Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:65](OC(C)(C)C)=O)[CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([N:5]([CH3:61])[C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>C(SC)C.C(S)(S)C>[NH:1]1[CH2:65][CH2:64][CH2:63][CH2:62][C@H:2]1[C:3]([N:5]([CH3:61])[C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Agent: CCSC
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-MeDTrp-PheOH (3.68 g.) and HDTrp-Leu-MetNH2 acetate salt (part B of Example 17, 3.32 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MeDTrp-Phe-DTrp-Leu-MetNH2 in 20% yield. De-t-butoxycarbonylation of BocPro-MeDTrp-Phe-DTrp-Leu-MetNH2 (1.00 g.) using trifluoroacetic acid in methyl ethyl sulfide and ethanedithiol gave HPro-MeDTrp-Phe-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate salt monohydrate in 67% yield.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(O)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH2:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=O>O>[CH3:27][O:26][C:23]1[C:22]2[C:32](=[O:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[CH2:29][O:28][C:21]=2[C:20]([O:19][CH3:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(OC)c(OCc2ccccc2C(=O)O)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c2c1OCc1ccccc1C2=O
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To 50 g of phosphorus pentoxide is slowly added 30 ml of ethanol at room temperature and the mixture is further stirred with heating at 100° C. for 1 hour. Thereto 10 g of 2-[(2,5-dimethyoxyphenyloxy)methyl]benzoic acid is added and the mixture is stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture is added with 300 ml of water and extracted with toluene. After the extract is successively washed with a saturated solution of sodium hydrogen carbonate, water and a saturated saline solution and dried over magnesium sulfate, the solvent is distilled off under reduced pressure to give 7 g of 1,4-dimethoxy-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 270(M+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCCCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Compound 2 (133 g, 0.5635 mol) was dissolved in 1.5 L of DCM, CBr4 (280.35 g, 0.8456 mol) was added to this stirring solution and the reaction mixture was cooled to 0° C. under an inert atmosphere. PPh3 (251.03 g, 0.9571 mol) was then added in portions maintaining the temperature below 20° C. and after complete addition, the reaction mixture was stirred for 3 hours at room temperature. After completion of reaction, solid (PPh3O) precipitated out from the reaction mixture was isolated by filtration and the filtrate was diluted with crushed ice (˜1.5 kg) and extracted with DCM (3×750 mL). The organic layer was separated, dried over anhydrous Na2SO4 and distilled under vacuum. The resulting crude compound was chromatographed on 60-120 mesh silica gel column using 0-5% ethyl acetate in hexanes as eluting system to afford compound 3 (150 g, 89%) as pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ=7.33-7.25 (m, 5H), 4.49 (s, 2H), 3.47-3.41 (m, 2H), 3.41-3.37 (m, 2H), 1.86-1.80 (m, 4H), 1.62-1.56 (m, 2H), 1.42-1.29 (m, 8H).
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:22][C:19](=[O:21])[CH3:20])[C:12]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCOc1ccnc(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCCCCCCCCOc1ccnc(COC(C)=O)c1C
Yield: 54.3 %

Procedure:
To 41.4 g (0.1 mol, 1.0 eq.) of 4-nonyloxy-2,3-dimethylpyridine, 40.8 g (0.4 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 7 hours at 88 to 92° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 16.7 g of 4-nonyloxy-2-acetoxymethyl-3-methylpyridine as a black brown oily matter (total yield of two processes 54.4%).
Reaction SMILES: S(Cl)(Cl)=O.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([OH:13])=[O:12].[C:14](=O)(O)[O-].[Na+]>CO>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(O)Cc1cccs1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cccs1
Yield: 98 %

Procedure:
Thionyl chloride (10.20 ml, 140.7 mmol) was added to a solution of thiophen-2-yl-acetic acid (10.0 g, 70.3 mmol) in MeOH (100 ml) at 0° C. The reaction mixture was heated to reflux for 18 h, the volatiles were evaporated and the crude reaction mixture was basified with aqueous sodium bicarbonate solution, extracted with DCM, washed with brine and dried over anhydrous sodium sulfate. After filtration the organic solvent was evaporated and dried to afford 10.75 g (98%) of methyl 2-(thiophen-2-yl)acetate as color less liquid.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: N#Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2cccc3c2oc2ccccc23)cc1
Yield: 78.2 %

