Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[Br:2][CH2:3][CH2:4][NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([F:6])=[CH:8][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCBr
Reactant: O=C(Cl)c1ccc(F)cc1[N+](=O)[O-]
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(NCCBr)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a stirred and cooled mixture of 32 parts of 2-bromoethanamine hydrobromide in 150 parts of water is added a solution of 23.5 parts of 4-fluoro-2-nitrobenzoyl chloride in 54 parts of benzene. While cooling to 0°-5° C and while stirring vigourously, there is added dropwise a solution of 13 parts of sodium hydroxide in 200 parts of water (exothermic reaction). Upon completion, stirring is continued for 2 hours at 0°-10° C. The precipitated product is filtered off, washed with water and dried, yielding 30 parts (93.6%) of N-(2-bromoethyl)-4-fluoro-2-nitrobenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]=1
Reactant: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2cc(CCC(=O)O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A mixture of ethyl 3-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (1.33 g), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionic acid (1.17 g, yield 93%), which was then recrystallized from tetrahydrofuran-hexane. melting point: 157–158° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O>[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:18]=[N+:19]=[N-:20])[CH2:10][CH2:9]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCl)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCN=[N+]=[N-])CC1
Temperature: 90 °C

Procedure:
Tert-Butyl-4-(3-Chloropropyl)-1-piperazine carboxylate and sodium-azide were dissolved (suspended) in 8 ml DMSO dry and heated to 90° C. for 15 h. The reaction mixture was allowed to cool to room temperature and pored into 50 ml of water. The product was extracted with DCM and the combined organic phases dried over MgSO4. The product was purified by flash column chromatography (n-heptane/ethylacetate 1:1, RF=0.34). Yield: 3.5 g.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([N:11]3[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=[N:12]3)[C:7](Cl)=[N:8][CH:9]=2)[CH2:3][CH2:2]1>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([N:11]3[C:15]([CH3:16])=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=[N:12]3)[CH:7]=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)cnn1-c1cc(C2CC2)cnc1Cl
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1cncc(C2CC2)c1
Yield: 52.5 %

Procedure:
Under hydrogen atmosphere, a mixed solution of 1-(5-cyclopropyl-2-chloropyridin-3-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (400 mg) in Reference Example 121 and palladium-activated carbon ethylenediamine complex (100 mg) in ethanol (50 ml) was stirred at room temperature. After completion of the reaction, the solution was filtered through Celite, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (184 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)O.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:15][CH:14]([CH3:24])[CH3:13]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CC(C)CC(O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a time-dried flask containing a near-solution of 650 mg of 4-hydroxycoumarin and 800 mg of 3-methyl-1-phenylbutan-1-ol of Preparation 16 in 25 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature. After 3 days the volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform Co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 30% to 40% ethyl acetate in hexane to yield 248 mg of the title product as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:11][C:10]=12)=[O:5])C.[OH-].[K+].O>C(O)(=O)C>[F:17][C:15]([F:16])([F:18])[C:14]1[N:9]2[CH:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[N:11]=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH:13]=1
Reactant: CCOC(=O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
A mixture of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine -8-carboxylic acid ethyl ester (5.6 g, 13.9 mmol), 2M potassium hydroxide solution (111 mL) and water (55 mL) was stirred at room temperature for 5 h, cooled (ice-water), and acetic acid (30 mL) was added. The mixture was evaporated, acetic acid (150 mL) was added and the stirred solution was heated under reflux conditions for 20 min. The reaction mixture was evaporated, water (150 mL) was added followed by extraction with ethyl acetate (2×300 mL). The combined organic layers were washed with brine (2×150 mL), dried (MgSO4) and evaporated. The crude product was further purified by cholumn chromatography on silica gel (ethyl acetate/heptane 1:1) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (1.93 g, 37%) as a yellow solid. MS (ISN) 374.3 [(M−H)−]; mp 231° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: Brc1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(OCc2ccccc2)c(-c2cncnc2)c1

