Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[N:7]1([CH2:12][C:13]2C=CC(NN)=C[CH:14]=2)C=NC=N1>O1CCOCC1.O>[NH:7]1[C:12]2[C:4](=[CH:5][CH:6]=[CH:14][CH:13]=2)[CH:3]=[CH:2]1
Reactant: C1=COCCC1
Reactant: NNc1ccc(Cn2cncn2)cc1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 37.2 %

Procedure:
3,4-Dihydro-2H-pyran (3.9 ml, 42.7 mmol) was added to a stirred solution of 4-(1,2,4-triazol-1-ylmethyl)phenyl hydrazine (EP 497,512; 4.0 g, 21.1 mmol) in dioxane/water/5N HCl (38 ml/14 ml/4.7 ml) and stirred at room temperature for 1.75 h. The solution was then refluxed for 1.5 h and the solvent removed under vaccum. The residue was taken up into CH2Cl2 and saturated aqueous K2CO3 solution. The aqueous was separated and further extracted with CH2Cl2 (×4). The combined organic extracts were dried (MgSO4) and evaporated and the residue chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (80:8:1) to give the title-indole (0.919 g, 17%), δ (250 MHz, CDCl3) 1.91-2.03 (2H, m, CH2), 2.84 (2H, t, J=7.9 Hz, CH2), 3.73 (2H, t, J=7.9 Hz, CH2), 5.43 (2H, s, CH2), 7.04 (1H, d, J=2.3 Hz, Ar--H), 7.11 (1H, dd, J=2.3 and 8.3 Hz, Ar--H), 7.35 (1H, d, J=8.3 Hz, Ar--H), 7.58 (1H, s, Ar--H), 7.97 (1H, s, Ar--H), 8.02 (1H, s, Ar--H), 8.18 (1H, s, NH).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[C:21]1([CH:27]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:28]([NH2:51])[CH:29]=[CH:30][S:31]([CH:34]=[CH:35][C@@H:36]([NH2:50])[CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:33])=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:52]1([CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:28]([NH:51][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH:1][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:29]=[CH:30][S:31]([CH:34]=[CH:35][C@@H:36]([NH:50][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:5])[CH3:6])[NH:1][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)(=[O:33])=[O:32])[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@H](C=CS(=O)(=O)C=C[C@@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 82 %

Procedure:
Cbz-Leu-Phe-VS-Ph was prepared from Cbz-Leu-OH and Phe-VS-Ph.HCl using standard mixed anhydride coupling method, yield 82%. 1H-NMR (CDCl3) δ 0.8-0.9 (2d, 6H, 2×Leu-CH3), 1.4-1.6 (m, 2H, Leu-CH2), 2.06 (m, 1H, Leu-CH), 2.9-3.0 (m, 2H, CH2-Phe), 3.9-4.0 (m, 1H, α-H), 4.8-4.9 (b, 1H, NH), 4.9-5.0 (m, 1H, α-H), 5.1 (m, 2H, Cbz) 6.3-6.4 (d & b, 2H, NH and CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.4 (m, 10H, 2×Ph), 7.5-7.7 (m, 5H, SO2-Ph). MS (ESI) m/z 535.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([CH3:17])[CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:3]=1[F:18].O.[NH2:20][NH2:21]>CS(C)=O>[F:18][C:3]1[C:4]([N:10]([CH3:17])[CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[NH:20][NH2:21]
Reactant: CSc1nc(Cl)c(F)c(N(C)Cc2nccs2)n1
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(NN)c(F)c(N(C)Cc2nccs2)n1
Temperature: 80 °C
Yield: 43.4 %

