Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].S(=O)(=O)(O)O.Cl[O-].[Na+].S([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COC1CCCC[C@@H]1O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@H]1CCCCC1=O
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 500-ml four-mouth flask equipped with a thermometer, dropping funnel, condenser, and stirrer was charged with 13.0 g (0.1 mol) of (S)-2-methoxycyclohexanol having an optical purity of 99.8% ee, 7 g of dichloromethane, and 30 g of 10% aqueous solution of sulfuric acid (30 mmol). The reactants were stirred at 20-25° C. The flask was further charged with 60 g of aqueous solution of sodium hypochlorite containing 12.1% effective chlorine over about 1 hour. Stirring was continued for 30 minutes. The reaction solution was analyzed by gas chromatography to confirm that the peak due to (S)-2-methoxycyclohexanol had disappeared. The reaction solution was given 2 g of sodium hydrogensulfite with stirring. It was confirmed that the reaction solution did not change potassium iodide starch paper into purple any longer. The reaction solution was extracted twice with 200 g of dichloromethane. The dichloromethane layers were combined together and washed with 30 g of 30% aqueous solution of sodium carbonate. After stirring at 20-25° C. for 1 hour, it was confirmed that the water layer had a pH higher than 7.5. The water layer was discharged, and the dichloromethane layer was washed with saturated aqueous solution of sodium chloride. Upon concentration and distillation, there was obtained 11.5 g (90 mmol) of (S)-2-methoxycyclohexanone. The chemical purity of this compound was 99.6%. One gram of this compound was placed in a glass ample and sealed, with the atmosphere therein replaced with argon. The ample was heated at a prescribed temperature for 60 hours. After cooling to room temperature, the ample was opened and the content was tested for optical purity. The results are shown in Table 2.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.[C:22]1([N:28]=[N:29][CH:30]([C:33]#[N:34])[C:31]#[N:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]2[N:16]=[C:31]([NH2:32])[C:30]([N:29]=[N:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:33]([NH2:34])[N:17]=2)=[N:6]1
Reactant: N=C(N)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Reactant: N#CC(C#N)N=Nc1ccccc1
Solvent: CCO
Product: Nc1nc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)nc(N)c1N=Nc1ccccc1
Temperature: 110 °C
Yield: 99 %

Procedure:
A suspension of 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamide (Intermediate-6, 0.38 mmol) and 2-(phenyldiazenyl)malononitrile (1 equiv) in ethanol (6 mL) in a sealed tube was heated at 110° C. for 2 h. The reaction was conc. to afford 2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine as an orange solid (>99% yield).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH2:13][C@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[CH2:13][OH:12])=[N:3][N:4]=2)[CH:7]=1
Reactant: OC[C@H]1CCCN1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: OC[C@H]1CCCN1c1nnc2ccc(F)cn12
Temperature: 160 °C
Yield: 53.5 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (R)-(−)-2-(hydroxymethyl)-pyrrolidine (704 mg, 9.96 mmol) in NMP (6 mL) was heated in the microwave at 160° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (75 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (220 mg, 53%). LCMS (Method 4): Rt 1.50, m/z 237 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.Br[C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[CH:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[CH:37]=[C:33]1[C:19]1[CH:20]=[CH:21][C:16]2[O:15][CH2:14][CH2:13][N:12]([C:10]3[S:9][C:5]4[C:6](=[O:8])[NH:7][C:2]([CH3:1])([CH3:31])[CH2:3][C:4]=4[N:11]=3)[C:17]=2[CH:18]=1
Reactant: Brc1cc2ccccc2s1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(B5OC(C)(C)C(C)(C)O5)cc43)sc2C(=O)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2nc(N3CCOc4ccc(-c5cc6ccccc6s5)cc43)sc2C(=O)N1
Yield: 6.1 %