Procedure:
A mixture of the product from step (ii) (0.2 g), 5-bromopyrimidine (0.16 g), sodium carbonate (0.21 g) and tetrakistriphenylphosphine palladium (0) (0.05 g) in dioxane (6 ml) was heated under reflux for 48 h. The mixture was partitioned between EtOAc and water, the organics separated, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 20% EtOAc/isohexane. Yield 0.283 g.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16]3[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=3)[N:10]=2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[O:32])C=CN=C1.C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[O:32])[CH2:21][CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(OCc1ccncc1)n1ccnc1
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3c(O)cccc3F)nc2c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)OCc4ccncc4)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg, 0.15 mmol), (pyridin-4-yl)methyl 1H-imidazole-1-carboxylate (53 mg, 0.26 mmol) and triethylamine (30.4 mg, 0.3 mmol) were added into a tube, followed by the addition of DMSO (1 mL). The mixture was stirred at room temperature for 18 h and then filtered, and purified via preparative reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) giving (pyridin-4-yl)methyl 4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate. LC/MS: m/z 474.30 (M+H)+ at 1.19 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[N:7][N:8]2COCC[Si](C)(C)C)=[CH:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>CO>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC(=O)N2CCCCC2)c2cc(-c3ccccc3)c(F)c(F)c21
Agent: Cl
Solvent: CO
Product: O=C(Nc1n[nH]c2c(F)c(F)c(-c3ccccc3)cc12)N1CCCCC1

Procedure:
80 mg of piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl)amide in 2.5 ml of methanol are treated with 0.82 ml of 2N HCl for 1 hour at reflux. After evaporation and purification by preparative LC/MS (acetonitrile/pH 9 buffer), 11 mg of piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl)amide are obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][C:3]=1[N+:16]([O-])=O.[CH3:19][C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1>>[NH2:16][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:2]=1[N:25]1[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C@H:20]1[CH3:19]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COc1ccc(Cn2ncc([N+](=O)[O-])c2Cl)cc1
Product: COc1ccc(Cn2ncc(N)c2N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)cc1

Procedure:
Following the procedure for Intermediate 33 starting with 5-chloro-1-(4-methoxybenzyl)-4-nitro-1H-pyrazole and (R)-tert-butyl 3-methylpiperazine-1-carboxylate gave (R)-tert-butyl 4-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a red gum (325 mg, 81% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.16-7.11 (m, 3H), 6.82 (d, J=8.6 Hz, 2H), 5.16 (d, J=14.8 Hz, 1H), 5.05 (d, J=14.8 Hz, 1H), 4.10-3.80 (m, 2H), 3.78 (s, 3H), 3.26-3.19 (m, 1H), 3.01 (td, J=11.4, 3.0 Hz, 1H), 2.86 (t, J=13.2 Hz, 1H), 2.66 (s, 2H), 2.57 (s, 2H), 1.47 (s, 9H), 0.81 (d, J=6.3 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14][C:15]1[NH:16][N:17]([C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([O-])=[O:33])=[CH:30][CH:29]=4)=[N:27][C:23]=3[CH:22]=2)[C:18](=[O:20])[CH:19]=1>>[CH3:14][C:15]1[NH:16][N:17]([C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:11][C:10]5[CH:12]=[CH:13][C:7]([N:4]6[CH2:3][CH2:2][O:1][CH2:6][CH2:5]6)=[CH:8][CH:9]=5)=[O:33])=[CH:30][CH:29]=4)=[N:27][C:23]=3[CH:22]=2)[C:18](=[O:20])[CH:19]=1
Reactant: Cc1cc(=O)n(-c2ccc3[nH]c(-c4ccc(C(=O)[O-])cc4)nc3c2)[nH]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: Cc1cc(=O)n(-c2ccc3[nH]c(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)nc3c2)[nH]1

Procedure:
Compound 451 was prepared from 4-morpholinoaniline and 4-(5-(3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C28H26N6O3: 495.22; found: 495.01.
Reaction SMILES: O[N:2]=[C:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.S(=O)(=O)(O)[OH:15]>C(O)C>[O:15]=[C:3]1[NH:2][CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)C1CCC(=NO)CC1
Solvent: CCO
Product: CCOC(=O)C1CCNC(=O)CC1

