Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:12]>C1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 258.7 %

Procedure:
To a stirred solution of 6-hydroxynicotinic acid (2 g, 14.38 mmol) in benzene (32 mL) and MEOH (8 mL) was added dropwise TMSCHN2 (1.97 mL, 3.953 mmol) at 0° C., and the resulting mixture was stirred for 2 hr at room temp. The mixture was quenched by the addition of AcOH and concentrated in vacuo. The residue was suspended in water and the solid was collected. The crude solid was washed with Et2O, and dried in vacuo to give 1.566 g (71%) methyl 2-hydroxypyridine-5-carboxylate as a pale brown crystalline powder. IR (KBr) 1655, 1645, 1610, 1433, 1300, 1113, 777, 642 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H), 6.37 (d, J=9.8 Hz, 1H), 7.99 (dd, J=2.4, 9.8 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H); MS (FAB) m/z 154 (M++1); Anal. Calcd for C7H7NO3: C, 54.90; H, 4.61; N, 9.15. Found: C, 54.89; H, 4.60; N, 9.13.
Reaction SMILES: N[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1C=CC=CC=1C=[O:23]>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C:2](=[O:23])[C:13]([OH:15])=[O:14])=[CH:5]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=Cc1ccccn1
Product: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Yield: 64 %

Procedure:
In a chemical method for producing 3-indole-pyruvic acid disclosed by Giovanna De Luca et al., 3-indole-pyruvic acid was produced with a yield of 50 to 62% by reacting tryptophan as a starting material with pyridine aldehyde in the presence of a base for dehydrating a proton acceptor (see JP Sho-62-501912 [Patent Document 1], International Publication 87/00169 Pamphlet [Patent Document 2]). In this method, the required base and pyridine aldehyde are expensive and the yield is low. As a result, production cost are very high. Politi Vincenzo et al. produced 3-indole-pyruvic acid with the yield of 64% by a condensation reaction using indole and ethyl-3-bromopyruvate ester oxime as raw materials followed by acid hydrolysis (see Europe Patent Application Publication No. 421946 [Patent Document 3]). This method, however, requires a purification step using silica gel, the yield is low, the raw materials are expensive and the industrial production cost is very high.
Reaction SMILES: C1(C)C=CC=CC=1.CS(O[CH2:13][C:14]1[S:15][C:16]2[CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][C:21]=2[N:22]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[N:36]1([CH2:13][C:14]2[S:15][C:16]3[CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][C:21]=3[N:22]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(COS(C)(=O)=O)sc2C1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2nc(CN3CCCCC3)sc2C1
Temperature: 25 °C
Yield: 30 %

Procedure:
To a toluene solution (14 ml) of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (2.01 mmol) was added potassium carbonate (10 mmol) and piperidine (1.1 eq.) and the resulting reaction mixture was refluxed for 16 h. It was cooled to room temperature, diluted with ethyl acetate and the organic layer was washed successively with water and brine. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica). Yield: 30%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH2:2][O:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=1)=[O:31]
Reactant: COc1cccc(N=C=O)c1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2cccc(OC)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[N:24]1([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27].[NH2:49][C@H:50]([C:63]([NH:65][C@H:66]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH:67]([CH3:69])[CH3:68])=[O:64])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57].Cl.C1C=C2C(N(O)N=NC2=CC=1)=O>CN(C)C=O>[N:24]1([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([NH:28][C@H:29]([C:33]([NH:49][C@H:50]([C:63]([NH:65][C@H:66]([C:70]([O:72][C:73]([CH3:74])([CH3:75])[CH3:76])=[O:71])[CH:67]([CH3:69])[CH3:68])=[O:64])[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:60])[CH3:61])=[O:57])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27]
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.38 ml of N-ethylmorpholine and 0.66 g of DCC are added, at 0° C., to a solution of 1.05 g of Z-Pro-Val-OH, 1.3 g of H-Lys(Boc)-Val-OtBu.HCl and 0.5 g of HOObt in 5 ml of dimethylformamide. The mixture is stirred at 0° C. for one hour and left to stand at room temperature overnight. The working-up is as in Example 8a. The residue is triturated with ether. The precipitate is filtered off with suction and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:15])[C:12]=2[CH2:13][OH:14])=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:15])[C:12]=2[CH:13]=[O:14])=[CH:6][CH:7]=1
Reactant: Cn1ncc(-c2ccc(F)cc2)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cn1ncc(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
A mixture of [4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]methanol (250 mg), activated manganese dioxide (1.0 g) and tetrahydrofuran (10 ml) was stirred at room temperature for 3 hrs. The reaction mixture was filtered, and the organic layer was concentrated to give 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (172 mg, yield 70%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[C:21]1([C:27]([NH2:30])([CH3:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:30][C:27]([CH3:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:28])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
70.0 mg (0.238 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 32.2 mg (0.238 mmol) of 2-phenylpropan-2-amine are placed in 2 ml of dimethylformamide and treated with 38.7 mg (0.286 mmol) of HOBt. After 10 mins' stirring, 59.4 mg (0.310 mmol) EDC hydrochloride are added and the mixture is stirred overnight at room temperature. After this, 32.2 mg (0.238 mmol) of 2-phenylpropan-2-amine, 38.7 mg (0.286 mmol) of HOBt and 59.4 mg (0.310 mmol) of EDC hydrochloride are again added to the reaction mixture and stirred for a further for two hours at room temperature. Without further workup, the mixture is purified directly by preparative HPLC [Method 10]. 44 mg (45% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:7](C(O)=O)[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C1C(=CC=CC=1)O>C(C1C=C(C(C)(C)C)C=C(C([O-])=O)C=1O)(C)(C)C.[Zn+2].C(C1C=C(C(C)(C)C)C=C(C([O-])=O)C=1O)(C)(C)C.[Zn]>[C:1]([C:5]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:7][C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(C(=O)[O-])c(O)c(C(C)(C)C)c1
Agent: O=C(O)c1ccccc1O
Agent: [Zn+2]
Product: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1

