Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(CCN2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
In DMF (100 ml) was dissolved 4—(2-bromoethyl)nitro-benzene (25.0 g), and to the solution were added piperidine (12.9 ml) and potassium carbonate (18.0 g). The mixture was stirred at 70° C. for 15 hours, and to the mixture was added water (900 ml), and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-[2—(4-nitro-phenyl)ethyl]piperidine (24.8 g) as orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.C(Cl)Cl.S(Cl)(Cl)=O.[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(#N)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[N:33]3[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34]3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(C(O)c3ccc4c(cnn4C)c3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cn1ncc2cc(C(c3ccc4c(cnn4C)c3)N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
A round bottom flask was charged with bis(1-methyl-1H-indazol-5-yl)methanol (50 mg, 0.17 mmol) and CH2Cl2 (5 mL). Thionyl chloride (25 μL, 342 mmol) was added, resulting in a cloudy solution. After 15 min the solution become a clear pink solution and was stirred at room temperature for 48 h. The solution was concentrated under reduced pressure. Acetonitrile was added and the solution was concentrated two times. Acetonitrile (7 mL) and tert-butyl piperazine-1-carboxylate (60 mg, 0.32 mmol) was added and the solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and purified by silica chromatography (100% CH2Cl2 to 3% MeOH in CH2Cl2) yielding tert-butyl 4-(bis(1-methyl-1H-indazol-5-yl)methyl)piperazine-1-carboxylate (53 mg, 56%) as a light brown oil. 1H NMR 400 MHz (CDCl3) δ 7.97-7.89 (m, 2H), 7.79 (s, 2H), 7.54 (dd, J=8.8, 1.5 Hz, 2H), 7.32 (d, J=8.7 Hz, 2H), 4.49 (s, 1H), 4.03 (s, 6H), 3.47 (s, 4H), 2.41 (s, 4H), 1.45 (s, 9H). LCMS (ESI, m/z): 483 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].O1CCOCC1.[OH-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH2:25]([O:24][C:22]([NH:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:7])[CH3:8])[C:3]([OH:5])=[O:4])=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: CC(C)SC(C)(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Reaction time: 6 h
Yield: 21 %

Procedure:
2-(R)-Amino-3-isopropylsulfanyl-3-methyl-butyric acid (approx. 27 mmol; crude material from the previous step) was dissolved in 40 mL of water and 40 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Ethyl chloroformate (3.3 mL) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 11) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times. Evaporation of the solvent in vacuo gave a yellow oil, which was purified by HPLC (RP-18; pH 2.3; H2O/CH3OH 3/7) to give 1.50 g (21%) of the title compound as a colorless oil. (+)-APCI-MS: 264 (MH−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:32]([CH:31]=[CH2:30])(=[O:34])=[O:33])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (5.0 g) and triethylamine (6.792 g) in dichloromethane (80 ml) was added dropwise at 0° C. a solution of 2-chloroethanesulfonyl chloride (4.11 g) in dichloromethane (20 ml), and the mixture was stirred at 0° C. for 30 minutes. The reaction solution was diluted with dichloromethane, washed with water, citric acid solution, sodium bicarbonate solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless amorphous of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-vinylsulfonyl-2-piperazinone (3.99 g).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[CH:23]/[C:24](O)=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[CH:23]/[C:24]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (60 mg, 0.14 mmol) obtained in Example 2 was dissolved in DMF (0.6 mL), N,N′-carbonyldiimidazole (92 mg, 0.57 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Methanesulfonamide (68 mg, 0.71 mmol) and DBU (106 μL, 0.71 mmol) were added to the reaction mixture, and the mixture was stirred at 80° C. for 2 hr. Water and 5% aqueous citric acid solution were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered to give the title compound (compound 12) (29 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:18]3=[O:25])[N:9]=2)[S:5][C:6]=1[Cl:7].CO.C(O)(=O)C.[Br:32]Br>ClCCl>[Br:32][C:13]1[C:8]([C:4]2[S:5][C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=2)=[N:9][C:10]([NH:14][CH2:15][CH2:16][N:17]2[C:21]([CH3:22])([CH3:23])[C:20](=[O:24])[NH:19][C:18]2=[O:25])=[N:11][CH:12]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc(Cl)c(Cl)s2)n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(Cl)c(Cl)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
