Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.Br[C:5]1[CH:6]=[C:7]([N+:17]([O-:19])=[O:18])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][CH:10]=1.[F:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I.O>[F:20][C:21]1[N:26]=[CH:25][C:24]([C:5]2[CH:10]=[N:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=[N+]([O-])c1cc(Br)cnc1-c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccc(F)nc2)cnc1-c1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocnee]dichloropalladium(II), w/DCM (7.32 mg, 8.96 μmol) was added to a solution containing 5-bromo-3-nitro-2-phenylpyridine (0.05 g, 0.179 mmol), (6-fluoropyridin-3-yl)boronic acid (0.025 g, 0.179 mmol), Copper(I) iodide (3.41 mg, 0.018 mmol) and Potassium carbonate (0.134 ml, 0.269 mmol) in DMF (Volume: 0.597 ml). Heated the reaction in a microwave at 110° C. for 15 minutes. Let the reaction cool to room temperature. Diluted reaction with water, dried, filtered, concentrated and purified with Combiflash using 0% to 25% ethyl acetate in hexanes to afford 6′-fluoro-5-nitro-6-phenyl-3,3′-bipyridine (0.03 g, 0.102 mmol, 56.7% yield).
Reaction SMILES: COC1C=C[C:6]([CH2:7][N:8](CC#C)[C:9]2[C:10](=[O:29])[N:11]([CH3:28])[N:12]=[C:13]([O:15][CH2:16][C@H:17]3[CH2:19][C@@H:18]3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:14]=2)=[CH:5]C=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C@H:18]2[CH2:19][C@@H:17]2[CH2:16][O:15][C:13]2[CH:14]=[C:9]([NH:8][CH2:7][C:6]#[CH:5])[C:10](=[O:29])[N:11]([CH3:28])[N:12]=2)=[N:21][CH:22]=1
Reactant: C#CCN(Cc1ccc(OC)cc1)c1cc(OC[C@H]2C[C@@H]2c2ccc(OC)cn2)nn(C)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C#CCNc1cc(OC[C@H]2C[C@@H]2c2ccc(OC)cn2)nn(C)c1=O

Procedure:
A solution of compound 2 (180 mg, 0.39 mmol) in TFA (5 mL) was stirred at room temperature for 2 h, then pH was adjusted to 7-8 with saturated NaHCO3 solution. Extracted with EtOAc (20 mL*3) and washed with H2O and brine, the organic phase was concentrated to give the title compound. ESI-MS: 341.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH2:32])[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([CH:30]([NH:32][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=2)[CH3:31])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: CCCOc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 98.2 %

Procedure:
Following a similar procedure to that described in Example (1a), 790 mg of 3-nitrophenyl 4-propoxyphenyl ketone, 870 mg of 1-(3,5-difluorophenyl)ethylamine, 1.54 ml of triethylamine, 0.37 ml of titanium tetrachloride, 733 mg of sodium cyanoborohydride and 0.24 ml of acetic acid were reacted, to obtain 1.16 g of the title compound as a yellow oil.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.N([O-])=[O:13].[Na+]>C(O)=O.C(O)(=O)C.Cl.O>[CH3:11][C:7]1[C:5]2[NH:6][C:2](=[O:13])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CC(=O)O
Product: Cc1cccc2sc(=O)[nH]c12
Temperature: 25 °C

Procedure:
5.00 g (30.5 mmol) 2-amino-4-methylbenzothiazole in 15.0 mL formic acid, 6.10 mL glacial acetic acid and 112 mL conc. hydrochloric acid were cooled to −5° C. with stirring and slowly combined with a solution of 2.10 g (30.5 mmol) sodium nitrite in 5.0 mL water. The reaction mixture was stirred for 20 min at this temperature, then heated to RT and then refluxed overnight. The cooled mixture was then mixed with water and extracted several times with EtOAc. The combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulphate, filtered and the filtrate was evaporated down.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5].[O-]S(C(F)(F)[F:41])(=O)=O.F[N+]1C(Cl)=CC=CC=1Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([C:31]=1[F:41])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2[nH]c3ccccc3c2F)s1