Procedure:
Referring to 3,5-di-tert-butylsalicylic acid as an example salicylic acid derivative, it is possible to selectively synthesize zinc 3,5-di-tert-butylsalicylate by adding drop by drop a solution containing a zinc provider to a solution of 3,5-di-tert-butylsalicylic acid in alkali to cause the reaction. For example, a sufficient amount of an alkaline aqueous solution is added to 2 mol of 3,5-di-tert-butylsalicylic acid (produced from the starting material 2,4-di-tert-butylphenol by the Kolbe-Schmitt reaction) and dissolved with heating. Separately, an aqueous solution incorporating 1 mol of a zinc provider is prepared. While heating this aqueous solution, the aforementioned aqueous solution of 3,5-di-tert-butylsalicylic acid is added drop by drop, and the reaction is carried out with heating and pH adjustment; after completion of the reaction, the reaction mixture is filtered and the cake filtered off is washed with water and dried. Examples of zinc providers include, but are not limited to, zinc sulfate, zinc chloride and zinc acetate.
Reaction SMILES: [C:1]([C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:10]12[CH3:11])[C:23]1[CH:22]=[CH:21][C:20]([C:27]([O:29]C)=[O:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]1[O:39]C2C=CC([Mg]Br)=CC=2[O:32]1>>[CH2:31]1[O:39][C:5]2[CH:4]=[CH:3][C:2]([C:1]([C@H:9]3[CH2:14][CH2:13][C@H:12]4[C@H:15]5[C@H:24]([CH2:25][CH2:26][C@:10]34[CH3:11])[C:23]3[CH:22]=[CH:21][C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=3[CH2:17][CH2:16]5)=[O:8])=[CH:7][C:6]=2[O:32]1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)c3ccccc3)CC[C@@H]12
Reactant: Br[Mg]c1ccc2c(c1)OCO2
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared by the method of Example 19 (iv) by replacing benzylmagnesium chloride with 3,4-methylenedioxyphenylmagnesium bromide.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#N.CC(C[AlH]CC(C)C)C.Cl.C1C[O:35]CC1>>[CH:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)nc2)CC1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-(6-cyano-pyridin-3-yl)-piperazine-1-carboxylate (2.15 mmol) in THF (20 mL) is added a solution of DIBAL-H in THF (1.0 M, 13 mmol) dropwise and the reaction mixture is stirred at room temperature for 15 minutes. After it is cooled to 0° C., the reaction mixture is mixed with a solution of aqueous HCl (2 N, 5 mL) after which the reaction mixture is partitioned between saturated Na2CO3 solution and EtOAc. The aqueous phase is extracted with EtOAc. The combined organic extracts are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (3:7 hexanes/EtOAc) to give tert-butyl 4-(6-formyl-pyridin-3-yl)-piperazine-1-carboxylate.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[Cl-].[OH:14][NH3+:15]>C(O)C>[CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=[N:15][OH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)CC(=O)c1ccccc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Product: CC(C)CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A mixture of the above ketone (20.6 g, 127 mmol), hydroxylammonium chloride (17.7 g, 254 mmol) and absolute ethanol (200 ml) was heated at reflux for 1 h and then stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo. The residue was suspended in water (200 ml) and the resulting mixture was extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 20.6 g of 3-methylbutyrophenone oxime.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH:13]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:18]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[N:17]=1)([CH3:15])[CH3:14].[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45]O)=[O:42])([CH3:39])([CH3:38])[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:13]([C:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:45][CH2:44][NH:43][C:41](=[O:42])[O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][CH:26]=2)[N:18]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[N:17]=1)([CH3:15])[CH3:14]
Reactant: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Diethylazodicarboxylate (259 mg) was added to a mixture of 4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained by Example 1-3 (305 mg), 2-t-butoxycarbonylaminoethanol (479 mg), and triphenylphosphine (390 mg) in tetrahydrofuran (3 ml). After stirring at room temperature for 7 hrs, diethylazod icarboxylate (17 mg) and triphenylphosphine (26 mg) was added to the reaction mixture.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1c2n(c3c(-c4ccc(OC(F)(F)F)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (84 mg, 87%), MS (ISP) m/z=386.4 [(M+H)+], mp 239° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH2:11][C@H:12]1[CH2:16][C@@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:14]=[CH:13]1)=[CH2:10])[CH3:6].C(N(CC)CC)C>>[CH2:5]([O:7][C:8](=[O:25])[CH:9]([CH2:10][S:3][C:1](=[O:4])[CH3:2])[CH2:11][C@H:12]1[CH2:16][C@@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:14]=[CH:13]1)[CH3:6]
Reactant: C=C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)OCC
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
Thioacetic acid (4 mL), which had been cooled to 0° C., was added to a mixture of 2-(cis4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-acrylic acid ethyl ester (0.56 g, 1.9 mmol) and triethyl amine (0.28 mL, 2.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, at room temperature for 19 h and then poured onto ice-water (400 mL). The aqueous layer was extracted with CH2Cl2. The organic phase was washed with saturated NaHCO3, dried and concentrated under reduced pressure to give 1.7 g of the crude product. Purification by flash chromatography (CH2Cl2/EtOAc: 1/0→68/32) afforded 2-acetylsulfanylmethyl-3-(cis4-tert-butoxycarbonylamino-cyclopent-2-enyl)-propionic acid ethyl ester (0.46 g, 65%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]([F:16])=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]=1[F:16]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCn2c1cc1c(F)c(F)cc(Br)c12
Product: O=C1NCCn2c1cc1c(F)c(F)cc(-c3ccc(F)cc3)c12