Procedure:
6-Chloro-5-fluoro-N-methyl-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (0.4928 g, 1.621 mmol) was dissolved in 5 mL of DMSO and hydrazine monohydrate (0.63 mL, 12.96 mmol). The reaction vessel was pressure sealed and heated to 80° C. for 2 hours. The reaction mixture was purified by RP-HPLC to provide 5-fluoro-6-hydrazino-N-methyl-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine as a beige solid (0.2112 g, 43%). LCMS: (M+H)+=301.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].C1(P(=[CH:32][C:33]#[N:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH:9]=[CH:32][C:33]#[N:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C[C@H](C=CC#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
In a 20 mL scintillation vial, ((R)-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (2.5 g, 14.4 mmol) and (triphenylphosphoranylidene)acetonitrile (6.52 g, 21.7 mmol) were mixed in dichloromethane (20 mL) and stirred at room temperature for 16 h. The solvent was evaporated to give the crude material, which was purified by column chromatography (silica gel, gradient n-hexanes ethyl acetate) to provide 1.8 g (63%) of ((R)-3-cyano-1-methyl-allyl)-carbamic acid tert-butyl ester in a 3:1 diastereoselectivity (E:Z) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 6.38-6.79 (m, 1H), 5.47 (dd, J=16.24, 1.89 Hz, 1H), 4.48 (bs, 1H), 4.47 (bs, 1H), 1.45 (s, 1H), 1.28 (d, J=7.18 Hz, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N+:4]([O-])[C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:15].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:11][OH:15])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)[n+]([O-])c(C)c1Br
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Cl)nc(CO)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-6-chloro-2,4-dimethylpyridine 1-oxide (28.7 g, 121 mmol) in CH2Cl2 (240 mL) was added trifluoracetic anhydride (240 mL, 1699 mmol). The reaction was stirred for 3 hours at room temperature and then concentrated. The residue was dissolved in MeOH (1.7 L) and cooled to 0° C. 1M K2CO3 (360 mL, 360 mmol) was added dropwise, and the reaction was stirred for 10 minutes at 0° C. and then warmed to r.t. for 1 hour. The reaction was then concentrated to a volume of 300 mL and diluted with EtOAc (1 L). Water (1 L) was added and the layers were separated. The aqueous layer was extracted with additional EtOAc (2×1 L). The organic layers were combined, washed with brine (1 L), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 75% EtOAc/heptanes afforded (3-bromo-6-chloro-4-methylpyridin-2-yl)methanol. LCMS=236.1 and 238.1 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.17 (s, 1H), 4.73 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 72.8 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-5-(trifluoromethyl)pyridine (138 mg, 0.76 mmol), DIEA (0.27 ml, 1.52 mmol) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (112 mg), a white solid, in 73% yield.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Br)nc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (125 g, 494 mmol), TEA (207.0 mL, 1483 mmol), and copper (I) iodide (0.941 g, 4.94 mmol) in THF (1255 mL) was added PdCl2(PPh3)2 (3.47 g, 4.94 mmol). The reaction mixture was cooled at about −5-0° C. and a solution of (trimethylsilyl)acetylene (65.0 mL, 470 mmol) in THF (157 mL) was added dropwise over about 15 min. The reaction mixture was stirred at about −5-0° C. for about 1.5 h and then allowed to warm to rt overnight. The reaction mixture was then filtered through a Celite® pad and washed with THF until no further product eluted. The filtrate was concd under reduced pressure to give a brown-orange solid. The solid was triturated and sonicated with warm petroleum ether (b.p. 30-60° C., 400 mL), cooled to rt, collected, washed with petroleum ether (b.p. 30-60° C.; 2×60 mL), and dried to give 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (124 g, 93%, 93% purity) as a brown solid: LC/MS (Table 1, Method b) Rt=2.51 min; MS m/z: 270, 272 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1>CC(N(C)C)=O>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:3][CH:4]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1cc(Br)cnc1Br
Solvent: CC(=O)N(C)C
Product: Cc1cc(Br)cnc1N1CCN[C@H](C)C1

Procedure:
Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc., Waterford, Conn.) (2.0 g, 7.97 mmol), (R)-2-methyl-piperazine (ChemPacific Corp., Baltimore, Md.; 3.2 g, 31.9 mmol) in DMA at 130° C. for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine as a solid.
Reaction SMILES: O[C:2]1([C:32]2C=CC=CC=2)[CH2:7][CH2:6][N:5]([C:8]2N=C[C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:19][C:18]=3[C:28]([F:31])([F:30])[F:29])=[O:16])=[CH:10][CH:9]=2)CC1.N[C:39]1C=C2C(=CC=1)NC=C2>>[NH:5]1[C:8]2[C:2](=[CH:32][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([CH3:39])[CH2:23]4)=[N:19][C:18]=3[C:28]([F:31])([F:29])[F:30])=[O:16])=[CH:10][CH:9]=2)[CH:7]=[CH:6]1
Reactant: O=C(Nc1ccc(N2CCC(O)(c3ccccc3)CC2)nc1)c1oc(N2CCCCC2)nc1C(F)(F)F
Reactant: Nc1ccc2[nH]ccc2c1
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ccc4c3)o2)C1