Procedure:
Ethyl 4-(hydroxyimino)cyclohexanecarboxylate was reacted in the presence of conc. sulfuric acid in ethanol to produce ethyl 7-oxoazepane-4-carboxylate.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]2=[CH:13][CH:14]=[CH:15][C:4]=12.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]2[CH2:13][CH2:14][CH2:15][C:4]1=2
Reactant: CCOC(=O)C1=CC2=CC=CC2=N1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2c(n1Cc1ccc(Cl)c(Cl)c1)CCC2
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Sodium hydride (25 mg, 60%), was added to a solution of ethyl cyclopenta[b]pyrrole-2-carboxylate (96 mg) (T. Aubert et al., J. Chem. Soc. Perkin Trans. 1, 1989, 1369) and the reaction stirred for 30 minutes. 3,4-Dichlorobenzyl bromide (154 mg) was added and stirring continued for a further 2 hours. The reaction was quenched by addition of water and extracted with ether. Combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatography using isohexane-5% ethyl acetate as eluent to give the product as a white crystalline solid (0.15 g, 83%), NMR d(DMSO) 1.18 (3H, t), 2.30 (1H, m), 2.53 (2H, m), 4.10 (2H, q), 5.40 (2H, s), 6.67 (1H, s), 6.92 (1H, dd), 7.25 (1H, s), 7.57 (1H, d); M/z (+) 338 (M+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[NH:17][C:16](=O)[CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>>[Cl:26][C:16]1[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=[C:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:17]=1
Reactant: O=c1cc(-c2ccccc2)nc(-c2ccccc2)[nH]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Yield: 65 %

Procedure:
Phosphorous oxychloride (9.30 mL, 99.8 mmol, 7.5 eq.) was added dropwise to 2,6-diphenyl-3H-pyrimidin-4-one (10) (3.3 g, 13.3 mmol) in a vigorous reaction. To this mixture was added slowly phosphorous pentachloride (2.77 g, 13.3 mmol, 1 eq.) and the reaction mixture was stirred at reflux for 3 hours. The reaction mixture was then quenched by pouring into ice-water, and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water and brine, dried (MgSO4) and then concentrated to give a yellow solid. This was recrystallised from hot ethanol to give fine white needles (65%). 1H NMR δ (CDCl3): 8.60-8.18 (m, 5H, Ar), 7.63 (s, 1H, Ar), 7.51-7.57 (m, 5H, Ar).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])C>C(O)C.O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([OH:19])=[O:5]
Reactant: CCOC(=O)c1ccccc1OCCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCCOc1ccccc1C(=O)O
Temperature: 50 °C
Reaction time: 7 h

Procedure:
1N sodium hydroxide solution (11.1 ml) is added to a solution of 2-(3-methoxypropoxy)-benzoic acid ethyl ester (2.4 g) in ethanol (20 ml) and water (10 ml), and the reaction mixture is stirred at 50° C. for 7 hours. The mixture is concentrated and the acidified aqueous phase is extracted with dichloremethane (3×40 ml). The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 2-(3-Methoxypropoxy)-benzoic acid, Rf (hexane-ethyl acetate-glacial acetic acid 1:2:0.1)=0.43, is obtained in the form of a yellowish oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])C.O[Li].O.Cl>CO.O>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:9]2[C:14](=[N:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
To a stirred solution of 1-Biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6) (850 mg, 2.4 mmol) in MeOH (8 mL) was added LiOH—H2O (100.2 mg, 4.8 mmol) and stirred at RT for 16 h. After completion of the reaction, distilled-off the solvent from the reaction and diluted with water. The aqueous part was acidified with 2 N HCl, extracted with EtOAC and organic layer was washed with brine. It was dried over Na2SO4, concentrated and the residue was purified by Prep-HPLC to get 1-Biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid (7) (88 mg, 11%) as off white solid.
Reaction SMILES: C([Li:5])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:22]([Sn:17]([Li:5])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: [Li][Sn](CCCC)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a Schlenk tube at −10° C., 1.7 ml (2.6 mmol) of butyllithium (1.5M in hexane) are added, dropwise, to a solution of 0.4 ml (2.6 mmol) of freshly distilled diisopropylamine in anhydrous THF (50 ml). After 5 min, 0.70 ml (2.6 mmol) of tributyltin hydride is added. The stirring is maintained for 30 min at 0° C. A pale green solution of tributylstannyllithium is obtained, which solution will be cooled to −78° C. before adding, dropwise, 294.5 μl (2.6 mmol) of 2-bromo-6-methyl-pyridine. The mixture is kept at −78° C. for two hours. After a return to ambient temperature, the solvent is evaporated off under vacuum. The residue is taken up with dichloromethane and then washed with water. The organic phase is dried over MgSO4, and evaporated to dryness. The product is purified by chromatography on an alumina column (eluent: ethyl acetate/petroleum ether=0.5/9.5), the stannylated pyridine 22 being isolated in the form of a yellow oil, with a yield of 82%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 81.7 %