Procedure:
The title compound, grey solid (70 mg, 89%), MS (ISP) m/z=317.1 [(M+H)+], mp 283.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8,9-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 4) (75.3 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.Cl.[I:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([I:13])[CH:15]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1cccc(I)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2cccc(I)c2)c2[nH]cnc2n1
Yield: 56.8 %

Procedure:
A solution of 2,6-dichloropurine (Aldrich Chemical Co., 1 g, 5.3 mmol), 3-iodobenzylamine hydrochloride (1.7 g, 5.8 mmol), and triethylamine (2.2 ml, 15.35 mmol) in ethanol (10 ml) was stirred for 5 days at room temperature. The colorless solid formed was collected by suction, washed with small amount of cold ethanol, and dried to yield 2-chloro-N6 -(3-iodobenzyl)adenine (1.16 g, 60%): m.p. 222°-224° C.; mass (EI) 385: 1H NMR (DMSO-d6 d 4.59 (br s, 2H, --CH2), 7.13 (pseudo t, J=8.2 and 7.5 Hz, 1H, Bn), 7.36 (d, J=7.5 Hz, 1H, Bn), 7.61 (d, J=7.5 Hz, 1H, Bn), 7.74 (s, 1H, Bn), 8.14 (s, 1H, H-8), 8.76 (br s, 1H, exchangeable with D2O, NH), 13.14 (br s, 1H, exchangeable with D2O, NH). UV (MeOH) 1max 281.7, 257.5, 232.5 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][C:10](=[O:19])[N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CO>[CH3:22][N:23](/[CH:25]=[C:9]1\[C:10](=[O:19])[N:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=[C:8]\1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:24]
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CN(C)/C=C1\C(=O)N(c2ccccc2)N=C1c1ccccc1F
Reaction time: 1 h