1-(2-(4-(4,5-Dichlorothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethyl imidazolidine-2,4-dione (300 mg, 0.75 mmol) was suspended in a 10% solution of methanol in dichloromethane (7 mL). Glacial acetic acid (1 mL) followed by bromine (120 mg, 0.75 mmol, 39 μL) [material immediately went into solution]were added, and the mixture was stirred at room temperature for 3 h. The reaction was concentrated in vacuo, diluted with deionized water (25 mL), stirred for 5 min, and then the product was collected by filtration to give a yellow solid (265 mg). The crude product was purified by flash chromatography (MeOH/DCM) to yield the title compound as a yellow powder (162 mg, 45%). MS (M+H)+ 478/480.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N:35]1([C@H:41]2[CH2:45][NH:44][CH2:43][C@@H:42]2[OH:46])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:44]4[CH2:45][C@H:41]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[C@@H:42]([OH:46])[CH2:43]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O[C@H]1CNC[C@@H]1N1CCOCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2C[C@H](O)[C@@H](N3CCOCC3)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3S,4S)-3-hydroxy-4-morpholin-4-ylpyrrolidin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-(3S,4S)-Morpholin-4-yl-pyrrolidin-3-ol following General Procedure C.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][I:16])[N:10]=[CH:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][I:16])[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)n1cnc(CCCI)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: ICCCc1c[nH]cn1

Procedure:
A solution of 5 g (14.2 mmol) of 3-(1-t-butyloxycarbonylimidazol-4-yl)-1-iodopropane (prepared as described in Example 6, part C) is stirred in a mixture of 5 ml of trifluoroacetic acid, 5 ml of CH2CH2 and 1 ml of anisole at 0° C. under nitrogen for 6 hours, then concentrated in vacuo and partitioned between CHCl3 and 15% aq Na2CO3. Evaporation of the organic extracts affords the title A compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[O:40][CH3:41])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC1(CC1)C(=O)N2C
Yield: 57.1 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 100 mg, 0.31 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 83 mg, 0.31 mmol) and p-toluenesulphonic acid monohydrate (149 mg, 0.78 mmol) were heated at 140° C. in 4-methyl-2-pentanol (4 mL) for 2 hours. The reaction mixture was loaded onto an SCX-3 column was pre-wet with methanol and the column washed with methanol and eluted with 2% 7N ammonia/methanol. The ammoniacal fraction was evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (97 mg, 57%)
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:21][CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.O.NN>CO.O1CCCC1>[NH2:23][CH2:22][CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[Br:1]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCN)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-1H-indole-6-carboxylate (3.96 g, 7.78 mmol) in methanol (50 ml) and tetrahydrofuran (30 ml) was added hydrazine monohydrate (1.88 ml, 38.7 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was filtered with celite and washed with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1-15:1) to give methyl 1-(2-aminoethyl)-2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (2.95 g, yield 100%).