5])C.Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][NH2:35])[CH:28]=[C:29]([Cl:32])[C:30]=1[OH:31].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN1C(=O)CCC1.CO.C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][NH:35][C:9]2[N:8]=[C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:15]=3)[C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=2)[CH:28]=[C:29]([Cl:32])[C:30]=1[OH:31]
Reactant: CCOC(=O)c1cnc(Cl)nc1Nc1cccc(C(C)O)c1
Reactant: NCCc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(O)c1cccc(Nc2nc(NCCc3cc(Cl)c(O)c(Cl)c3)ncc2C(=O)O)c1

Procedure:
2-Chloro-4-{[3-(1-hydroxyethyl)phenyl]amino}pyrimidine-5-carboxylic acid ethyl ester synthesized in accordance with the method described in WO 99/31073 and 2-(3,5-dichloro-4-hydroxyphenyl)ethylamine hydrochloride were allowed to undergo the reaction at 80 to 90° C. in NMP in the presence of diisopropylethylamine, and the resulting compound was allowed to react with 1 M sodium hydroxide aqueous solution under heating in a mixed methanol-THF solution to obtain 2-{[2-(3,5-dichloro-4-hydroxyphenyl)ethyl]amino}-4-{[3-(1-hydroxyethyl)phenyl]amino}pyrimidine-5-carboxylic acid. F: 463
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=O)[C:9]#[CH:10])[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.Cl.[C:37]([NH2:40])(=[NH:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][N:40]=[C:37]([CH3:38])[N:39]=2)[C:5]2[C:12]([O:34][CH3:35])=[N:13][N:14]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[CH:3]=1
Reactant: CC(=N)N
Reactant: C#CC(=O)c1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3ccnc(C)n3)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)prop-2-yn-1-one (60B, 63 mg, 0.132 mmol) was dissolved in acetonitrile (3 ml), charged with acetamidine hydrochloride (14.95 mg, 0.158 mmol) and sodium carbonate (34.9 mg, 0.330 mmol) and allowed to stir at 70° C. for 2 h. The solution was filtered through a syringe filter and the solvents were removed in vacuo. The residue was purified on silica gel 2-25% EtOAc/DCM to afford 6-chloro-3-methoxy-4-(2-methylpyrimidin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (63B, 58 mg, 0.112 mmol, 85% yield). MS: [M+H]+ m/z 518.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1.S(=O)(=O)(O)O>CO>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1ccc(OCCBr)c(-c2ccnn2C)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cn1nccc1-c1cc(N)ccc1OCCBr
Temperature: 90 °C
Yield: 98.6 %

Procedure:
To a solution of N-[4-(2-Bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (3 g, 8.9 mmole) in methanol (6 mL) was added Sulfuric acid (2.2 mL, 42 mmole, 4.78 eq) at 0° C. while stirring. The reaction mixture was refluxed at 90° C. for 1 hour 20 minutes. Crude was quenched with water, neutralized with saturated sodium hydroxide solution until pH 8, extracted with ethyl acetate, and then concentrated in vacuo to give title compound as a solid (2.6 g, 99%). Exact mass calculated for C12H14BrN3O 295.0, found 296.1 (M+H79Br, 100), 298.2 (M+H81Br, 98).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[C:15]1(=O)[CH2:20]CC[CH2:17][CH2:16]1>>[NH2:12][C:10]1[C:9]2[N:8]([C:15]([CH3:20])=[C:16]([CH3:17])[N:13]=2)[CH:7]=[C:6]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:14])[CH:11]=1
Reactant: CC(C)OC(=O)c1cnc(N)c(N)c1
Reactant: O=C1CCCCC1
Product: Cc1nc2c(N)cc(C(=O)OC(C)C)cn2c1C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5,6-diamino-nicotinic acid isopropyl ester (1 eq., 5.1 g) in cyclohexanone (50 ml) bromobutanone (1.2 equiv., 3.4 ml) was added over 10 min. The dark brown mixture was heated to 100° C. (inner temperature) and stirred 1.5 h at this temperature. The suspension was cooled to room temperature and the pale yellow solid was filtered off and was washed with TBME (3×10 ml). Drying under reduced pressure at 45° C. Yield: 6.0 g (74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[N:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[N:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C#N)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of methyl 3-bromo-4-cyanobenzoate (200 mg, 0.83 mmol) in dichloromethane (1.5 mL) and methanol (1.5) was added 1.0 N aqueous sodium hydroxide (1.7 mL, 1.7 mmol). The mixture was stirred vigorously for 2 h at room temperature. The volatile solvents were then removed in vacuo. The aqueous residue was acidified with 1 N aqueous hydrochloric acid and was then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to provide 3-bromo-4-cyanobenzoic acid (190 mg, 0.83 mmol, quantitative yield). 1H NMR (400 MHz, CDCl3): 8.42 (d, 1H), 8.15 (dd, 1H), 7.80 (d, 1H).