Procedure:
Compound 44 was prepared by the general procedure for compound 1, by using intermediates A-10 and 5-aminoindole as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 11.10 (br s, 1H), 10.01 (s, 1H), 7.36 (m, 2H), 7.30 (br d, 1H, J=6.8 Hz), 6.41 (s, 1H), 4.12 (m, 2H), 3.29 (br s, 1H), 3.05 (t, 1H, J=12.3 Hz), 2.74 (t, 1H, J=12.2 Hz), 1.70 (m, 3H), 1.53 (m, 1H), 1.15 (m, 1H), 0.94 (d, 3H, J=6.0 Hz). MS (M+1): 393.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:34][C:35]([OH:39])([CH3:38])[CH2:36]O.CN(C=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:34][C:35]([CH3:38])([OH:39])[CH3:36])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)O
Temperature: 10 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
N-Benzyloxycarbonyl-L-valine (2.02 g, 8.0 mmol), 4-dimethylaminopyridine (100 mg, 0.8 mmol), and), and dicyclohexylcarbodiimide (2.04 g, 9.9 mmol, in 20 mL CH2Cl2) were added to 2-methyl-1,2-propanediol (12.2 mmol) in 30 mL dry CH2Cl2, with cooling in an ice bath. DMF (5 mL) was added. After stirring for 5 h at 10° C., the reaction mixture was filtered, concentrated, and then redissolved in ethyl acetate. The organic solution was washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated. Flash column chromatography (silica, 2/1 petroleum ether—ethyl acetate) gave 2.3 g of the title compound.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]=O)=O)=[CH:11][CH:10]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:17]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[N:4]=1
Reactant: O=CC(=O)c1ccc(F)cc1
Reactant: CSC(=N)NN
Solvent: O
Product: CSc1nncc(-c2ccc(F)cc2)n1
Yield: 63.1 %

Procedure:
3-(Methylsulfanyl)-5-(4-fluorophenyl)-1,2,4-triazine (6.00 g, 69%) was prepared from methyl hydrazinecarbimidothioate (4.51 g, 43.0 mmol) and 4-fluorophenylglyoxal monohydrate (6.60 g, 43.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:26][CH2:27]Cl)(=[O:25])[CH2:23][CH3:24]>CC(C)=O>[C:22]([O:26][CH2:27][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])(=[O:25])[CH2:23][CH3:24]
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Reactant: CCC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCC(=O)OCn1ccnc1C(C)c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of the compound of Example 1 (120 mg, 0.6 mmol) and caesium carbonate (731 mg, 1.8 mmol) in acetone (4 ml), under nitrogen, was added chloromethyl propionate (Eur. J. Pharm. Sci: 24; 5; 2005; 433-440, 183 mg, 1.5 mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered and the filtrate was concentrated in vacuo.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:19]([O:21][C:22]([C:24]1([NH2:33])[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])[CH3:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:19]([O:21][C:22]([C:24]1([NH:33][C:10]([C:6]2[C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:12])[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2c1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of 2,3-dihydro-benzofuran-7-carboxylic acid (394 mg, 2.4 mmol) in DCM (10 mL) is added oxalyl chloride (0.85 mL, 9.6 mmol). The resulting solution is stirred at RT for 2 h. After the removal of DCM and excess oxalyl chloride, the residue, 2-amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.4 mmol) and DIPEA (3.17 mL, 19.2 mmol) are dissolved in DCM (20 mL). The resulting solution is stirred at RT overnight. The reaction solution is diluted with DCM (40 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give a pure product (39) as white solid (635 mg, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:17]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:17])=[O:11])[CH2:7]1
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(OC2CN(C(N)=O)C2)c1
Reaction time: 18 h
Yield: 50 %

Procedure:
A stirred solution of 3.92 g (0.01 mole) of crude (57.59%) 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated with 1.9 g (2 ml) (0.03 mole) of 57% ammonium hydroxide. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water. The oil which separated solidified on standing, (3.2 g), and was recrystallized from isopropanol, yielding 1 g (50%) of fine white crystals, m.p. 167°-168° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]1=[O:25])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]([CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:5]1=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N=[N+]=[N-])CCCC1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)CCCC1c1ccccc1
Yield: 100.3 %

Procedure:
A solution of 8.95 g of this azide in 75 ml ethanol is hydrogenated over 2 g 10% Pd-C at 45° C. for 5 hr. The soluion is then filtered and concentrated to afford 8.3 g 3-amino-1-t-butoxycarbonylmethyl-7-phenylperhydroazepin-2-one. NMR (CDCl3, TMS): δ1.4 (s, 9H); δ1.7-2.5 (m+s, 8H); δ3.4 (d, 1H, J=17 hz); δ3.95 (d, 1H, J=17 hz); δ4.0 (broad m, 1H); δ4.95 (broad d, 1H); δ7.3 (s, 5H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([CH2:19][CH2:20][CH2:21][N:22]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[N:23]3)=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:33]N1C(=O)CCC1=O>C1COCC1>[Br:33][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([CH2:19][CH2:20][CH2:21][N:22]4[CH:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:24]=[N:23]4)=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCn3cc(-c4ccccc4)cn3)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCCn3cc(-c4ccccc4)cn3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a solution of 9-pentyl-3-[3-(4-phenyl-1H-pyrazol-1-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (234 mg, 0.543 mmol) in THF (45 ml) at room temperature was added N-bromosuccinimide (145 mg, 0.814 mmol). After stirring at 70° C. for 1 hour, the reaction mixture was concentrated and then purified by preparative LCMS to give the desired product (106 mg, 38%) as white solid. LCMS calculated for C23H26BrN8O (M+H): 509.1, 511.1; found: 509.0, 511.1.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][OH:6])=[CH2:3].[CH3:7][S:8](Cl)(=[O:10])=[O:9]>C(N(CC)CC)C>[CH:5]([O:6][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:4][C:2](=[CH2:1])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)CCO
Solvent: CCN(CC)CC
Product: C=C(C)C=COS(C)(=O)=O