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:2].C[Si]([N:22]=[N+:23]=[N-:24])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:8][C:5]1([CH3:9])[N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([CH3:17])([C:1]2[N:22]=[N:23][NH:24][N:2]=2)[CH2:7][O:6]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C#N)COC1(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A mixture of 317 mg of tert-butyl 4-cyano-2,2,4-trimethyl-1,3-oxazolidine-3-carboxylate, 307 mg of trimethylsilyl azide, 67 mg of dibutyltin oxide, and 10 ml of toluene was stirred for 8 hours under heating to reflux. The reaction mixture was left to be cooled to room temperature and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 168 mg of tert-butyl 2,2,4-trimethyl-4-(2H-tetrazol-5-yl)-1,3-oxazolidine-3-carboxylate.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([O:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[N:16][C:15]=2[N:14]([CH3:36])[C:13]1=[O:37])(C(C)(C)C)(C)C.Cl>C(O)C.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:37])[N:14]([CH3:36])[C:15]=3[N:16]=[C:17]2[O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:28][CH:27]=1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
Step 2 1-(3-((tert-Butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol) was dissolved in ethanol (5 mL) and 6N aqueous HCl (1 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to a golden oil. The oil was purified using a 2000 micron preparative TLC plate eluted with ethyl acetate. Target band was scraped off plate, eluted off silica gel with ethyl acetate and evaporated under reduced pressure to give 7-(4-chlorobenzyl)-8-(cyclopentyloxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.028 g, 14% yield) as a white solid. LCMS retention time=3.656 min and 98% purity, LCMS MH+ 433. 1H NMR (DMSO-d6) δ 7.34 (dd, 4H, J=12 and 48 Hz), 5.34-5.40 (m, 1H), 5.18 (s, 2H), 4.42 (t, 1H, J=4 Hz), 3.89 (t, 2H, J=8 Hz), 3.38-3.45 (m, 2H), 3.36 (s, 3H), 1.55-1.93 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6](O)O[C:8](=[O:10])[CH:9]=1)=[O:4].[NH2:12][C@@H:13]([CH2:17][CH3:18])[C:14]([NH2:16])=[O:15].[H][H]>CO.[Pd]>[NH2:16][C:14]([C@@H:13]([N:12]1[C:8](=[O:10])[CH2:9][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)[CH2:17][CH3:18])=[O:15]
Reactant: COC(=O)C1=CC(=O)OC1O
Reactant: [H][H]
Reactant: CC[C@H](N)C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC[C@@H](C(N)=O)N1CC(C(=O)OC)CC1=O
Temperature: 25 °C
Yield: 43 %

Procedure:
2-Hydroxy-5-oxo-2,5-dihydro-furan-3-carboxylic acid methyl ester (3.08 g) in methanol (40 ml) is added to a solution of (2S)-2-aminobutyramide (2.0 g) in methanol (30 ml) in a hydrogenation reactor and the mixture is maintained for at least 2 hours at room temperature. Then Pd/C catalyst (10 w/w %; Johnson Matthey 5% Pd on carbon—type 87L) is added and hydrogen introduced into the system under pressure. The temperature is kept at 40° C. maximum and the hydrogen pressure between 4 bar and 5 bar, followed by stirring for at least 20 hours following the initial reaction. The solution is then cooled between 15° C. and 25° C. and filtered to remove the catalyst. The solvent is evaporated under vacuum and the resulting yellow product is purified by preparative liquid chromatography (eluent: dichloromethane/methanol (95:5)) (Yield 43%).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)=[CH:9][C:8]=1[C:34]([F:37])([F:36])[F:35])[CH3:5]>C(O)(C)C.C1COCC1.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)=[CH:9][C:8]=1[C:34]([F:36])([F:37])[F:35])[CH3:3]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
Sodium hydroxide (50 mg) was added to a solution of ethyl 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D37) (83 mg) in isopropanol (5 mL), THF (3 mL), water (1.5 mL). The reaction mixture was stirred at room temperature overnight. The organic solvents were removed. 2 M HCl was used to adjust the pH value to around 6.0. The crude product was purified by Mass Directed Auto Prep to afford 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E15) (40 mg). δH (DMSO-d6, 400 MHz): 1.41 (6H, d), 2.64 (2H, t), 3.01 (2H, t), 5.56 (1H, m), 7.22 (1H, t), 7.29 (1H, d), 7.84 (1H, d), 7.96 (1H, dd), 8.79 (1H, d), 9.36 (1H, d), 10.86 (1H, s), 12.07 (1H, br s); MS (ES): C22H19F3N4O4 requires 460; found 461.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.P([Cl:30])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[C:6]1([N:5]=[C:3]([Cl:30])[C:2]([F:13])([F:12])[F:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccccc1)C(F)(F)F