Procedure:
A stirred solution of Example 292 (0.048 g, 0.109 mmol), 2-bromobenzothiophene (0.035 g, 0.163 mmol), potassium phosphate (0.045 g, 0.212 mmol), tetra-n-butyl-ammonium bromide (0.045 g, 0.140 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.008 g, 0.007 mmol) in THF (2 mL) and H2O (0.5 mL) was heated to 100° C. in a sealed vessel under a nitrogen atmosphere for 1 h. The reaction mixture was diluted with DCM (10 mL) and washed with water (10 mL) and brine (10 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.003 g, 7%) as a white solid. δH (CDCl3) 8.35 (1H, d, J 2.1 Hz), 7.88-7.73 (2H, m), 7.46 (1H, s), 7.41 (1H, dd, J 8.5 and 2.1 Hz), 7.37-7.28 (2H, m), 7.01 (1H, d, J 8.5 Hz), 5.27 (1H, s), 4.42-4.35 (2H, m), 4.23-4.17 (2H, m), 2.91 (2H, s), 1.42 (6H, s). LCMS (ES+) 448 (M+H)+, RT 4.37 minutes (Method 1).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:40])[C@@H:16]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:17][C:18]2[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:41]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])[CH:42]=[CH2:43].C(N(CC)CC)C>CN(C=O)C.C(O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([CH:7]([O:14][C:15](=[O:40])[C@@H:16]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH:43]=[CH:42][C:41]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:22][CH:23]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C
Yield: 53.8 %

Procedure:
Bis(triphenylphosphine) palladium dichloride (120 mg, 0.2 mmol) was added to a deoxygenated mixture of (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[4-[[(trifluoromethyl)sulfonyl]oxy]phenyl]propanoic acid diphenylmethyl ester (3.0 g, 5.2 mmol), t-butyl acrylate (1.5 mL, 10.2 mmol) and triethylamine (4.0 mL, 30.0 mmol) in DMF (50 mL) and the well-stirred suspension was then heated at 90° C. (24 h). The solvent was removed in vacuo and the resulting residue was purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and hexanes (8:1) to give the (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]propanoic acid diphenylmethyl ester (1.6 g, 2.8 mmol) in 54% yield, mp. 135°-137° C., [α]D -5.35° (0.97 % in ethanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH2:26]([O:28][C:29](=[O:34])[C:30](Br)([CH3:32])[CH3:31])[CH3:27].[OH-].[Na+].Cl>CC(N(C)C)=O>[CH2:26]([O:28][C:29](=[O:34])[C:30]([O:9][C:6]1[CH:5]=[CH:4][C:3]([CH:10]([CH3:25])[C:11]([OH:16])([C:17]2[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[C:12]([F:15])([F:13])[F:14])=[C:2]([Cl:1])[C:7]=1[Cl:8])([CH3:32])[CH3:31])[CH3:27]
Reactant: CC(c1ccc(O)c(Cl)c1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 46.2 %