Procedure:
An example of the method for synthesizing Compound (1) includes a method described below in Production Examples 1 and 2. In such a method, first, isoprenol is reacted with methanesulfonyl chloride in the presence of a base such as triethylamine to obtain methanesulfonic acid isoprenyl ester. Next, if needed, the obtained product is isolated and purified by a conventional method, and the obtained methanesulfonic acid isoprenyl ester is reacted with a malonic acid dialkyl ester in the presence of a base such as sodium ethoxide. As needed, a neutralization step is carried out using an acid to obtain Compound (1).
Reaction SMILES: Cl[C:2]([N:4]([C:12]1[C:20]2[O:19][CH:18]([CH3:21])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[NH:5][C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[O:3].C(N(C(C)C)CC)(C)C>CO>[CH3:21][CH:18]1[CH2:17][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N:4]3[N:5]=[C:6]([N:8]([O:10][CH3:11])[CH3:9])[O:7][C:2]3=[O:3])[C:20]=2[O:19]1
Reactant: CON(C)C(=O)NN(C(=O)Cl)c1cccc2c1OC(C)C2
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)c1nn(-c2cccc3c2OC(C)C3)c(=O)o1
Reaction time: 18 h

Procedure:
3.4 g of 1F, 2.5 g of N,N-diisopropyl-N-ethylamine and 75 ml of methanol were mixed. The resulting solution was allowed to stand at room temperature for 18 hours, then was warmed on a steam bath for 24 hours. The solvent was evaporated under reduced pressure and the residue was flash chromatographed over silica gel, a 2:15:33 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane being used as eluent. One product, Rf =0.14, was obtained as an off-white solid. Recrystallization from ether/hexane gave 2, m.p.: 91°-93° C. A second product, Rf =0.17, was obtained as an off-white solid. Recrystallization from ether/hexane gave 1, m.p.: 147°-149° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].I[CH2:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[CH2:21]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCn1ccc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl 1H-indole-5-carboxylate (6.0 g) in methylsulfoxide (30 mL) was added potassium t-butoxide (3.88 g). The mixture was stirred at room temperature for 10 minutes at which time 1-iodobutane (1.8 mL) was added. The mixture was stirred at room temperature for 5 h then partitioned between water and methylene chloride. The layers were separated and the organic layer washed three times with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 10% ethyl acetate in hexanes as eluent to give 6.18 g of the title compound: 1H NM (CDCl3) δ 0.923, 1.38, 1.83, 3.9, 4.14, 6.58, 7.15, 7.34, 7.9, 8.39.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:17]([C:21]1[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]2[O:28][C:27](=[O:29])[CH:26](O)[C:25]=2[CH:31]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCCl.O>[C:17]([C:21]1[CH:22]=[C:23]([C:32]([CH3:34])([CH3:35])[CH3:33])[C:24]2[O:28][C:27](=[O:29])[CH:26]([C:7]3[C:2]([CH3:1])=[C:3]([CH3:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=3[CH3:8])[C:25]=2[CH:31]=1)([CH3:19])([CH3:18])[CH3:20]
Reactant: Cc1cc(C)c(C)c(C)c1C
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: Cc1c(C)c(C)c(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)c(C)c1C
Yield: 89.3 %

Procedure:
11.5 g (77.5 mmol) of pentamethylbenzene and 10 ml (85.0 mmol) of tin tetrachloride are added to a solution of 19.7 g (75.0 mmol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 50 ml of 1,2-dichloroethane and the reaction mixture is refluxed for 1 hour. The reaction mixture is diluted with water and extracted three times with toluene. The organic phases are combined, washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 26.3 g (89%) of 5,7-di-tert-butyl-3-(2,3,4,5,6-pentamethylphenyl)-3H-benzofuran-2-one, m.p. 185°-190° C. (compound (111), Table 1).