Procedure:
N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-indole-2-carboxamide is dissolved in dichloroethane, and reacted with 1-fluoro-2,6-dichloropyridinium triflate to give N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-fluoroindole-2-carboxamide.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5]>C(N(CC)CC)C.CC(=O)CC>[C:4]([CH:3]([CH2:2][CH2:3][C:4](=[O:6])[CH3:5])[C:2](=[O:7])[CH3:1])(=[O:6])[CH3:5]
Reactant: CC(=O)CC(C)=O
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CCC(C(C)=O)C(C)=O
Reaction time: 42 h
Yield: 61.6 %

Procedure:
60 g of 2,4-pentandione and 0.1 g of triethyl amine were mixed, and 28 g of 2-butanone was added dropwise at room temperature. The mixture was stirred for 42 hours and the raw product was distilled off. Re-distillation gave 31.4 g of 3-acetyl-2,6-heptandione.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:21]=[CH:22]S(C2C=CC=CC=2)(=O)=O)[CH:15]=[CH:16][C:17]=1[CH3:18].COC(C)(C)C>C1COCC1>[CH2:1]([O:8][CH:22]=[CH:21][C:20](=[N:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=1)[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1cccc(OC(C=CS(=O)(=O)c2ccccc2)=Nc2ccc(C)c(C)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cccc(OC(C=COCc2ccccc2)=Nc2ccc(C)c(C)c2)c1
Reaction time: 0.5 h
Yield: 114.8 %

Procedure:
To a solution of benzyl alcohol (0.78 g) in THF (15 mL) was added 60% sodium hydride (90 mg) under a nitrogen atmosphere under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added dropwise to a solution of 3-methylphenyl N-(3,4-dimethylphenyl)-3-(phenylsulfonyl)acrylimidate (0.78 g) in anhydrous THF (15 mL) under ice-cooling. The mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added tert-butyl methyl ether (80 mL), which was washed with a 1N aqueous sodium hydroxide solution, water and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 3-methylphenyl 3-benzyloxy-N-(3,4-dimethylphenyl)acrylimidate (0.82 g).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.P(Cl)(Cl)(Cl)=O.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](S)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].Cl.[CH:32]([OH:35])([CH3:34])[CH3:33]>C(OCC)C>[OH:35][C:32]1([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH2:3][N:2]([CH3:13])[CH3:1])[C:34]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH2:25][CH2:33]1
Reactant: Cc1ccc(S)cc1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: CC(C)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC=C(c1ccccc1)C1(O)CCCc2ccccc21

Procedure:
By using a method similar to that described in Example 35, but starting from 3-dimethylaminoacrylophenone (5 g), phosphorus oxychloride (2.47 cc), 4-methylthiophenol (3.55 g) and sodium cyanoborohydride (1 g), and after evaporating the organic phase to dryness under reduced pressure (2.7 kPa) at 40° C., an orange oil is obtained which is dissolved in isopropanol (40 cc). A 5.6N solution (7 cc) of hydrochloric acid gas in ethyl ether is added to this solution. The precipitate formed is separated off by filtration and then recrystallised from isopropanol (40 cc). In this way 1-dimethylamino-3-(4-methylphenylthio)-3-phenyl-2-propene (Z) hydrochloride (3.3 g) is obtained in the form of a white solid melting at 197°-198° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[S:15][C@H:14]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:11].C1(OC)C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]([OH:24])=[O:23])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[S:15][C@H:14]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Sc2ccccc21
Agent: Br
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 25 °C
Yield: 78.3 %

Procedure:
While a mixture of 5 g of tert-butyl trans-3-(2-indolecarboxamido)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 15 ml of acetic acid and 2 ml of anisole is stirred at room temperature, 21 ml of a 30% solution of hydrobromic acid-acetic acid is added to the mixture dropwise. After the mixture is stirred at room temperature for 9 hours, the resulting crystals are collected by filtration and washed with ethyl acetate to give 3.5 g of trans-3-(2-indolecarboxamido)- 4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, m.p. 260°-270° C. (decomposition).
Reaction SMILES: [C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16]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.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH:24][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:17][CH2:16]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
Reactant: NCCCN1CCC(NC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(NC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 51.3 %