Procedure:
5-[2-(2,3-Dichloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 197, step 5; 198 mg, 0.50 mmol) and 2-bromo-2-methyl-propionic acid ethyl ester (0.23 mL, 1.5 mmol), were dissolved in 1 ml dimethylacetamide and treated with 60 mg NaOH (finely powdered). After 3 h stirring at rt 2-bromo-2-methyl-propionic acid ethyl ester (0.11 mL, 0.75 mmol) was added, followed by 30 mg NaOH (finely powdered). After 19 h stirring at rt, the reaction mixture was poured on ice-water (10 mL) and the pH adjusted to 3 with aqueous 2N HCl. The reaction mixture was then extracted twice with ethyl acetate, the combined organic phases washed with water and brine, dried over magnesium sulfate, filtered-off and concentrated in vacuo. The residue was purified by flash chromatography (8 g SiO2, EtOAc/heptane 2:1) to give 118 mg of the title compound as colorless viscous oil. MS (M+H+)=510.2
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C([C@@H]1C[C@H](O)C[C@@H]1C(OCC)=O)C.C(N(CC)CC)C.[N+:66]([C:69]1[CH:89]=[CH:88][C:72]([C:73]([O:75][C@@H:76]2[CH2:80][C@@H:79]([CH2:81][CH3:82])[C@@H:78]([C:83]([O:85][CH2:86][CH3:87])=[O:84])[CH2:77]2)=[O:74])=[CH:71][CH:70]=1)([O-:68])=[O:67]>C1COCC1>[N+:66]([C:69]1[CH:89]=[CH:88][C:72]([C:73]([O:75][CH:76]2[CH2:80][CH:79]([CH2:81][CH3:82])[CH:78]([C:83]([O:85][CH2:86][CH3:87])=[O:84])[CH2:77]2)=[O:74])=[CH:71][CH:70]=1)([O-:68])=[O:67]
Reactant: CCOC(=O)[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1CC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCOC(=O)[C@H]1C[C@@H](O)C[C@H]1CC
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To triphenylphosphine (34.9 g, 133 mmol) in THF (150 mL) at about 0° C. was added a solution of DIAD (26.2 mL, 133 mmol) in THF (20 mL) through an additional funnel. After about 30 min, a solution of 4-nitrobenzoic acid (22.26 g, 133 mmol) in THF (150 mL) was added followed by a solution of a scalemic mixture enriched with (1S,2R,4S)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (16.54 g, 89 mmol) in THF (20 mL) and triethylamine (55.7 mL, 400 mmol). After about 1 h, the ice water bath was removed and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was diluted with heptane (800 mL), washed with water (200 mL), saturated aqueous NaHCO3 (150 mL) and brine (150 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. After about 300 mL of solvent was removed, the solid was filtered off and washed with heptane (25 mL). The filtrate was concentrated under reduced pressure and the residue was purified using silica gel chromatography eluting with 10-40% EtOAc in heptane to give a scalemic mixture enriched with (1R,3S,4R)-3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate (26.77 g, 90%): LC/MS (Table 1, Method b) Rt=2.84 min; MS m/z: 394 (M−H)−.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[S:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[S:36][N:35]=[CH:34][N:33]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@H]2CCCCC[C@@H]2c2ccccc2)cc1F
Yield: 79.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-phenylcycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (140 mg, 0.227 mmol) prepared in Example 7a, triethylsilane (0.3 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (84.4 mg, 80%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:21]([O:23][C:24]2[CH:33]=[CH:32][C:27]([C:28](OC)=[O:29])=[CH:26][CH:25]=2)[CH3:22])=[N:6][CH:7]=1.[CH3:34][NH2:35]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[CH:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:35][CH3:34])=[O:29])=[CH:32][CH:33]=2)[CH3:22])=[N:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1ccc(OC(C)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Product: CNC(=O)c1ccc(OC(C)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1