Procedure:
To a mixture of dibenzofuran-4-boronic acid (40 g, 0.19 mol), 4-bromobenzonitrile (34 g, 0.19 mol), sodium carbonate (120 g) in toluene (500 mL) and water (500 mL) was added tetrakis (triphenylphosphine)palladium (0) (11 g, 0.0095 mol) with stirring under N2 atmosphere. The reaction mixture was refluxed for 20 h. Toluene layer was separated, washed with water, dried and concentrated. The crude product was purified by column chromatography over silica gel (chloroform) to give the title compound (40 g, 79%).
Reaction SMILES: [P:1]([C:5]1([P:15]([OH:18])([OH:17])=[O:16])[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH2:10][NH+:11]2[CH3:14])=[CH:6]1)([OH:4])([OH:3])=[O:2].[Na]>>[CH3:14][N:11]1[CH:12]2[CH:7]([CH2:6][C:5]([P:15]([OH:17])(=[O:16])[OH:18])([P:1]([OH:3])(=[O:2])[OH:4])[CH2:13]2)[CH2:8][CH2:9][CH2:10]1
Reactant: C[NH+]1CC=CC2=CC(P(=O)(O)O)(P(=O)(O)O)C=C21
Agent: [Na]
Product: CN1CCCC2CC(P(=O)(O)O)(P(=O)(O)O)CC21

Procedure:
Dihydro-6,6-diphosphono-1-methyl-1-pyrindinium inner salt, monosodium salt [prepared as described in Example 4 hereinbefore] is hydrogenated using essentially the same procedure as described in Example 1 (part B) hereinbefore to provide octahydro-1-methyl-1-pyrindine-6,6-diphosphonic acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([O:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:17]=3)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([O:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:17]=3)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCS(C)(=O)=O)cc3n2C2CCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)COc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To [4-(3-Cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.21 g, 2.47 mmol) in CH2Cl2 (6 mL) was added TFA (2 mL) and stirred at room temperature for 1 h. The reaction mixture was diluted in CH2Cl2, washed with aq. NaHCO3, dried and concentrated. Trituration with acetone (5 mL) provided 2-(4-amino-phenyl)-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indole-3-carbonitrile (891 mg, 91%) as a light pink solid.
Reaction SMILES: O1[CH:7]2[CH:2]1[C:3]([CH3:20])([CH3:19])[O:4][C:5]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:6]=12.Cl([O-])(=O)(=O)=O.[Li+].[C:27]1([CH2:33][CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:15][O:14][CH2:13][O:12][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:6]2[CH:7]([NH:35][CH2:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:2][C:3]([CH3:20])([CH3:19])[O:4][C:5]=2[CH:11]=1
Reactant: COCOc1cc2c(cc1[N+](=O)[O-])C1OC1C(C)(C)O2
Reactant: NCCc1ccccc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCOc1cc2c(cc1[N+](=O)[O-])C(NCCc1ccccc1)CC(C)(C)O2
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 3,4-epoxy-7-methoxymethoxy-2,2-dimethyl-6-nitro-3,4-dihydro-2H-1-benzopyrane (332 mg, 1.18 mmol) in dioxane (1.3 mL), lithium perchlorate (126 mg, 1.18 mmol) and phenylethylamine (214 mg, 1.77 mmol) were added at room temperature, and the resulting mixture was stirred for 2 hours. Upon the completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=3/1) and the aimed product was obtained (yield: 73%).
Reaction SMILES: CO[C:3](=[O:23])[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[N:22])[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.OC(C(O)(C)C)(C)C.[BH4-].[Na+]>CO>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([CH:5]3[CH2:4][C:3](=[O:23])[NH:22][CH2:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=4)=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: COC(=O)CC(c1ccc2[nH]ccc2c1)c1ccccc1C#N
Agent: CC(C)(O)C(C)(C)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC(c2ccc3[nH]ccc3c2)c2ccccc2CN1
Reaction time: 0.75 h