Procedure:
5-(2-Fluorophenyl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2.5 g, 8.1 mmol) and N,N-dimethylformamide dimethylacetal (1.2 g, 9.7 mmol, 1.2 equiv) were combined in methanol (3 mL) and placed into a preheated oil bath at 60° C. for 1 hour. The mixture was cooled to ambient and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([OH:21])=[O:20])[C@@H:8]([O:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:9][C@@H:3]1[CH2:4][CH2:5]2.O[NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([NH2:29])=[O:28]>O1C=COC=C1.O1CCOCC1>[CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([OH:21])=[O:20])[C@@H:8]([O:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[CH2:9][C@@H:3]1[CH2:4][CH2:5]2.[C:24]([NH2:23])(=[O:30])[CH2:25][CH2:26][C:27]([NH2:29])=[O:28]
Reactant: NC(=O)CCC(=O)NO
Agent: C1=COC=CO1
Agent: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)O)[C@@H](OC(=O)c1ccccc1)C2
Solvent: C1COCCO1
Product: NC(=O)CCC(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzoylecgonine (BE) (4 mg) was dissolved in dry dioxin (500 ul) and N-hydroxysuccinamide (NHS) (4 mg) added. 1-Ethyl-3-(3-dimethylaminopropul)carbodiimide hydrochloride (8 mg) was suspended/dissolved in dioxan (1 ml) and immediately added to the mixture. The mixture was shaken at ambient temperature for 2 hours (to form BE-succinamide). To this was added diamino terminated polyethyleneglycol (mol. wt. 20,000) dissolved in 1 ml of 0.1M sodium bicarbonate solution. The solution was left overnight (about 16 hrs) and was then diluted with tris/triton buffer.
Reaction SMILES: [PH3:1].[CH2:2]=[C:3]([CH3:5])[CH3:4]>>[CH2:2]([P:1]([CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH:3]([CH3:5])[CH3:4]
Reactant: C=C(C)C
Reactant: P
Product: CC(C)CP(CC(C)C)CC(C)C
Yield: 13.5 %

Procedure:
By subjecting a mixture of hydrogen phosphide and isobutene in a glass vessel to irradiation with ultraviolet light at 20° C., it is also possible by the process just described to produce triisobutylphosphine, which is obtained in a yield of about 13.5%, after 150 minutes.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[Br:9][C:10]1[N:15]=[CH:14][C:13]2[CH:16]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[NH:18][C:12]=2[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[N:15]=[CH:14][C:13]2[C:16]([Cl:8])=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[NH:18][C:12]=2[CH:11]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cn1cc(-c2[nH]c3cc(Br)ncc3c2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
NCS (48 mg, 0.361 mmol) was added to a solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 100 mg, 0.361 mmol) in DMF (1.1 mL). The reaction mixture was stirred overnight at room temperature before being filtered on an SCX-2 column and concentrated under vacuum. The residue was purified via Biotage silica gel column chromatography eluting with (DCM/EtOH 99/1 to 95/5) to afford the title product as a white solid (86 mg, 76%). 1H NMR (500 MHz, CD3OD) δ 4.01 (s, 3H), 7.54 (d, J=0.8 Hz, 1H), 8.05 (s, 1H), 8.28 (s, 1H), 8.47 (d, J=0.8 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 2.84 min, 312 [(M+H+), 100%].
Reaction SMILES: N1C=CC([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=CC=1.[BrH:30].O1[CH2:36][CH2:35]OCC1>O>[BrH:30].[BrH:30].[N:10]1[CH:36]=[CH:35][C:16]([CH:9]2[CH2:8][NH:7][CH2:12][CH2:11][N:10]2[CH2:13][C:14]([C:16]2[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[O:15])=[CH:14][CH:13]=1
Reactant: C1COCCO1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: Br
Solvent: O
Product: CC(C)(Oc1ccc(C(=O)CN2CCNCC2c2ccncc2)cc1)C(=O)O
Temperature: 95 °C

Procedure:
A mixture of methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]-acetyl]phenoxy]isobutyrate (50 mg), 48% w/v hydrobromic acid (0.74 ml), dioxane (1 ml) and water (3 ml) was heated at 95° C. for 4 hours. The solution was cooled, diluted with water and freeze-dried to give the title compound, 40 mg, as a pale yellow solid: m.p. 163°-167° C.; NMR (D2O) δ 8.40 (2H, d), 8.16 (2H, d), 7.40 (2H, d), 7.21 (2H, d), 5.21 (2H, s), 4.32 (4H, b), 3.89 (4H, bt), 1.86 (6H, s); m/e 384 (M+H)+ ; calculated for C21H25N3.2HBr.2H2O: C, 43.3; H, 5.3; N, 7.2. found: C, 43.6; H, 5.3; N, 7.3%.