Procedure:
3.12 g of 4-(diphenylmethylamino)-1-piperidinepropanamine and 1.72 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 180° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure. The residue was crystallized by the addition of ethyl ether-hexane (1:3), collected by filtration, washed with hexane and dried to yield 1.83 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([OH:10])[N:3]=1.Cl[CH:12](Cl)[C:13]([CH2:15]Cl)=O.[NH2:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([NH:25][C@H:26]([C:32]([OH:34])=[O:33])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:21][CH:20]=1.N([O-])=O.[Na+].C([O-])(=O)C.[Na+]>>[CH:21]1[C:22]([C:23]([NH:25][C@H:26]([C:32]([OH:34])=[O:33])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:35][CH:36]=[C:19]([NH:18][CH2:15][C:13]2[N:9]=[C:5]3[C:4]([N:3]=[C:2]([NH2:1])[NH:7][C:6]3=[N:8][CH:12]=2)=[O:10])[CH:20]=1
Reactant: Nc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reactant: Nc1nc(N)c(N)c(O)n1
Reactant: O=C(CCl)C(Cl)Cl
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Product: Nc1nc(=O)c2nc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2[nH]1

Procedure:
At present, PteGlu of folic acids is industrially produced through chemical synthesis. Briefly, three components of 2,4,5-triamino-6-hydroxypyrimidine, 1,1,3-trichloroacetone and p-aminobenzoylglutamic acid are condensed in the presence of sodium nitrite in a solution of sodium acetate to give a crude product of folic acid, PteGlu, and the product is purified through recrystallization.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23]1>>[OH:22][CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1CO1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: CC(C)C(O)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 58 with 1,2-epoxy-3-methylbutane gave 2-(3-(3-(2-hydroxy-3-methylbutoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (1.105 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.11-8.14 (m, 1H), 7.52-7.57 (m, 2H), 7.33-7.36 (m, 1H), 7.17-7.21 (m, 1H), 6.85 (s, 1H), 6.74 (dd, J=8.4, 2.0 Hz, 1H), 3.75 (d, J=5.6 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.84-2.03 (m, 5H), 1.03 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][Mg]Br.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Br:9][C:10]1[CH:11]=[C:12]([CH2:13][CH:1]([NH2:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Br[Mg]Cc1cccc(Br)c1
Reactant: N#Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NC(Cc1cccc(Br)c1)c1ccccc1
Yield: 31.4 %

Procedure:
Benzonitrile (500 mg, 4.849 mmol) was added dropwise to a solution of 3-bromobenzylmagnesium bromide (0.275 M solution in diethyl ether, 21.1 ml, 5.818 mmol) under an atmosphere of nitrogen at room temperature. The reaction mixture was then heated to reflux for a period of 2 hours then allowed to cool. Lithium aluminium hydride (1.0 M in THF, 4.85 ml, 4.849 mmol) was then added cautiously and the reaction mixture was allowed to heat at reflux for a further 16 hours. Upon cooling, the reaction was quenched by cautious and dropwise addition of water (5 ml) and then partitioned between water (20 ml) and ethyl acetate (100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. Purification by ion exchange chromatography afforded the desired compound (420 mg, 31%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](C=O)[CH:8]=2)[CH:3]=[CH:2]1.C(O)(=O)C.NC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)CC1C=C(F)C=C(F)C=1.[BH4-].[Na+]>CC(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: c1ccc2[nH]ccc2c1
Reaction time: 12 h
Yield: 62.8 %