Procedure:
To a mixture of 3-(2-cyano-phenyl)-3-(1H-indol-5-yl)-propionic acid methyl ester and pinacol (1:2 molar ratio, 2.1 g) in methanol (100 mL) was added sodium borohydride (2.6 g, 14 mmol), portionwise over 45 minutes. Stirring continued for 15 hours at room temperature. The reaction mixture was then filtered through Celite, washed with methanol, and the combined filtrates were concentrated. The crude material so obtained was partitioned between ethyl acetate and 5% aqueous ammonium hydroxide. The organic layer was dried over sodium sulfate, filtered and concentrated to a yellow oil which contained a mixture of 5-(1H-Indol-5-yl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one and uncyclized 3-(2-aminomethyl-phenyl)-3-(1H-indol-5-yl)-propionic acid methyl ester (not shown in Scheme B). This crude oil was suspended in 1,4-dioxane (100 mL) and heated to reflux for 40 hours, then cooled and concentrated to a brown oil and purified by flash chromatography (methanol/ethyl acetate) to afford pure 5-(1H-Indol-5-yl)-1,2,4,5-tetrahydro-benzo[c]azepin-3-one as a white solid (0.50 g). MS (M+H)=277.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:19])=[C:16](I)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.N.O.C[C:39]([N:41](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:39]([C:16]1[CH:15]=[C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=2)[CH:29]=[CH:28][C:17]=1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:19])#[N:41]
Reactant: CC(=O)N(C)C
Reactant: O=C(NCc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1I
Agent: [Fe+2]
Agent: [Pd]
Agent: N
Solvent: O
Product: N#Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a solution of 0.19 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-iodo-N-(2-pyridylmethyl)benzoic acid amide (Compound of the present invention No. 5-065) synthesized similarly to Synthetic Example 4 in 10 ml of dimethylacetamide, 36.0 mg of zinc cyanide, 4.8 mg of zinc, 11.0 mg of tris(dibenzylideneacetone) dipalladium and 13.5 mg of 1,1′-bis(diphenylphosphino)ferrocene were added, and stirred under nitrogen atmosphere at 80 to 120° C. for 5 hours. After the completion of the reaction, 30 ml of ammonia water and 20 ml of water were added in the reaction mixture, and extracted with ethyl acetate (50 ml×1). The organic phase was washed with 30 ml of water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethylacetate-hexane (2:1), and 0.05 g of the aimed product was obtained as brown resinous substance.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[F:10][C:11]1[C:16]([C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([CH:25]([S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34])[S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[C:19]([F:40])[C:18]=2[F:41])=[C:15]([F:42])[C:14]([F:43])=[C:13](F)[C:12]=1[F:45].O.Cl>N1C=CC=CC=1>[CH2:1]([O:7][C:13]1[C:12]([F:45])=[C:11]([F:10])[C:16]([C:17]2[C:18]([F:41])=[C:19]([F:40])[C:20]([CH:25]([S:26]([C:29]([F:30])([F:31])[F:32])(=[O:27])=[O:28])[S:33]([C:36]([F:37])([F:38])[F:39])(=[O:35])=[O:34])=[C:21]([F:24])[C:22]=2[F:23])=[C:15]([F:42])[C:14]=1[F:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(C(c1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCOc1c(F)c(F)c(-c2c(F)c(F)c(C(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(F)c2F)c(F)c1F
Temperature: -20 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
Hexanol (1.5 mL, 12 mmol) was added to a pyridine (10 mL) solution dissolved with 60% sodium hydride containing mineral oil (0.56 g, 14 mmol) at 0° C., and the resultant solution was stirred for 1 hour at room temperature. After the solution was cooled to −20° C., {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}bis(triflyl)methane (1.2 g, 2 mmol) was added. The reaction solution was stirred at −20° C. for 5 hours. After the reaction, the solution was acidified with 4 M hydrochloric acid water, and was extracted with diethylether. After drying with magnesium sulfate, the solution was filtrated, and the solvent was removed under reduced pressure. The crude product was purified by sublimation (0.2 to 0.3 torr, 80° C.), and {4-(4-hexanoxy-2,3,5,6-tetrafluorophenyl)-2,3,5,6-tetrafluorophenyl}bis(triflyl)methane was obtained at 94% yield (1.27 g, 1.88 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.83 to 0.94 (m, 3H), 1.26 (br, 2H), 1.33 to 1.38 (m, 2H), 1.45 to 1.52 (m, 2H), 1.84 (5, J=6.8 Hz, 2H), 4.38 (t, J=6.8 Hz, 2H), 4.32 (s, 1H); 19F NMR (CDCl3, 282 MHz) δ−75.0 (s, 6F, 2CF3), −128.4 to −128.3 (m, 1F), −133.6 (dt, J=9.1, 21.3 Hz, 1F), −134.8 (dt, J=9.1, 21.3 Hz, 1F), −139.8 to −139.6 (m, 2F), −140.7 (br, 1F), −156.5 (d, J=19.7 Hz, 2F).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.CC1(C)OC(=O)[C:35]2([CH2:37][CH2:36]2)[C:34](=O)[O:33]1.[Cl-].[NH4+]>CN(C)C=O.O>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([N:1]4[CH2:37][CH2:36][CH2:35][C:34]4=[O:33])=[CH:30][CH:29]=3)=[N:8][C:9]=2[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:11]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N4CCCC4=O)cc3)nc21
Temperature: 100 °C
Yield: 51.3 %