Procedure:
9.6 g of N-benzyloxycarbonyl-DL-isoleucine, 3.7 g of triethylamine, 150 ml of chloroform, 3.9 of ethyl chlorocarbonate and 3.7 g of 2-amino-1,3,4-thiadiazole were subjected to a reaction similar to that in Example 1(i) to obtain 10.3 g (yield: 82%) of 2-(N-benzyloxycarbonyl-DL-isoleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 145°-149° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH3:28][NH2:29]>>[CH3:28][NH:29][C:22](=[O:23])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[CH:15][CH:16]=1
Reactant: CN
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)NC
Yield: 74 %

Procedure:
The title compound (0.23 g, 74%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.8 mmol) obtained in example 26 and methylamine (40% solution) ( 2 mL) by an analogous procedure to that described in example 32.mp: 97-99° C.
Reaction SMILES: [F:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C1COCC1.C(Cl)Cl>[Cl:10][C:9]1[C:2]([F:1])=[C:3]([CH2:4][OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(Cl)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-3-chloro-benzaldehyde (4.74 g, 30 mmol) in THF (20 mL) was added NaBH4 (1.48 g, 40 mmol). The resulting mixture was stirred at room temperature for 30 min before diluting with DCM. The organic layer was washed with water and brine. The combined organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give desired product without further purification (4.8 g, 100%). MS: 161.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc(C2(Br)CCCCC2)nc1CBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1oc(C2=CCCCC2)nc1CN1CCOCC1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
1.25 g 2-(1-Bromo-cyclohexyl)-4-bromomethyl-oxazole-5-carboxylic acid ethyl ester was dissolved in 15 ml tetrahydrofuran. 1.38 ml morpholine and 0.5 ml DBU were added and the reaction mixture stirred at 65° C. for three hours. The solvent was removed in vacuo and the resulting crude material was purified by reversed phase HPLC. The lyophilisate was dissolved in ethyl acetate and washed with saturated NaHCO3 and 2N NaOH solution the organic layer was dried over MgSO4. The solvent was removed in vacuo to obtain 580 mg 2-Cyclohex-1-enyl-4-morpholin-4-ylmethyl-oxazole-5-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[N:6]=[C:5]2[N:13]1[CH:17]=NC=N1.[CH3:18][O:19][CH2:20]CN>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[N:6]=[C:5]2[NH:13][CH2:17][CH2:18][O:19][CH3:20]
Reactant: Nc1nc(-n2cncn2)c2cc(Br)ccc2n1
Reactant: COCCN
Product: COCCNc1nc(N)nc2ccc(Br)cc12

Procedure:
The title compound was synthesized by a method analogous to example 23 using 6-Bromo-4-[1,2,4]triazol-1-yl-quinazolin-2-ylamine and 2-methoxyethylamine. The product was characterized as follows: MS (m/z) 297[M+H]+; HPLC Rt=1.05 minutes (Method B).