Procedure:
To a stirred solution of 1H-indole-6-carbaldehyde (99 mg, 0.68 mmol) and tert-butyl (1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate acetate 3 (256 mg, 0.68 mmol) in 2-propanol (3 mL) was added sodium borohydride (30 mg, 0.82 mmol). The reaction mixture was stirred for 12 h., quenched with methanol, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided indole (50 mg): 1H NMR (300 MHz, CDCl3) δ 8.41 (br s, 1H), 7.60 (d, J=8 Hz, 1H), 7.38 (s, 1H), 7.21 (t, J=3 Hz, 1H), 7.04 (dd, J=8, 1 Hz, 1H), 6.71–6.73 (m, 3H), 6.61–6.68 (m, 1H), 6.53 (s, 1H), 5.38 (br s, 2H), 4.66 (d, J=9 Hz, 1H), 3.89 (s, 2H), 3.49–3.54 (m, 1H), 2.91–2.98 (m, 1H), 2.62–2.73 (m, 3H), 1.35 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([OH:18])=[CH:9][CH:8]=2)=[O:4].Cl[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([O:18][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cn3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 18 from 5-hydroxyindole-1-(4-isopropoxyphenyl)-2,3-dicarboxylic acid dimethyl ester (104 mg, 0.27 mmol, see (a) above) and 2-chloro-5-trifluoromethylpyridine (74 mg, 0.41 mmol). Yield 100 mg (70%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=[CH:25][CH:24]=2>O>[CH2:7]([O:33][C:31](=[O:32])[CH2:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][C:21]=1[CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c2ccccc2c1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon gas, potassium carbonate (2.52 g) and benzyl bromide (1.2 mL) were added to dimethyl formamide (20 mL) solution containing 2-(2-methylindol-3-yl)acetic acid (1.73 g), which was stirred at room temperature for 2 hours. The reaction mixture was radiationally cooled and water was added, and then the mixture was extracted by ethyl acetate. The extract was sequentially washed with water and saturated brine and dried by sulfuric anhydride sodium, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give a title compound (2.63 g) having the following physical properties was obtained.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)(=O)C>[Cl:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([S:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][CH:6]=1
Reactant: N#Cc1nc(Cl)cnc1Cl
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cnc1Sc1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In 50 mL of N,N-dimethylformamide was dissolved 10.0 g of 3,6-dichloro-2-pyrazinecarbonitrile. After adding 6.49 mL of thiophenol and 11.91 g of potassium carbonate successively, the mixture thus obtained was stirred at 40° C. for 3 hours. The reaction mixture was poured into a mixture of 100 mL of ethyl acetate and 100 mL of water, and pH was adjusted to 2 with 6 mol/L hydrochloric acid. The organic layer was separated, washed successively with water and saturated aqueous solution of sodium chloride, and dried on anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: toluene:n-hexane=1:3] to obtain 3.80 g of 6-chloro-3-(phenylsulfanyl)-2-pyrazinecarbonitrile as a light yellow-colored oily product.
Reaction SMILES: C1(C2SC=[C:10]([C:12]([C:14]3[CH:19]=[C:18](OC)[C:17](OC)=[C:16](OC)[CH:15]=3)=O)[N:11]=2)C=CC=CC=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]1[S:36][CH2:37][CH:38]([C:40]([OH:42])=O)[N:39]=1.N[C@H](C(O)=O)CS>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]1[S:36][CH:37]=[C:38]([C:40]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][CH:10]=[CH:12]3)=[O:42])[N:39]=1
Reactant: O=C(O)C1CSC(c2cc3ccccc3[nH]2)=N1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Agent: N[C@@H](CS)C(=O)O
Product: O=C(c1ccc2[nH]ccc2c1)c1csc(-c2cc3ccccc3[nH]2)n1

Procedure:
(2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone (21) was prepared using the similar method as used of compound 1h from 2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. 1H NMR (500 MHz, CDCl3) δ 9.60 (s, 1H), 9.26 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.83 (dd, 1H), 7.69 (d, 1H), 7.53-7.49 (m, 2H), 7.41 (t, 1H), 7.33 (t, 1H), 7.21-7.18 (m, 2H), 7.13 (s, 1H). MS (ESI) m/z 366.1 (M+Na)+, 341.9 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:36])[C:22]([OH:35])([C:27]3[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=3)[C:23]([F:26])([F:25])[F:24])=[C:17]([Cl:37])[CH:16]=2)=[N:6][CH:5]=1.[OH-].[Na+].Cl.CCOC(C)=O>O1CCCC1>[Cl:37][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[CH:21]([CH3:36])[C:22]([OH:35])([C:27]1[CH:32]=[CH:31][C:30](=[O:33])[N:29]([CH3:34])[CH:28]=1)[C:23]([F:26])([F:24])[F:25])[O:14][C:7]1[CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]([C:3]([OH:38])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccc(Oc2cc(C(F)(F)F)c(C(=O)O)cn2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of 6-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-propyl]-phenoxy}-4-trifluoromethyl-nicotinic acid methyl ester (Example 163, 65 mg) in tetrahydrofuran (0.5 ml) was added a 1 M aqueous sodium hydroxide solution (0.23 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 3 h. The mixture was cooled in an ice bath. 2 M aqueous HCl (0.12 ml) and EtOAc were added. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:1=>EtOAc=>EtOAc/MeOH 4:1) to give the title compound (61 mg) as a colorless solid. MS (m/e)=551.3 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]1([CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:44]([CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:46])=[O:45])=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Yield: 73 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (265 mg, 0.54 mmol), phenylmethanesulfonyl chloride (98 mg, 0.51 mmol) and triethylamine (185 mg, 1.83 mmol) in dry tetrahydrofuran (23 ml). This gave the title compound (240 mg) as a gum. MS: 645 (MH+).