Procedure:
To a solution of 8-(4-amino-benzyl)-1-benzyl-3-butyl-3,7-dihydro-purine-2,6-dione (60 mg) in N,N-dimethylformamide (2 mL) was added 6,6-dimethyl-5,7-dioxa-spiro[2.5]octane-4,8-dione (Lancaster) (34 mg) and the mixture heated to 100° C. under argon for 16 hrs. The reaction mixture was cooled to RT and poured into saturated aqueous ammonium chloride, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification by chromatotron using a 2 mm silica plate eluted with 95:5 chloroform/methanol gave the desired product as a pale yellow solid (36 mg). MS, m/z(M+)=471.2272.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(CC)CC.[Cl:15][C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[C:36]4[CH2:40][CH2:41][NH2:42])[N:27]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[C:36]4[CH2:40][CH2:41][NH:42][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:27]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:24])[CH3:25]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN)c[nH]c34)no2)cc1Cl
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CNCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.3 %

Procedure:
Ethyl bromoacetate (167 mg) and Et3N (101 mg) were added to the solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethanamine (D84) (530 mg) in toluene (3 mL). The resulting reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by Mass Directed Auto Prep to afford ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}glycinate (D86) (132 mg) as a yellow solid. MS (ES): C25H27ClN4O4 requires 482; found 483.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])([O-:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1cc(Cl)ccc1O
Yield: 44.8 %

Procedure:
Using 5-chlorosalicylic acid and 4-nitro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4](Cl)[N:3]=1.CC1C=CC=CC=1C.[NH:19]1[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1.[OH-].[Na+]>O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:19]2[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: C1=CCNCC1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Temperature: 5 °C

Procedure:
155 G. of 2,4-diamino-6-chloropyrimidine-3-oxide are mixed under an argon atmosphere with 640 ml. of o-xylene and 260 ml. of 1,2,5,6-tetrahydropyridine and the mixture is stirred. The mixture is then heated to reflux for 30 minutes, the internal temperature rising from 115° C. to 123° C. The mixture is then cooled to 5° C., treated with 40 g. of sodium hydroxide in 400 ml. of water and stirred at 5° C. for 1 hour. The precipitate formed is filtered off, washed with 200 ml. of water and recrystallized from 3000 ml. of water, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-pyrimidine-3-oxide, having a melting point of 263°-265° C. (decomposition).
Reaction SMILES: OC1C=CC=C2C=1[NH+]=CC=C2.[O:12]=[C:13]1[C@@H:16]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:15][N:14]1S([O-])(=O)=O.CC(C)=O>C(O)C>[C:22]1([CH2:21][O:20][C:18]([NH:17][C@H:16]2[CH2:15][NH:14][C:13]2=[O:12])=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@H]1CN(S(=O)(=O)[O-])C1=O)OCc1ccccc1
Agent: Oc1cccc2ccc[nH+]c12
Solvent: CCO
Solvent: CC(C)=O
Product: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A stirred suspension of 1.00 g of (3S)-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, 8-hydroxyquinolinium salt in 75 ml of anhydrous ethanol under nitrogen was placed in a 95° C. oil bath. The mixture was refluxed for 20 minutes, then cooled to 20° C. with an ice water bath. The solvent was removed on the rotary evaporator (bath temperature ≥30° C.). The residue was taken up in 10 ml of water and 80 ml of ethyl acetate. About 600 mg of MgSO4 was added followed by 570 mg of sodium bicarbonate. The mixture was stirred to effect solution. The organic layer was separated, washed with 5 ml of water, and dried over MgSO4. The solvent was evaporated to afford a white solid, which was tranferred to a 25 ml flask with acetone. The acetone was removed in vacuo and the solid residue was suspended in ca. 5 ml of ethyl acetate. Ether (ca. 6 ml) was added and the mixture was stored for 60 minutes at 0° C. The solid was isolate by filtration, washed with ether, and dried in vacuo to afford 392 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]2)[CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:30])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([OH:29])[CH2:24]2)[CH:3]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@H](O)C3)c12
Reactant: N
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@H](O)C3)c12

Procedure:
Prepared analogously to example 1.4 from 5.6 g racemic racemic 4-[4-Fluoro-2-((trans)-3-hydroxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 100 ml ammonia (0.5 M in THF).