Procedure:
Prepared from hydrolysis of methyl 4-(1-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}ethoxy)benzoate (EXAMPLE 137.1) followed by methylamine coupling, using a similar procedure as described in the preparation of examples 132.11.1 and B2.11.2. MS: M+H=484.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH:2]([NH:1][C:37]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12)=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol (2.89 g, 8.04 mmol) in acetonitrile (50 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (1.51 g, 8.04 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.31 g, 12.06 mmol) and 1-hydroxybenzotriazole hydrate (1.23 g, 8.04 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to give the objective substance (2.75 g, 65%) as an amorphous compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:10]([CH3:11])[C:9]([CH3:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:17].C(Cl)Cl.[OH-].[Na+]>O>[Cl:17][C:4]1[C:5]2[N:10]([CH3:11])[C:9]([CH3:12])=[C:8]([CH3:13])[C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(C)c(C)n(C)c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(Cl)c2c(n1)c(C)c(C)n2C
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A mixture of 2,5,6,7-tetramethyl-3H,4H,5H-pyrrolo[3,2-d]pyrimidin-4-one N9b (0.334 g, 1.75 mmol) and POCl3 (4 ml) is stirred at 100° C. for 17 hours. At 0° C. DCM (30 ml) and aqueous sodium hydroxide (1 mol/1, 20 ml) is added under vigorous stirring. The water phase is made basic with an aqueous solution of sodium hydroxide (1 mol/l) and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is used without further purification. Yield: 330 mg (90%). HPLC-MS: M+H=210; tR=0.92 min (METHOD—1).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:21]=[O:22]>>[CH3:1][C:2]1[CH:6]([CH:21]=[O:22])[C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NN(c2ccccc2)C(=O)C1C=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
29 Grams of 3-methyl-1-phenyl-2-pyrazoline-5-one and 40 ml of dimethylformamide were charged into a 200-ml three-necked flask, stirred and cooled to 0° C. in an ice-acetone bath. Then, 18.5 g of phosphorus oxychloride (POCl3) was placed in a dropping funnel, and while it was maintained at 10 to 20° C., it was dropwise added. After the addition, the mixture was heated for 1 hour, then, a reaction mixture was poured into 600 ml of ice water, and the mixture was allowed to stand for one day and night. A crystal was recovered by suction filtration, fully washed with water and dried to give the captioned compound. Yield: 65%, Melting point: 178-180° C. (documented value: 174-175° C.).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:20]([NH:22][C:23]4[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=4)[O:26][CH2:27][C:28]([OH:30])=[O:29])=[N:19][CH:18]=[N:17][C:16]=3[O:15][C:14]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:9][CH:8]=1.Cl>ClCCl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:20]([NH:22][C:23]4[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=4)[O:26][CH2:27][C:28]([OH:30])=[O:29])=[N:19][CH:18]=[N:17][C:16]=3[O:15][C:14]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC(=O)O)c4)c23)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(O)cc4)c23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Add 109 mg (0.435 mmol) of boron tribromide at RT to a mixture of 170 mg (0.364 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxyacetic acid and 4.5 ml of dichloromethane. Stir the mixture at RT overnight and then hydrolyse with 1N hydrochloric acid. After adding dichloromethane, filter off the insoluble solid and dry overnight under high vacuum. 128.6 mg of the target compound are obtained, which can be purified further by recrystallization from isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([S:24][CH2:25][CH3:26])[C:21]([F:27])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH3:28]OC(OC)N(C)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:27])=[C:22]([S:24][CH2:25][CH3:26])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:28]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(SCC)nc1Nc1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(SCC)c(F)cc2c1=O
Yield: 70.1 %

Procedure:
In 3 ml of benzene was dissolved 160 mg of ethyl 2-[2-(2,4-difluorophenylamino)-6-ethylthio-5-fluoronicotinoyl]acetate, and 72 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 2.5 hours. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene-ethyl acetate (10:1 by volume)] to obtain 115 mg (yield 70.1%) of ethyl 1-(2,4-difluorophenyl)-7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 169.5°-171° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:19]([OH:21])=O)[CH:5]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>>[NH:36]1[C:35]([NH:34][C:19]([C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][CH2:17][CH3:18])=[CH:14][CH:15]=3)[N:7]=2)=[O:21])=[N:39][N:38]=[N:37]1
Reactant: CCNc1ccc(-c2cc(OCC)cc(C(=O)O)n2)cc1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCNc1ccc(-c2cc(OCC)cc(C(=O)Nc3nnn[nH]3)n2)cc1
Yield: 69.5 %

Procedure:
In the same manner as described in Example 1-(1), 4-ethoxy-6-(4-ethylaminophenyl)-2-pyridinecarboxylic acid (0.28 g), carbonyldiimidazole (0.17 g) and 5-aminotetrazole (0.09 g) are reacted to give N-(5-tetrazolyl)-4-ethoxy-6-(4-ethylaminophenyl)-2-pyridinecarboxamide (0.24 g). M.P. 255°-257° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[O-:27][CH2:28][CH3:29].[Na+]>>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][O:27][CH2:28][CH3:29])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: CC[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: [Na+]
Product: CCOCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (50 mg) was added to a freshly prepared sodium ethoxide solution (0.087M, 2 ml), and the reaction stirred at room temperature for 72 hours. The reaction was partitioned between ethyl acetate and water, the organic phase dried (sodium sulphate) and reduced to dryness under vacuum. The residue was purified by HPLC to give, after evaporation of the solvent, N-cyclopropyl-4′-[5-(ethoxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.