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: FC(F)(F)C(Cl)=Nc1ccccc1
Temperature: 82 °C
Yield: 81.2 %

Procedure:
Seven grams (37.0 mmol) of 2,2,2-trifluoro-N-phenylacetamide, 19.84 g (74.0 mol) of diphenyl chlorophosphate, 7.44 g (74.0 mmol) of triethylamine, and 28 ml of acetonitrile were introduced into a 100 ml flask and reacted for 15 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 28 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 6.24 g of N-phenyl-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 81.2%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C=O.[CH3:6][C:7]1[N:15]2[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH2:18][CH2:19][C:13]3=[C:14]2[C:9](=[CH:10][CH:11]=[CH:12]3)[C:8]=1[CH3:24].[C:25]([O-])(=O)C([O-])=O>C(O)(=O)C>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:6][C:7]1[N:15]2[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH2:18][CH2:19][C:13]3=[C:14]2[C:9](=[CH:10][CH:11]=[CH:12]3)[C:8]=1[CH3:24]
Reactant: CNC
Reactant: O=C([O-])C(=O)[O-]
Reactant: Cc1c(C)n2c3c(cccc13)CCc1ccccc1-2
Agent: C=O
Solvent: CC(=O)O
Product: Cc1c(CCN(C)C)n2c3c(cccc13)CCc1ccccc1-2
Temperature: 90 °C
Yield: 69.5 %

Procedure:
2.34 ml (1.5 × 0.0085 mol) of 5.4-N ethanolic dimethylamine was added, below the surface and with cooling, to 13.6 ml of glacial acetic acid. 0.95 ml (1.5 × 0.0085 mol) of a 40% formaldehyde solution were also added, followed by 2.1 g (0.0085 mol) of 6,7-dihydro-1,2-dimethylindolo[1,7-ab][1]benzazepine. The mixture was heated for 7 hours at 90° C, evaporated in vacuo and taken up in water and ether. The ether was separated and extracted with 2-N hydrochloric acid. The combined acid/aqueous extracts were made alkaline and extracted with ether. The latter ether extract was evaporated and distilled at ca 130° C (air-bath temperature)/10-4 mm Hg to give 1.8 g (69.5% yield) of 1-(2-dimethylaminoethyl)-6,7-dihydro-2-methylindolo[1,7-ab][1]benzazepine whose oxalate melted at 154°-155° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1.C1C2C(=CC=CC=2)C=CC=1.[N:32]1C=C[CH:35]=[CH:34][CH:33]=1>>[N:32]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: c1ccccc1
Reactant: c1ccncc1
Solvent: c1ccc2ccccc2c1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: c1ccc2ncccc2c1

Procedure:
As the aromatic, low-boiling solvent, use may be made of any solvents having a boiling point of not more than 250° C., which includes benzene, toluene, xylene, pyridine, raw naphthalene oil, gas light oil, tar light oil and a mixture thereof. The reason why the boiling point of the solvent is limited to not more than 250° C. is based on the facts that such a solvent is easy to be recovered from the solution after the removal of the insoluble matter and that high molecular weight components corresponding to high heat-reactive pyridine insoluble matter in the pitch can efficiently be removed because this solvent exhibits an adequate dissolving power to the pitch. That is, the aromatic solvent having a boiling point of more than 250° C. is generally high in the dissolving power, so that if the pitch is dissolved in the latter solvent such as anthracene oil, only the quinoline insoluble matter such as free carbon, inorganic matter and the like naturally contained in the pitch is substantially separated and removed and consequently the obtained pitch still contains high molecular weight components corresponding to the pyridine insoluble matter. When such a pitch is subjected to a heat treatment, the high molecular weight components having a rich heat reactivity are polycondensed to form mesophase as a secondary quinoline insoluble matter, so that it is difficult to produce a precursor pitch of homogeneous phase suitable for the production of carbon fibers. For this reason, the use of the aromatic solvent having a boiling point of more than 250° C. such as anthracene oil, quinoline and derivatives thereof is not favorable to the invention.